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"Survodutide", "count": 2 }, { "name": "Tirzepatide", "count": 2 }, { "name": "Dulaglutide", "count": 1 } ] }, { "slug": "weight-maintenance-regain", "id": "weight-maintenance-regain", "label": "Maintenance and regain", "findingCount": 13, "drugs": { "Weight-loss Physiology (drug-agnostic)": 2, "GLP-1 RA class": 3, "Multiple (review)": 1, "Liraglutide": 1, "Retatrutide": 2, "Semaglutide": 2, "Tirzepatide": 2 }, "grades": { "moderate": 6, "low": 5, "very-low": 2 }, "topDrugs": [ { "name": "GLP-1 RA class", "count": 3 }, { "name": "Weight-loss Physiology (drug-agnostic)", "count": 2 }, { "name": "Retatrutide", "count": 2 }, { "name": "Semaglutide", "count": 2 }, { "name": "Tirzepatide", "count": 2 } ] }, { "slug": "heart-failure", "id": "heart-failure", "label": "heart-failure", "findingCount": 12, "drugs": { "Liraglutide": 5, "Semaglutide": 5, "Tirzepatide": 2 }, "grades": { "moderate": 7, "high": 4, "low": 1 }, "topDrugs": [ { "name": "Liraglutide", "count": 5 }, { "name": "Semaglutide", "count": 5 }, { "name": "Tirzepatide", "count": 2 } ] }, { "slug": "blood-pressure", "id": "blood-pressure", "label": "Blood pressure", "findingCount": 10, "drugs": { "CagriSema": 2, "Orforglipron": 1, "Retatrutide": 1, "Semaglutide": 1, "Survodutide": 2, "Tirzepatide": 1, "Mazdutide": 1, "Pemvidutide": 1 }, "grades": { "low": 3, "moderate": 5, "high": 1, "very-low": 1 }, "topDrugs": [ { "name": "CagriSema", "count": 2 }, { "name": "Survodutide", "count": 2 }, { "name": "Orforglipron", "count": 1 }, { "name": "Retatrutide", "count": 1 }, { "name": "Semaglutide", "count": 1 } ] }, { "slug": "osa", "id": "osa", "label": "Obstructive sleep apnoea", "findingCount": 10, "drugs": { "Multiple (review)": 1, "GLP-1 RA class": 2, "Liraglutide": 1, "Retatrutide": 2, "Semaglutide": 1, "Tirzepatide": 3 }, "grades": { "low": 3, "high": 5, "very-low": 2 }, "topDrugs": [ { "name": "Tirzepatide", "count": 3 }, { "name": "GLP-1 RA class", "count": 2 }, { "name": "Retatrutide", "count": 2 }, { "name": "Multiple (review)", "count": 1 }, { "name": "Liraglutide", "count": 1 } ] }, { "slug": "health-economics-adherence", "id": "health-economics-adherence", "label": "health-economics-adherence", "findingCount": 6, "drugs": { "Semaglutide": 3, "Tirzepatide|semaglutide (head-to-head)": 1, "Tirzepatide": 2 }, "grades": { "low": 6 }, "topDrugs": [ { "name": "Semaglutide", "count": 3 }, { "name": "Tirzepatide", "count": 2 }, { "name": "Tirzepatide|semaglutide (head-to-head)", "count": 1 } ] } ], "findings": [ { "id": "C-ALBI-CARDIO-01", "sourceId": "PMID30291013", "drug": "albiglutide", "drugRoot": "albiglutide", "drugSlug": "albiglutide", "drugLabel": "Albiglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.78 (95% CI 0.68-0.90; P<0.0001 non-inferiority; P=0.0006 superiority); 7% vs 9%. MI-driven (MI HR ~0.75); stroke and CV death individually non-significant. Median 1.6 years.", "finding": "In T2D with established CVD, albiglutide reduced MACE versus placebo, a superiority result driven notably by reduced myocardial infarction.", "population": "HARMONY Outcomes: N=9463; T2D with established CVD; double-blind placebo-controlled RCT; median 1.6 years (short).", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "ADDED. MI-driven superiority, contrasting the stroke-driven SUSTAIN-6/REWIND; recorded as observation. Albiglutide later withdrawn from market for commercial (not safety) reasons.", "crossRef": "C-CLASS-CARDIO-01", "grade": "high", "source": { "citation": "Hernandez AF et al., Lancet, 2018", "url": "https://doi.org/10.1016/S0140-6736(18)32261-X", "identifiers": "PMID30291013", "date": "2018-10-27", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - GlaxoSmithKline", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-ALBIGLUTIDE-LANDSCAPE-01", "sourceId": "PMID26577795", "drug": "albiglutide", "drugRoot": "albiglutide", "drugSlug": "albiglutide", "drugLabel": "Albiglutide", "drugClass": "GLP-1 receptor monoagonist (GLP-1 dimer fused to human albumin, once-weekly s.c.)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c approx -0.8% vs placebo (HARMONY 2); MACE hazard ratio 0.78 (HARMONY Outcomes); modest weight change", "finding": "Once-weekly albiglutide (30/50 mg) monotherapy reduced HbA1c by approx 0.8% vs placebo (HARMONY 2); in HARMONY Outcomes it reduced MACE by ~22% vs placebo. Weight loss was modest and lower than competing GLP-1 RAs.", "population": "HARMONY 2: T2D inadequately controlled with diet/exercise, 52 weeks, placebo-controlled. HARMONY Outcomes: 9463 T2D with CV disease, median 1.6 years, vs placebo", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Mechanism: two tandem GLP-1(7-36) copies fused to recombinant human albumin (once-weekly). Marketed Tanzeum (US)/Eperzan (EU); GSK withdrew worldwide July 2018 for commercial reasons (lower efficacy/weight effect) despite positive CV outcomes. Historical/withdrawn landscape row.", "crossRef": "", "grade": "moderate", "source": { "citation": "Hernandez AF et al., Lancet 2018 (HARMONY Outcomes); Reusch J et al., Diabetes Obes Metab 2014 (HARMONY 2)", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705137/", "identifiers": "PMID 26577795 (HARMONY 2); DOI 10.1016/S0140-6736(18)32261-X (HARMONY Outcomes)", "date": "2018-10-08", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - GlaxoSmithKline", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-ALENIGLIPRON-LANDSCAPE-01", "sourceId": "DOI10.1038/S41591-026-04476-6", "drug": "aleniglipron", "drugRoot": "aleniglipron", "drugSlug": "aleniglipron", "drugLabel": "Aleniglipron", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "ACCESS phase 2b: -8.2/-9.8/-11.3% placebo-adjusted (45/90/120 mg) at wk 36, N=230. ACCESS II: -16.3% placebo-adjusted (180 mg) at wk 44", "finding": "Oral non-peptide GLP-1RA (GSBR-1290, Structure Therapeutics). In ACCESS phase 2b (230 adults, obesity/overweight), once-daily aleniglipron at 45/90/120 mg achieved placebo-adjusted weight loss of -8.2/-9.8/-11.3% at week 36. ACCESS II topline reported placebo-adjusted mean weight loss of 16.3% at the 180 mg dose at 44 weeks - described by the sponsor as the highest weight loss for an oral GLP-1RA to date.", "population": "ACCESS phase 2b: 230 adults obesity/overweight, once-daily, 36 wk, placebo-controlled. ACCESS II: phase 2, up to 180 mg, 44 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "MECHANISM: oral non-peptide small-molecule GLP-1R agonist, once daily. aleniglipron = GSBR-1290 (Structure Therapeutics). ACCESS phase 2b peer-reviewed (Nature Medicine 2026); ACCESS II 180 mg result is press topline. Highest reported oral GLP-1RA weight loss per sponsor - recorded as observation.", "crossRef": "", "grade": "moderate", "source": { "citation": "Structure Therapeutics press (ACCESS, ACCESS II, 2025-2026); Nature Medicine ACCESS phase 2b 2026", "url": "https://www.nature.com/articles/s41591-026-04476-6", "identifiers": "GSBR-1290; Nat Med DOI 10.1038/s41591-026-04476-6", "date": "2026-03-16", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Structure Therapeutics (sponsor of record; disclosed)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-APITEGROMAB-BODYCOMP-01", "sourceId": "NCTNCT06445075", "drug": "apitegromab + tirzepatide", "drugRoot": "apitegromab", "drugSlug": "apitegromab", "drugLabel": "Apitegromab", "drugClass": "anti-(pro/latent)-myostatin monoclonal antibody; muscle-preserving combo with GIP/GLP-1 dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Company topline (press): +1.9 kg (4.2 lb) lean mass preserved, 54.9% relative vs tirzepatide alone (P=0.001); quality of weight loss 85% fat / 15% lean (apitegromab) vs 70% fat / 30% lean (tirzepatide alone).", "finding": "Scholar Rock phase-2 EMBRAZE trial (NCT06445075): apitegromab added to tirzepatide preserved additional lean mass versus tirzepatide alone over 24 weeks. The only major muscle-preservation combo studied on TIRZEPATIDE (a GIP/GLP-1 dual agonist) rather than semaglutide. NON-GRADUATING: company press topline only.", "population": "EMBRAZE phase-2 RCT, N=102, double-blind placebo-controlled, 24 weeks, adults overweight/obese; apitegromab 10 mg/kg IV q4w + tirzepatide vs placebo + tirzepatide.", "comparators": "placebo + tirzepatide", "endpointType": "imaging/physiological surrogate", "notes": "NON-GRADUATING press claim (very-low) per the press rule; recorded for provenance until a PMID/DOI appears. Registry confirmed NCT06445075 (Scholar Rock, Completed, primary = change in lean body mass over 24 wk). COI (Council): manufacturer-issued topline (Scholar Rock), no peer-reviewed verification, selective-disclosure risk. Apitegromab+tirzepatide - UNTESTED on retatrutide.", "crossRef": "C-ENOBOSARM-BODYCOMP-01; C-MUSCLE-PRESERVATION-MECH-01", "grade": "very-low", "source": { "citation": "Scholar Rock, EMBRAZE phase-2 topline press release, 18 Jun 2025; NCT06445075", "url": "https://clinicaltrials.gov/study/NCT06445075", "identifiers": "NCT06445075", "date": "2025-06-18", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~102)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-BI3034701-LANDSCAPE-01", "sourceId": "NCTNCT06352437", "drug": "BI 3034701", "drugRoot": "BI 3034701", "drugSlug": "bi-3034701", "drugLabel": "BI 3034701", "drugClass": "GLP-1/GIP/NPY2 receptor triple agonist (peptide)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Phase 1: 'encouraging' weight loss reported by sponsor (specific magnitudes not disclosed in this pass)", "finding": "BI 3034701 (Boehringer Ingelheim / Gubra) is an investigational, potential first-in-class triple GLP-1 / GIP / NPY2 receptor agonist peptide for obesity. The phase 1 first-in-human trial demonstrated a favourable safety/tolerability profile and showed encouraging weight loss; Boehringer plans to initiate phase 2 in mid-2026.", "population": "Phase 1 (NCT06352437): randomised first-in-human placebo-controlled, two parts - Part A healthy men 18-55; Part B adults 18-65 with overweight/obesity otherwise healthy; ~124 participants; completed H2 2025", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "MECHANISM CORRECTION: a triple agonist but the third axis is NPY2 (peptide YY pathway), NOT glucagon or amylin - distinguishes it from the GIP/GLP-1/glucagon triples (retatrutide, efocipegtrutide, HM15275) and from amylin agents. Gap-filled by parent; flagged as a real triple by the amylin cluster. NCT06352437 confirmed.", "crossRef": "", "grade": "very-low", "source": { "citation": "Boehringer Ingelheim / Gubra press releases (phase 1 start 2024; phase 2 advance 2026)", "url": "https://www.gubra.dk/mfn_news/boehringer-ingelheim-advances-gubra-originated-obesity-triple-agonist-peptide-into-phase-2-development/", "identifiers": "NCT06352437", "date": "2024-07-01", "design": "observational cohort", "maturity": "press", "funding": "industry (company press release on own pipeline)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-BIMAGRUMAB-BODYCOMP-02", "sourceId": "PMID33439265", "drug": "bimagrumab (monotherapy)", "drugRoot": "bimagrumab", "drugSlug": "bimagrumab", "drugLabel": "Bimagrumab", "drugClass": "anti-activin type II receptor (ActRII) monoclonal antibody", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Fat mass -20.5% (-7.5 kg) vs -0.5% placebo (P<0.001); lean mass ROSE +3.6% (+1.70 kg) vs -0.8% placebo (P<0.001); weight -6.5% (-5.9 kg); waist -9.0 cm; HbA1c -0.76 pts. (80% CIs in source.)", "finding": "Foundational human readout for muscle preservation: in adults with T2D and overweight/obesity, bimagrumab MONOTHERAPY (no GLP-1RA) produced large fat-mass loss with a simultaneous GAIN in lean mass over 48 weeks, establishing that ActRII blockade is anabolic for muscle while reducing adiposity. This is lean-mass GAIN, distinct from the lean-PRESERVATION seen when such agents are added to incretins.", "population": "Phase-2 double-masked placebo-controlled RCT, N=75 randomised (58 completers), 48 weeks, IV q4w, adults with T2D, BMI 28-40; 9 US/UK sites.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "NEW. IDENTIFIER CORRECTION (gather agent): a commonly-cited PMID 33464334 is the WRONG paper (a stroke-thrombectomy trial); the correct Heymsfield bimagrumab T2D paper is PMID 33439265 / NCT03005288. Small N, completers-only, 80% CIs, monotherapy, DXA surrogate (not function). Drug since Novartis -> Versanis -> Eli Lilly. Mechanistic foundation for BELIEVE (C-BIMAGRUMAB-LANDSCAPE-01). Robustness moderate (phase-2, N=75, completer-only, 80% CIs). SURROGATE-NOT-FUNCTION (Council): the lean-mass GAIN is DXA mass and has NOT been shown to translate into proportional muscle-strength/function gain.", "crossRef": "C-BIMAGRUMAB-LANDSCAPE-01; C-MUSCLE-PRESERVATION-MECH-01", "grade": "moderate", "source": { "citation": "Heymsfield SB et al., JAMA Netw Open, 2021", "url": "https://doi.org/10.1001/jamanetworkopen.2020.33457", "identifiers": "PMID33439265", "date": "2021-01-04", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novartis (bimagrumab; disclosed)", "scopeLimits": "small sample (N~75); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-BIMAGRUMAB-LANDSCAPE-01", "sourceId": "PMID41772149", "drug": "bimagrumab (+/- semaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "anti-activin type II receptor (ActRII) antibody; muscle-preserving combo with GLP-1RA", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "BELIEVE PRIMARY (abstract-verified, absolute body-weight change at wk48): bimagrumab 30 mg/kg -9.3 kg, semaglutide 2.4 mg -14.2 kg, combination -17.8 kg vs placebo -3.3 kg (all P<0.001). SECONDARY (DXA, NOT in the Nat Med abstract; design-consistent but not abstract-verified): combo fat-mass -45.7% and ~92.8% of weight lost as fat (vs 71.8% semaglutide alone); bimagrumab monotherapy lean +2.5% vs semaglutide-alone -7.4%.", "finding": "BELIEVE phase-2b (Eli Lilly/Versanis) tested bimagrumab alone or added to semaglutide. The combination drove fat-selective weight loss with lean-mass preservation; bimagrumab monotherapy GAINED lean while semaglutide alone lost it. Now PEER-REVIEWED (Heymsfield et al., Nat Med 2026).", "population": "BELIEVE phase-2b RCT, N=507, 48-week treatment (results to wk72), randomised double-blind placebo-controlled, 9 arms; bimagrumab IV q12w +/- semaglutide sc weekly; adults overweight/obese with >=1 comorbidity.", "comparators": "placebo; semaglutide 1.0 mg; semaglutide 2.4 mg; bimagrumab 10 mg/kg; bimagrumab 30 mg/kg", "endpointType": "imaging/physiological surrogate", "notes": "DEEPENED (D2): upgraded from landscape note to the peer-reviewed BELIEVE result. VALIDATOR: PMID 41772149 RESOLVED (Heymsfield et al., Nat Med 2026;32(3):869-882, NCT05616013) - status verified, no fallback needed. The per-arm lean DXA percentages (mono +2.5%, sema -7.4%, 92.8% fat fraction, fat -45.7%) are SECONDARY results not in the Nat Med abstract; design-consistent but flagged as not-abstract-verified. Distinguishes lean GAIN (bimagrumab mono) from lean PRESERVATION (combo). Surrogate DXA/BIA, phase-2b, 9 arms dilute per-arm N -> moderate; Lilly-sponsored.", "crossRef": "C-BIMAGRUMAB-BODYCOMP-02; C-TREVOGRUMAB-LANDSCAPE-01", "grade": "moderate", "source": { "citation": "Heymsfield et al., Nat Med 2026; presented ADA 2025", "url": "https://pubmed.ncbi.nlm.nih.gov/41772149/", "identifiers": "PMID 41772149; NCT05616013; DOI 10.1038/s41591-026-04204-0", "date": "2026-01-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-BIMAGRUMAB-SEMA-BODYCOMP-01", "sourceId": "PMID38218536", "drug": "bimagrumab + semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "activin type II receptor antagonist (mAb) + GLP-1 receptor agonist combination", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Bimagrumab alone: lean mass ~+10% with simultaneous fat-mass decrease (diet-induced obese mice). Combination preserved lean mass and gave superior fat loss vs semaglutide alone (rodent). Narrative cites up to ~40% of GLP-1 weight loss as lean mass as the rationale.", "finding": "Muscle-preserving combination landscape: bimagrumab (ActRII blockade) is reported to add lean mass while reducing fat, and is being combined with semaglutide to counter GLP-1-associated lean-mass loss; preclinical work shows combination preserves muscle while enhancing fat loss vs semaglutide alone.", "population": "Preclinical (diet-induced obese mice) plus clinical-development narrative/review; combination under clinical study", "comparators": "semaglutide", "endpointType": "imaging/physiological surrogate", "notes": "Muscle-preserving agent that reshapes the body-composition landscape. Rodent-primary for the combination mechanism plus a clinical review; clinical combination (e.g. BELIEVE-type programmes) tagged for follow-up. Records the 'lean mass can be increased pharmacologically during weight loss' pole. Trevogrumab/garetosmab and enobosarm/pemvidutide are in the same muscle-preserving class per SCWD workshop (PMID 41362110).", "crossRef": "C-PEMVIDUTIDE-BODYCOMP-01", "grade": "very-low", "source": { "citation": "Nunn E et al., Mol Metab, 2024 (preclinical); Kaiser M et al., Cardiol Rev, 2025 (review)", "url": "https://doi.org/10.1016/j.molmet.2024.101880", "identifiers": "PMID 38218536, DOI 10.1016/j.molmet.2024.101880; PMID 41248895, DOI 10.1097/CRD.0000000000001113", "date": "2024-01-11", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CAGRILINTIDE-LANDSCAPE-01", "sourceId": "NCTNCT05567796", "drug": "cagrilintide", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin/calcitonin receptor agonist (amylin analogue, once-weekly s.c.)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "phase 2: ~6.0% to 10.8% across 0.3-4.5 mg vs 3.0% placebo at 26 wk; REDEFINE 1 monotherapy: 11.5% at 68 wk", "finding": "Once-weekly cagrilintide monotherapy produced dose-dependent weight loss in adults with overweight/obesity; 4.5 mg gave ~10.8% (~11.5 kg) at 26 weeks vs ~3.0% placebo, curves not plateaued. As a 2.4 mg monotherapy arm within REDEFINE 1 (68 wk, T2D-free), cagrilintide alone gave 11.5% mean weight reduction.", "population": "phase 2: adults overweight/obesity, 0.3-4.5 mg, 26 wk, placebo-controlled; REDEFINE 1: cagrilintide 2.4 mg arm within 3,417 adults, 68 wk", "comparators": "placebo; liraglutide 3.0 mg (phase 2); semaglutide 2.4 mg (REDEFINE 1); CagriSema (REDEFINE 1)", "endpointType": "surrogate/biomarker", "notes": "Mechanism: amylin analogue at amylin/calcitonin receptors (AMY1-3), central satiety via area postrema/hypothalamus; reported to restore leptin sensitivity. Mostly developed as the cagrilintide component of CagriSema. Mechanistic paper PMC12270663 (AMY1/AMY3).", "crossRef": "C-CAGRISEMA-LANDSCAPE-01", "grade": "moderate", "source": { "citation": "Lau et al., Lancet 2021 (phase 2); Novo Nordisk REDEFINE 1, NEJM 2025", "url": "https://clinicaltrials.gov/study/NCT05567796", "identifiers": "NCT05567796 (REDEFINE 1 arm)", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CAGRISEMA-BODYCOMP-01", "sourceId": "CIT:ravussin-e-et-al-redefine-1-body-composition-obe", "drug": "CagriSema", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue (cagrilintide) + GLP-1 (semaglutide) combination", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Weight -23.9% (CagriSema), -16.6% (sema), -15.0% (cagrilintide), -2.8% (placebo). Lean-soft-tissue fraction of weight lost: 33.1% CagriSema, 30.3% sema, 37.1% cagrilintide, 43.3% placebo.", "finding": "REDEFINE-1 DXA subgroup (Week 68): CagriSema produced the greatest weight reduction; of weight lost, 66.9% was fat mass and 33.1% lean soft tissue. In participants achieving >=30% weight loss, fat-mass proportion fell from 46.3% to 33.2% while lean-soft-tissue proportion rose from 51.3% to 63.2%.", "population": "DXA subgroup of REDEFINE-1 RCT in overweight/obesity; CagriSema 2.4/2.4 mg vs semaglutide 2.4 mg vs cagrilintide 2.4 mg vs placebo; 68 weeks", "comparators": "semaglutide; cagrilintide; placebo", "endpointType": "imaging/physiological surrogate", "notes": "Conference/sponsor channel. Lean fraction (33.1%) higher than semaglutide alone (30.3%) in this readout - records the pole; cagrilintide monotherapy had the highest lean fraction (37.1%). Direction-of-proportion claims are descriptive; 'why' open. [VALIDATION 2026-06-21: source was an ObesityWeek 2025 conference PDF. RE-CHECK 2026-06-22: same DXA substudy re-presented at ECO 2026 (33rd European Congress on Obesity, Istanbul, 12 May 2026) and independently reported by Pharmaceutical Technology - every figure matches: weight -23.9%/-16.6%/-15.0%/-2.8%; of weight lost 66.9% fat / 33.1% LST (semaglutide 69.7% fat -> 30.3% lean; cagrilintide 62.9% fat -> 37.1% lean); in >=30% responders fat fraction 46.3%->33.2%, LST 51.3%->63.2%. The -23.9% is the DXA-substudy weight (distinct from the REDEFINE-1 ITT -22.7%, NEJM-published), correctly labelled a subgroup. Channel remains conference/sponsor for the DXA readout - report as class context, not as a graduated trio result.]", "crossRef": "C-SEMAGLUTIDE-BODYCOMP-01", "grade": "low", "source": { "citation": "Ravussin E et al., REDEFINE-1 body composition, ObesityWeek 2025 / ECO 2026 presentations (Novo Nordisk)", "url": "https://sciencehub.novonordisk.com/content/dam/sciencehub/global/en/congresses-and-scientific-publications/congresses/ow2025/ravussin/sliders/PPT_Ravussin_OW25_REDEFINE_1_Body_comp_For_submission.pdf", "identifiers": "ObesityWeek 2025 (Ravussin); ECO 2026 analyst coverage", "date": "2025-11", "design": "observational cohort", "maturity": "conference-abstract", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-CARDIO-BP-01", "sourceId": "DOI10.1161/HYPERTENSIONAHA.125.26055", "drug": "CagriSema", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1RA combination", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "SBP -10.9 mmHg (CagriSema) vs -8.5 (sema 2.4) vs -2.8 (placebo) over 68 weeks.", "finding": "CagriSema reduced SBP versus placebo and versus semaglutide alone in REDEFINE 1.", "population": "Adults without diabetes, BMI >=30 or >=27 + complication; REDEFINE 1 phase 3a; 68 weeks.", "comparators": "semaglutide 2.4 mg; cagrilintide 2.4 mg; placebo", "endpointType": "surrogate/biomarker", "notes": "DOI from publisher page, not PubMed-verified - identifier needs confirmation.", "crossRef": "", "grade": "low", "source": { "citation": "REDEFINE 1 BP analysis, Hypertension, 2025/2026", "url": "https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.125.26055", "identifiers": "DOI 10.1161/HYPERTENSIONAHA.125.26055 (unverified)", "date": "2025-01-01", "design": "narrative review", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-CARDIO-RENAL-01", "sourceId": "NCTNCT06131372", "drug": "CagriSema (cagrilintide + semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1RA combination", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "n/a", "magnitude": "Pending. NCT06131372: ~618 participants with CKD (eGFR >15, UACR >100), T2D + overweight/obesity; primary endpoint UACR change at 26 weeks.", "finding": "No published renal-outcome results; a dedicated phase 2 CKD RCT is registered but results not yet available.", "population": "Registry record; REDEFINE 1/2 reported weight but no renal endpoints.", "comparators": "semaglutide; cagrilintide; placebo", "endpointType": "other", "notes": "No human renal results as of search date; entry records the registered trial and data absence. NCT from web; date = search date.", "crossRef": "", "grade": "very-low", "source": { "citation": "ClinicalTrials.gov NCT06131372", "url": "https://clinicaltrials.gov/study/NCT06131372", "identifiers": "NCT06131372", "date": "2026-06-20", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry/sponsor of record - Novo Nordisk A/S (disclosed via registry)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-LANDSCAPE-01", "sourceId": "DOI10.1056/NEJMOA2502081", "drug": "CagriSema (cagrilintide + semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "fixed-combination amylin analogue + GLP-1 receptor agonist (once-weekly s.c.)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "22.7% (efficacy estimand) / ~20.4% (treatment-policy) at 68 wk vs 3% placebo; >=25% weight loss in 40.4%", "finding": "In phase 3 REDEFINE 1, once-weekly CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) gave 22.7% mean weight reduction at 68 weeks vs 3% placebo in overweight/obesity without T2D (efficacy estimand; treatment-policy ~20.4%). 40.4% reached >=25% weight loss (vs 16.2% sema, 6.0% cagrilintide, 0.9% placebo); 88% with prediabetes returned to normoglycaemia. As reported, the 22.7% fell short of the company's pre-trial ~25% expectation, prompting commentary that the result underwhelmed expectations.", "population": "REDEFINE 1: 3,417 adults obesity/overweight + >=1 comorbidity, no T2D; 68 wk; randomised 21:3:3:7 CagriSema:semaglutide:cagrilintide:placebo", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "surrogate/biomarker", "notes": "Mechanism: dual amylin + GLP-1 pathway. Headline Dec 2024, full data ADA/NEJM 2025. The 'fell short of 25%' framing recorded AS REPORTED commentary, not a verdict. REDEFINE 2 (T2D) is the companion trial.", "crossRef": "C-CAGRILINTIDE-LANDSCAPE-01", "grade": "high", "source": { "citation": "Coadministered Cagrilintide and Semaglutide in Overweight/Obesity, NEJM 2025 (REDEFINE 1); ADA 2025", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2502081", "identifiers": "NCT05567796; DOI 10.1056/NEJMoa2502081", "date": "2025-06-23", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-REDEFINE2-GI-01", "sourceId": "PMID40544432", "drug": "CagriSema", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "GLP-1 + amylin (cagrilintide-semaglutide)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "REDEFINE-2 (T2D, n=1206, 68 wk): gastrointestinal adverse events 72.5% CagriSema vs 34.4% placebo, mostly transient mild-moderate.", "finding": "In the T2D registrational trial, CagriSema roughly doubled gastrointestinal adverse events versus placebo (72.5% vs 34.4%), mostly transient.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "safety-event/signal", "notes": "Adds the REDEFINE-2 GI-AE table (the efficacy is already in the corpus). Shares source PMID 40544432.", "crossRef": "", "grade": "high", "source": { "citation": "Davies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)", "url": "https://doi.org/10.1056/NEJMoa2502082", "identifiers": "PMID 40544432; DOI 10.1056/NEJMoa2502082; NCT05394519", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-SAFETY-DC17", "sourceId": "PMID40544433", "drug": "CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "GI AEs 79.6% vs 39.9% placebo; overall AE discontinuation 6% vs 3.7%; GI-specific discontinuation 3.6%", "finding": "In REDEFINE 1, GI AEs common but AE-related discontinuation modest; only a small fraction discontinued specifically for GI events.", "population": "REDEFINE 1 phase 3, adults with overweight/obesity without T2D", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "safety-event/signal", "notes": "Discontinuation figures from Novo press/HCPLive summary; PMID/DOI confirmed (reconciled with GI-domain record C-CAGRISEMA-SAFETY-GI07). GI-tolerability overlap.", "crossRef": "C-ORF-SAFETY-DC16; C-CAGRISEMA-SAFETY-GI07", "grade": "high", "source": { "citation": "Garvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)", "url": "https://doi.org/10.1056/NEJMoa2502081", "identifiers": "PMID 40544433; DOI 10.1056/NEJMoa2502081; NCT05567796", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CAGRISEMA-SAFETY-GI07", "sourceId": "PMID40544433", "drug": "CagriSema (cagrilintide + semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Any GI AE 79.6% vs 39.9% placebo (nausea 55% vs 12.6%, constipation 30.7% vs 11.6%, vomiting 26.1% vs 4.1%); overall AE discontinuation 6% vs 3.7%; GI-specific discontinuation 3.6%", "finding": "GI AEs much more frequent than placebo, mainly transient and mild-to-moderate; GI-specific discontinuation modest.", "population": "REDEFINE 1: 3417 adults overweight+complication or obesity, no diabetes; 68 weeks; phase 3a RCT", "comparators": "semaglutide 2.4 mg; cagrilintide 2.4 mg; placebo", "endpointType": "other", "notes": "PMID confirmed. Within-study sema-alone and cagri-alone arms enable GI comparison; per-arm splits need full text. Per-symptom % from press summaries.", "crossRef": "C-SEMA-SAFETY-GI01", "grade": "high", "source": { "citation": "Garvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)", "url": "https://doi.org/10.1056/NEJMoa2502081", "identifiers": "PMID 40544433; DOI 10.1056/NEJMoa2502081; NCT05567796", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CLASS-APP-FOODNOISE-01", "sourceId": "PMID40628707", "drug": "GLP-1-based class (food-noise folk-claim verdict)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "Craving reduction is instrument-measured (CoEQ, Food Craving Inventory, appetite VAS) across semaglutide and tirzepatide, with reduced reward-circuit fMRI for tirzepatide. The specific 'food noise' construct only acquired a formal definition + instruments (RAID-FN 27-item; 5-item FNQ) in 2025 (Dhurandhar). 'Valued above weight loss' has only survey/anecdote support (e.g. the manufacturer-sponsored retrospective INFORM survey, n=550: median FNQ 13->6).", "finding": "FOLK-CLAIM VERDICT ('these drugs silence food noise'): MIXED. The craving/appetite-reduction CORE is TRUE and instrument-measured (real, not placebo or weight-loss halo). BUT (1) 'food noise' as a distinct intrusive-rumination construct was only defined and given instruments in 2025 and has NEVER been a pre-registered trial endpoint - the trials measured cravings/appetite, which overlap but are not identical; (2) 'valued above the weight loss itself' rests entirely on surveys/anecdote - UNPROVEN; (3) drug-specificity is lopsided - robust for semaglutide, mechanistically strong for tirzepatide, THIN and indirect for retatrutide.", "population": "Narrative cross-agent verdict over the craving/appetite evidence (CoEQ/FCI/VAS RCTs; tirz fMRI; reta early/indirect data) + the 2025 food-noise construct literature.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "BELIEF-VS-REALITY: the brain-quieting/craving effect is real and measured; the 'food noise' label outruns its (brand-new) instruments; and 'valued above weight loss' is the softest, least-evidenced part. Folk-claim frequency: EXTREMELY COMMON (the single most-repeated positive claim). The construct paper (Dhurandhar) is the anchor; the craving RCTs (moderate) and the survey (very-low) are graded separately in the cross-ref rows. Cross-ref C-SEMAGLUTIDE-APP-05; C-TIRZEPATIDE-APP-01; C-RETATRUTIDE-APP-01.", "crossRef": "C-SEMAGLUTIDE-APP-05; C-TIRZEPATIDE-APP-01; C-RETATRUTIDE-APP-01; C2-SEMAGLUTIDE-APP-01", "grade": "low", "source": { "citation": "Dhurandhar EJ et al. Defining and measuring food noise (RAID-FN / FNQ). Nutr Diabetes 2025;15:... (PMID 40628707). Verdict consolidates C-SEMAGLUTIDE-APP-05, C-TIRZEPATIDE-APP-01, C-RETATRUTIDE-APP-01 + the existing appetite-intake rows.", "url": "https://doi.org/10.1038/s41387-025-00382-x", "identifiers": "PMID40628707", "date": "2025-07-01", "design": "narrative review", "maturity": "review", "funding": "academic (Dhurandhar et al.; food-noise construct/measurement paper)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-01", "sourceId": "PMID41996180", "drug": "incretin class (liraglutide, semaglutide, tirzepatide, dulaglutide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1 incretin therapies", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Median muscle-based-index loss 28.3% of weight lost (IQR 15.9-39.9%); BIA/DXA studies ~29% (67% exceeding 25% benchmark); CT/MRI studies ~25.3% (two-thirds exceeding 15% benchmark). Comparator lifestyle/placebo weight loss median -2.5%.", "finding": "Systematic review (Annals of Internal Medicine): across 35 RCTs, incretin therapies consistently reduced fat mass and visceral adiposity; muscle-based-index loss was highly heterogeneous, with median 28.3% of total weight loss attributable to muscle-based indices and ~two-thirds of interventions exceeding pre-specified muscle-loss benchmarks. No study reported objective physical-function outcomes.", "population": "35 RCTs (median duration 26 weeks, median N 78) of liraglutide, semaglutide, tirzepatide or dulaglutide in adults with obesity; BIA/DXA/CT/MRI; Jan 2003-Feb 2026", "comparators": "placebo; lifestyle", "endpointType": "imaging/physiological surrogate", "notes": "Class-level synthesis; heterogeneity precluded meta-analysis. Note the FFM/muscle benchmark is measurement-method-dependent (~25% for BIA/DXA, ~15% for CT/MRI). Anchors the comparison matrix. The 'no objective physical function outcomes' gap is a recurring caveat.", "crossRef": "C-TIRZEPATIDE-BODYCOMP-01", "grade": "moderate", "source": { "citation": "Batsis JA et al., Ann Intern Med, 2026", "url": "https://doi.org/10.7326/ANNALS-25-00478", "identifiers": "PMID 41996180; DOI 10.7326/ANNALS-25-00478", "date": "2026-04-17", "design": "meta-analysis", "maturity": "review", "funding": "academic-none/no external funding (independent)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-02", "sourceId": "PMID41851969", "drug": "GLP-1 class (general)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 / incretin therapies", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "n/a (qualitative synthesis); flags scarcity of studies rigorously assessing SMM + function + structure together.", "finding": "Narrative review of human studies on GLP-1 therapies and sarcopenia: results are mixed - some studies emphasise excessive skeletal-muscle-mass loss while others argue for a protective effect via improved muscle quality (less myosteatosis); no definitive conclusion on net detriment or benefit to skeletal muscle.", "population": "Human studies of GLP-1-based therapies assessing skeletal-muscle mass, strength/function and structure/quality", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "Explicitly preserves BOTH poles of the sarcopenia question (harm vs muscle-quality benefit). Good neutrality anchor for the muscle-quality column. Echoes the SCWD/FDA workshop (PMID 41362110, DOI 10.1002/jcsm.70147) on endpoint challenges.", "crossRef": "C-CLASS-BODYCOMP-01", "grade": "low", "source": { "citation": "Scheen AJ, Expert Opin Drug Saf, 2026", "url": "https://doi.org/10.1080/14740338.2026.2640980", "identifiers": "PMID 41851969; DOI 10.1080/14740338.2026.2640980", "date": "2026-03-23", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-03", "sourceId": "PMID41877354", "drug": "incretin class (semaglutide, tirzepatide, liraglutide) vs lifestyle", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1 incretin therapies vs lifestyle (meta-analysis)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Lean fraction of total weight lost: semaglutide 35.2% (95% CI 31.5-38.9), tirzepatide 25.4% (22.8-28.0), liraglutide 26.8% (23.1-30.5), lifestyle 26.2% (24.1-28.3; p=0.42 vs incretins), lifestyle+resistance 17.5% (14.2-20.8). I-squared 68% (moderate heterogeneity). Absolute lean-kg pooled as co-primary (drug-specific kg in full text, not extracted here).", "finding": "Systematic review and meta-analysis (20 RCTs, 15,782 adults, DXA/MRI) with absolute lean-mass change (kg) and lean fraction of weight lost as CO-PRIMARY outcomes. Lean mass was ~25-39% of total weight lost across incretin agents and broadly comparable to lifestyle intervention (no significant difference, p=0.42). The only modality that materially lowered the lean fraction was lifestyle PLUS resistance training (17.5%). Retatrutide is NOT included.", "population": "20 RCTs, 15,782 adults with overweight/obesity; semaglutide, tirzepatide, liraglutide or lifestyle; DXA or MRI; searched to 20 Jan 2026; random-effects, RoB 2, GRADE.", "comparators": "lifestyle intervention; lifestyle plus resistance training", "endpointType": "imaging/physiological surrogate", "notes": "NEW source. Most direct head-to-class lean-fraction comparison and the closest thing to an absolute-lean-kg anchor. Decision-relevant: incretin lean fraction is no worse than diet-induced loss of similar magnitude (p=0.42); resistance training is the lever, not the drug. CRUCIAL GAP: retatrutide is ABSENT, so the class benchmark exists but no reta point sits in it. Meta-analysis graded moderate by default. DXA/MRI lean is not muscle function. VALIDATOR: confirm PMID 41877354 resolves to this DOM 2026 meta and the per-drug fractions (sema 35.2%, tirz 25.4%). Cross-ref T5-014, T5-010.", "crossRef": "C-CLASS-BODYCOMP-01; T5-010; T5-014", "grade": "moderate", "source": { "citation": "Eisa N, Barood O et al., Diabetes Obes Metab, 2026", "url": "https://doi.org/10.1111/dom.70666", "identifiers": "PMID41877354", "date": "2026-03-24", "design": "meta-analysis", "maturity": "review", "funding": "academic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-04", "sourceId": "PMID39719170", "drug": "GLP-1 RA and GLP-1/GIP dual agonist class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA and GLP-1/GIP dual agonists (network meta-analysis)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Lean mass MD -0.86 kg (95% CI -1.30 to -0.42); total weight MD -3.55 kg; fat mass MD -2.95 kg; lean-mass loss ~25% of weight lost; RELATIVE lean mass (% of body weight) UNCHANGED. Liraglutide the only agent with significant weight loss without significant lean-mass reduction; tirzepatide 15 mg and semaglutide 2.4 mg most effective for fat loss but among the least lean-preserving.", "finding": "Network meta-analysis (22 RCTs, 2258 participants): GLP-1RAs reduced absolute lean mass by ~0.86 kg (~25% of weight lost), but the RELATIVE proportion of body weight that is lean was unaffected. The same dataset supports both poles of the debate: 'relative lean unchanged' feeds the adaptive reading; the absolute -0.86 kg and the tirz/sema-least-preserving ordering feed the caution reading.", "population": "Systematic review + network meta-analysis, 22 RCTs, N=2258, adults with diabetes and/or overweight/obesity; DXA/BIA.", "comparators": "placebo; liraglutide; semaglutide; tirzepatide; dulaglutide; exenatide", "endpointType": "imaging/physiological surrogate", "notes": "NEW. The numeric backbone both poles cite; meta-analysis graded moderate by default. Entirely a MASS meta-analysis: no strength/gait/SPPB pooled because the component trials did not measure them. Consistent with the Annals review (C-CLASS-BODYCOMP-01, ~25-28% lean fraction). COROLLARY (Council Methodologist): 'relative lean unchanged' is a COROLLARY of the fixed lean-fraction-of-weight-lost property (cf. SURMOUNT-1 placebo parity), NOT an independent adaptive signal, and does not address absolute lean-kg or function. Cross-ref C-CLASS-BODYCOMP-01.", "crossRef": "C-CLASS-BODYCOMP-01; C-CLASS-BODYCOMP-05; C-CLASS-BODYCOMP-06", "grade": "moderate", "source": { "citation": "Karakasis P et al., Metabolism 2024", "url": "https://doi.org/10.1016/j.metabol.2024.156113", "identifiers": "PMID:39719170 / DOI:10.1016/j.metabol.2024.156113", "date": "2024-12-22", "design": "network meta-analysis", "maturity": "review", "funding": "academic / independent - no specific grant funding", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-05", "sourceId": "PMID38937282", "drug": "GLP-1-based therapies (GLP-1RA and GLP-1/GIP dual)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1 / GIP-GLP-1 incretin therapies (review)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Lean-mass loss as proportion of weight lost: 40-60% (higher pole) versus <=15% (lower pole) across studies; MRI muscle-volume change described as commensurate/adaptive; no single pooled number.", "finding": "ADAPTIVE-POLE anchor (both poles preserved): reported lean-mass loss as a proportion of weight lost is heterogeneous (40-60% in some studies, <=15% in others); on contemporary evidence including MRI muscle-volume work the skeletal-muscle changes appear largely ADAPTIVE (commensurate with the weight loss achieved, with improved insulin sensitivity and reduced muscle fat infiltration suggesting improved muscle QUALITY), rather than pathological wasting. Older age / disease severity flagged as risk modifiers.", "population": "Narrative review of trial + MRI-based evidence on GLP-1RA and dual GLP-1/GIP effects on lean body mass and muscle health in overweight/obesity.", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "ADAPTIVE pole. KEY caveat the authors themselves make: DXA 'lean mass' includes organ, bone, fluid, so 'lean preserved' is NOT 'muscle/function preserved'; the adaptive reading rests on MRI muscle-volume + quality inference, NOT strength/function endpoints (which are largely absent, see C-CLASS-BODYCOMP-08). This is the thread-5 T5-014 cross-ref. Counter-pole: C-CLASS-BODYCOMP-06. Companion paper Linge/Birkenfeld/Neeland Circulation 2024 (PMID 39401279) makes the same case; folded here to avoid a duplicate row. COI (validation): co-author J. Linge is employed by AMRA Medical (a commercial MRI muscle-composition analytics firm), directly relevant to the MRI-based 'muscle quality preserved / adaptive' inference. CONFIDENCE (Council Evidence-grader + Red-team): this adaptive/muscle-quality inference is held at NO HIGHER confidence than the caution pole (C-CLASS-BODYCOMP-06); it is down-weighted because the MRI-composition methodology underpinning the 'quality preserved' claim is the AMRA-employed co-author's commercial product. Improved muscle quality / reduced IMAT has NOT been shown to offset quantity loss in any function endpoint (none exist), and IMAT reduction may track total fat loss rather than a muscle-specific effect.", "crossRef": "C-CLASS-BODYCOMP-02; C-CLASS-BODYCOMP-06; T5-014", "grade": "low", "source": { "citation": "Neeland IJ et al., Diabetes Obes Metab, 2024", "url": "https://doi.org/10.1111/dom.15728", "identifiers": "PMID38937282", "date": "2024-06-27", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-06", "sourceId": "PMID38687506", "drug": "incretin class (liraglutide, semaglutide, tirzepatide, retatrutide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 RA, GLP-1/GIP dual and GLP-1/GIP/GCGR triple agonists (review)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Lean-mass loss ~10% or ~6 kg, framed as 'comparable to a decade or more of ageing'; contrasted with supervised resistance training (separate literature) able to add ~3 kg lean / ~25% strength. Review-summarised, not a primary measurement.", "finding": "CAUTION-POLE anchor (both poles preserved): narrative review argues incretin agents (liraglutide, semaglutide, tirzepatide, retatrutide named) inducing ~15-24% weight loss also cause rapid lean-mass loss of ~10% / ~6 kg, threatening muscle mass/function and raising sarcopenia/frailty risk, motivating resistance exercise and muscle-preserving adjuncts. The same DXA numbers the adaptive camp reads as benign are read here as a threat: the disagreement is INTERPRETIVE, not over the raw number.", "population": "Narrative review; adults with overweight/obesity on incretin therapy; older-adult sarcopenia/frailty framing.", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "CAUTION pole. Names retatrutide in the lean-loss list but cites NO reta-specific function data (see C-RETATRUTIDE-BODYCOMP-03 gap). Still a MASS argument, not strength data. The ~10%/~6 kg figure is a CLASS generalisation; NO reta-specific lean-kg supports reta's inclusion (the review names reta but does not measure it; Council Methodologist). The 'decade of ageing' is a framing analogy. Two further caution reviews fold here to avoid duplicates: Stefanakis/Mantzoros Metabolism 2024 (PMID 39481534, '>25% of loss is fat-free mass') and the JAMA viewpoint Conte/Hall/Klein 2024 (PMID 38829659, which frames the harm-vs-adaptive question as explicitly UNRESOLVED). Counter-pole: C-CLASS-BODYCOMP-05.", "crossRef": "C-CLASS-BODYCOMP-05; C-CLASS-BODYCOMP-08; C-RETATRUTIDE-BODYCOMP-03", "grade": "low", "source": { "citation": "Locatelli JC et al., Diabetes Care 2024", "url": "https://doi.org/10.2337/dci23-0100", "identifiers": "PMID:38687506 / DOI:10.2337/dci23-0100", "date": "2024-10-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-07", "sourceId": "PMID35196654", "drug": "sarcopenic-obesity diagnostic framework (class-relevant yardstick)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "ESPEN/EASO consensus diagnostic framework", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "n/a (consensus diagnostic criteria; a muscle-FUNCTION test precedes the body-composition/mass test in the algorithm).", "finding": "DEFINITIONAL YARDSTICK: the ESPEN/EASO consensus defines sarcopenic obesity as excess adiposity PLUS low muscle MASS PLUS low muscle FUNCTION, with a two-step diagnostic pathway that confirms via a muscle-FUNCTION test (e.g. strength) before a mass measure. By this standard, calling incretin lean-mass loss 'sarcopenia' REQUIRES a demonstrated FUNCTION deficit, which the trials have not measured.", "population": "ESPEN + EASO international expert consensus statement.", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "The NEUTRAL yardstick for the harm-vs-adaptive debate: function-first diagnosis means DXA mass loss alone does not equal sarcopenia. Co-authored by Prado and Barazzoni (sarcopenic-obesity authorities). Predates the GLP-1 surge; applied here as the standard, not as a drug study. Graded LOW (expert consensus/guidance, no pooled estimate; Council Evidence-grader). BIDIRECTIONAL (Council Red-team): by ESPEN/EASO criteria, DXA mass loss alone CANNOT be called sarcopenia without a demonstrated function deficit, AND the absence of measured function CANNOT be called muscle-safe either - the class is currently undiagnosable in both directions. This yardstick governs adjudication of the harm-vs-adaptive poles.", "crossRef": "C-CLASS-BODYCOMP-06; C-CLASS-BODYCOMP-08", "grade": "low", "source": { "citation": "Donini LM, Busetto L, Bischoff SC, Barazzoni R, Prado CM et al. (ESPEN/EASO Consensus), Obes Facts, 2022", "url": "https://doi.org/10.1159/000521241", "identifiers": "PMID35196654", "date": "2022-02-23", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-08", "sourceId": "PMID39344838", "drug": "incretin weight-loss class (general)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA, dual and triple agonists", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "n/a - not measured. Only protocol-stage RCT (PMID 39269759, N=20, open-label, older adults, semaglutide vs lifestyle) targets grip strength + SPPB; results pending. The strongest function-adjacent signals are HF PROs (STEP-HFpEF 6MWD +20.3 m, PMID 37622681; SUMMIT KCCQ +6.9, PMID 39555826), which measure heart-failure status, NOT muscle strength.", "finding": "CLASS GAP (the absence is the finding): direct measurement of muscle FUNCTION (grip strength, gait speed, SPPB, chair-stand) is essentially ABSENT from the pivotal incretin weight-loss trials; body composition is captured almost entirely as DXA/MRI MASS. Multiple reviews (Neeland 2024; Dubin/Heymsfield 2024; Conte/Hall/Klein; Drucker 2024) converge that strength/function/mobility were not assessed and call for them. Authoritative safety reviews (Drucker, Diabetes Care 2024, PMID 38843460) list muscle strength as an under-characterised SAFETY domain for the class, including retatrutide, survodutide and MariTide.", "population": "Class-wide gap across STEP / SURMOUNT / SUMMIT / SUSTAIN body-composition substudies; synthesised in reviews + one protocol-stage older-adult RCT.", "comparators": "", "endpointType": "symptom/PRO", "notes": "THE ABSENCE IS THE FINDING. Dubin reviewed 28 GLP-1RA trials, all DXA mass, no functional testing, and call for MRI + functional testing. The two HF-PRO signals (6MWD, KCCQ) are folded into the magnitude with an explicit NOT-muscle-strength tag, so they are captured without miscategorising HF symptom relief as muscle function. Drucker PMID 38843460 folded here. Class-level counterpart to the reta-specific gap (C-RETATRUTIDE-BODYCOMP-03). The folded 6MWD/KCCQ are heart-failure-STATUS PROs confounded by dyspnoea/fluid/symptom relief - NOT gait-speed or strength - and do NOT narrow the muscle-function gap (Council Evidence-grader).", "crossRef": "C-CLASS-BODYCOMP-01; C-CLASS-BODYCOMP-07; C-RETATRUTIDE-BODYCOMP-03", "grade": "low", "source": { "citation": "Dubin RL, Heymsfield SB, Ravussin E, Greenway FL, Diabetes Obes Metab, 2024 (28-trial gap synthesis, DXA-only, calls for function testing)", "url": "https://doi.org/10.1111/dom.15913", "identifiers": "PMID39344838", "date": "2024-09-30", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-MUSCLELOSS-FOLK-01", "sourceId": "PMID41996180", "drug": "GLP-1-based class (muscle-loss folk-claim verdict)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Systematic review (Batsis, Ann Intern Med 2026, 35 RCTs): median ~28.3% of weight lost was fat-free mass (IQR 15.9-39.9%); ~two-thirds of incretin arms exceeded the ~25% DXA benchmark - but so did ~half of lifestyle weight-loss arms; no study measured objective physical function. SURMOUNT-1 DXA (Look 2025): ~75% fat / 25% lean, the SAME split in the placebo arm. Reta phase-2 DXA (Coskun 2025): lean-loss FRACTION similar to other agents despite the largest fat loss.", "finding": "FOLK-CLAIM VERDICT ('I'm losing MUSCLE not just fat; eat protein and lift'): MIXED, leaning TRUE-but-reframed. Lean-mass loss is real (~25-40% of weight lost is fat-free mass), but the 'losing muscle' framing overstates it - most is obligatory for any large weight loss, the split mirrors placebo/lifestyle, and the LEAN FRACTION is NOT worse with the more potent agents (incl. retatrutide), only the absolute kg. The protein+resistance-training rule is mechanistically sound but its GLP-1-specific trial evidence is MIXED. The genuine concern is functional (sarcopenia in older/sarcopenic-obese patients) and is UNDER-MEASURED (no trial assessed physical function).", "population": "Systematic review (35 RCTs) + DXA substudies of SURMOUNT-1 (tirzepatide) and the reta phase-2 T2D trial.", "comparators": "placebo; lifestyle weight loss", "endpointType": "imaging/physiological surrogate", "notes": "GRADE moderate (systematic review of RCT DXA data). MATCHED to the D2 lean-mass thread; this row adds the folk-verdict + the reframe (fraction not worse with potency; function under-measured) + the new systematic-review anchor. Belief-vs-reality: the scale drop is ~25-40% fat-free mass (expected, similar to placebo/lifestyle), mostly benign with composition improving - but the older/sarcopenic functional risk is real and untested, and protein+lifting is the right hedge. Reta loses most weight -> most ABSOLUTE lean kg, but not a worse fraction. Cross-ref the D2 body-composition rows.", "crossRef": "C-CLASS-SAFETY-HAIRLOSS-01; C-CLASS-BODYCOMP-08", "grade": "moderate", "source": { "citation": "Batsis JA et al., Ann Intern Med, 2026", "url": "https://doi.org/10.7326/ANNALS-25-00478", "identifiers": "PMID 41996180; DOI 10.7326/ANNALS-25-00478", "date": "2026-04-17", "design": "meta-analysis", "maturity": "review", "funding": "academic-none/no external funding (independent)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BODYCOMP-OZEMPICFACE-01", "sourceId": "PMID42162206", "drug": "GLP-1-based weight-loss class (Ozempic-face folk-claim verdict)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "Dermatology/plastic-surgery systematic reviews (e.g. Barone 2026, 40 studies) document facial volume loss, dermal thinning, collagen/elastin loss and skin laxity after GLP-1-induced weight loss; risk factors are advanced age, prolonged obesity, RAPID weight loss, poor hydration, low protein. The same facial change is documented after BARIATRIC surgery (midface volume loss ~86%, perioral ~59% at BMI 38->27). Reviews conclude evidence for DRUG-specific (rather than weight-loss-mediated) facial fat atrophy is LACKING.", "finding": "FOLK-CLAIM VERDICT ('Ozempic face'): MIXED - the gaunt/hollow/aged/sagging face is REAL (TRUE), but the attribution to the DRUG is FALSE: it is a WEIGHT-LOSS-mediated effect (non-selective loss of facial fat pads + dermal laxity that fails to retract, worse with age), not a drug-specific facial toxicity. The same occurs with any rapid/large weight loss including bariatric surgery and diet. NOT semaglutide-specific (named for first-mover fame); class-wide - and tirzepatide/retatrutide likely produce MORE facial change purely via GREATER weight loss. Folk preventatives (slower loss, more protein, hydration, fillers/microneedling) are mechanistically coherent with the volume-loss explanation.", "population": "Dermatology + plastic-surgery systematic reviews of case reports/cohorts + authoritative clinical commentary (Cleveland Clinic); bariatric-surgery facial-change cohorts as the weight-loss-generic comparator.", "comparators": "bariatric-surgery weight loss; diet weight loss", "endpointType": "imaging/physiological surrogate", "notes": "GRADE low: dermatology/plastic-surgery review of mostly case reports + commentary; facial appearance has NEVER been a controlled GLP-1 trial endpoint, and no head-to-head drug-vs-equivalent-diet-weight-loss facial comparison exists. The directional verdict (weight-loss-mediated, not drug-specific) is consistent and well-supported; a minority direct-drug hypothesis (Kruglikov 2025, dermal white-adipose effect) is unproven. BELIEF-VS-REALITY: people believe 'the drug gives you the face'; reality - losing a lot of weight fast gives you the face, and the drug is just an efficient way to do that. Folk-claim frequency: EXTREMELY COMMON as a cultural term.", "crossRef": "C-CLASS-SAFETY-BONE16", "grade": "low", "source": { "citation": "Barone M et al. GLP-1 receptor agonists and skin quality: a systematic review (incl. facial volume loss / 'Ozempic face'). Aesthetic Plast Surg 2026 (PMID 42162206); + Cleveland Clinic clinical commentary (health.clevelandclinic.org/ozempic-face).", "url": "https://doi.org/10.1007/s00266-026-05820-4", "identifiers": "PMID42162206", "date": "2026-01-01", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-BMD-COHORT-01", "sourceId": "PMID41655226", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "DXA cohort (n=255, 92% female, mean 64y): total-hip/femoral-neck BMD fell with weight loss; GREATER hip loss in non-diabetics (-1% vs -0.6%, p=0.04), diabetes-status-modified.", "finding": "In an older mostly-female cohort, semaglutide/tirzepatide-associated bone loss tracked weight loss and was greater in non-diabetic patients.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "WEIGHT-LOSS-MAGNITUDE-MEDIATED, DM-status-modified; implies the T2D meta understates loss in obesity/non-diabetic use. Retrospective, single-centre.", "crossRef": "", "grade": "low", "source": { "citation": "Semaglutide/tirzepatide skeletal effects (DXA cohort, n=255), J Clin Endocrinol Metab 2026", "url": "https://doi.org/10.1210/clinem/dgag052", "identifiers": "DOI:10.1210/clinem/dgag052", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-BMD-LIRA-RCT-01", "sourceId": "PMID38916894", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "RCT DXA secondary analysis (n=195, non-diabetic obesity): liraglutide alone reduced hip/spine BMD MORE than exercise at matched weight loss (hip -0.013, p=0.03); exercise co-therapy preserved BMD.", "finding": "In a randomised DXA study, liraglutide reduced bone density more than exercise at the same weight loss, and resistance exercise prevented the loss.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "THE PARTLY-DRUG-INTRINSIC bone row (the one not purely weight-mediated - BMD fell beyond what matched weight loss explains). Non-elderly (mean 43y); resistance exercise is protective. Must NOT be mislabelled weight-mediated.", "crossRef": "", "grade": "high", "source": { "citation": "Liraglutide vs exercise on bone density (RCT DXA secondary analysis), JAMA Netw Open 2024", "url": "https://doi.org/10.1001/jamanetworkopen.2024.16775", "identifiers": "DOI:10.1001/jamanetworkopen.2024.16775", "date": 2024, "design": "double-blind RCT", "maturity": "human-primary", "funding": "academic / non-commercial (Novo Nordisk Foundation + Danish academic bodies; drug supplied in-kind; disclosed)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-BMD-META-01", "sourceId": "PMID39985672", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "no-change", "magnitude": "25-RCT meta (T2D): no fracture increase (RR 0.80, NS, RETAINED and confirmed); BMD point estimates modestly higher than control at spine/hip/femoral-neck in T2D RCTs - a reassurance-of-NO-LOSS, NOT a demonstrated bone gain, and CONTESTED as a generalisable effect.", "finding": "In T2D-only RCTs, GLP-1 RAs showed no fracture excess (RR 0.80, NS) and no detectable BMD loss (BMD point estimates modestly higher than control) - a reassurance-of-absence in diabetic bone, NOT a demonstrated bone-building effect. This does NOT generalise to obesity/weight-loss populations, where the direct double-blind Hansen RCT and DXA cohorts show resorption-dominant BMD loss.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "REMEDIATED (WI-BMD-01): re-scoped from a near-anabolic class reading to a CONTESTED, T2D-meta-analytic-specific pole. T2D bone tends high-density/low-quality, so a meta of T2D RCTs can report 'no loss / modestly higher BMD' while the direct double-blind weight-loss RCT (Hansen, C-CLASS-BONE-MECH-RCT-01: P1NP null, CTX up, lumbar/hip aBMD down) and obesity cohorts (C-CLASS-BONE-BMD-COHORT-01) show loss. The discordance is explained by population (T2D vs obesity) and weight-loss magnitude; the higher-BMD reading must NOT be transferred to the rapid-weight-loss obesity setting. The fracture RR 0.80 NS is real and retained.", "crossRef": "C-CLASS-SAFETY-BONE-CONS01; C-CLASS-BONE-MECH-RCT-01; C-CLASS-FRACTURE-NMA-01", "grade": "moderate", "source": { "citation": "GLP-1 RA bone density and turnover (25-RCT meta-analysis), Acta Diabetol 2025", "url": "https://doi.org/10.1007/s00592-025-02468-5", "identifiers": "DOI:10.1007/s00592-025-02468-5", "date": 2025, "design": "meta-analysis", "maturity": "review", "funding": "academic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-FRAC-ELDERLY-01", "sourceId": "PMID41665888", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Cohort (n=46,177, >=65y T2D): first fragility fracture HR 1.11 (95% CI 1.01-1.21) vs SGLT2i/DPP-4i, competing-risk-adjusted.", "finding": "In adults aged 65+ with T2D, GLP-1 RA initiation carried a modestly increased fragility-fracture risk versus other glucose-lowering drugs.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Modest and uncertain: observational, active-comparator-confounded (SGLT2i carries its own fracture history), CI lower bound hugs 1.01. SHIFTS the verdict off neutral-reassurance but does NOT establish a fracture excess - not a fracture alarm.", "crossRef": "C-CLASS-SAFETY-BONE-CONS01", "grade": "low", "source": { "citation": "GLP-1 RA and fragility fracture in adults >=65 (cohort, n=46,177), J Clin Endocrinol Metab 2026", "url": "https://doi.org/10.1210/clinem/dgag056", "identifiers": "DOI:10.1210/clinem/dgag056", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-FRAC-TIRZ-01", "sourceId": "PMID41218687", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "TriNetX cohort (n=66,329/group): new osteoporosis/fragility fracture HR 1.44 (95% CI 1.22-1.69) vs other GLP-1 RAs (other GLP-1 RA vs non-users ~null, HR 1.07).", "finding": "Real-world data associate tirzepatide with higher osteoporosis/fragility-fracture risk than other GLP-1 RAs - a greatest-weight-loss/dual-agonist signal.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "SHORT 14-month window (too short for fragility-fracture accrual) - hypothesis-generating; coding-based outcomes; weight-loss magnitude the likely mediator; residual confounding. Larger than any RCT signal - do not over-read.", "crossRef": "", "grade": "low", "source": { "citation": "Tirzepatide and osteoporosis/fragility fracture (TriNetX cohort), Diabetes Res Clin Pract 2025", "url": "https://doi.org/10.1016/j.diabres.2025.112995", "identifiers": "DOI:10.1016/j.diabres.2025.112995", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-MECH-RCT-01", "sourceId": "PMID38737002", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "52-wk double-blind RCT (n=64, 55 postmenopausal women + 9 men, increased fracture risk): bone-FORMATION marker P-PINP did NOT rise (ETD +3.8 mug/L, 95% CI -5.6 to 13.3, p=0.418); RESORPTION marker P-CTX higher (ETD +166.4 ng/L, 95% CI 25.5-307.3, p=0.021); lumbar-spine aBMD -0.018 g/cm2 (95% CI -0.031 to -0.005, p=0.007) and total-hip aBMD -0.020 g/cm2 (95% CI -0.032 to -0.008, p=0.001) LOWER vs placebo; femoral-neck NS; body weight -6.8 kg (p<0.001).", "finding": "In a 52-week double-blind RCT in adults with increased fracture risk (mostly postmenopausal), semaglutide 1.0 mg did NOT raise bone formation (P-PINP null) but RAISED bone resorption (CTX) and LOWERED lumbar-spine and total-hip BMD versus placebo - a resorption-dominant pattern, not bone-building.", "population": "Semaglutide bone phase-2 double-blind RCT (Hansen et al., EClinicalMedicine 2024, NCT04702516); 64 adults at increased fracture risk (T-score < -1.0 and/or recent low-energy fracture), two Danish hospitals.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "THE direct double-blind DXA/turnover RCT counterweight to the T2D meta (C-CLASS-BONE-BMD-META-01 / -TURNOVER-01): shows resorption-dominant loss, NOT the meta's favourable-turnover/higher-BMD reading. Graded moderate (phase-2), but it is a direct double-blind randomised DXA + bone-turnover measurement, methodologically stronger than the meta's pooled T2D RCTs for the obesity/weight-loss question. UNSETTLED whether drug-intrinsic or weight-loss-mediated - NO diet-only comparator arm, and the authors attribute the CTX rise to the accompanying weight loss. Postmenopausal/modest n; not an obesity-dose (1.0 mg) trial. Corrects and re-scopes the contested anabolic pole.", "crossRef": "C-CLASS-BONE-TURNOVER-01", "grade": "moderate", "source": { "citation": "Hansen MS, Wolfel EM, Jeromdesella S, et al. Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial. EClinicalMedicine 2024;72:102624.", "url": "https://doi.org/10.1016/j.eclinm.2024.102624", "identifiers": "DOI:10.1016/j.eclinm.2024.102624", "date": 2024, "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic/investigator-initiated (Region of Southern Denmark + Novo Nordisk Foundation + Gangsted Foundation; Novo Nordisk supplied study drug only, not sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-PILOT-OLDER-01", "sourceId": "DOI10.3389/FRAGI.2025.1691007", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "no-change", "magnitude": "20-wk open-label pilot RCT (n=20, mean age 72.7y, sema+lifestyle vs lifestyle alone): whole-body BMD change NS between groups (p=0.77); regional leg/pelvis/lumbar BMD and CTX/P1NP all NS; semaglutide arm lost more weight (-5.3% vs -0.9%, p<0.01) and trended to lower BMD/higher turnover. ONLY significant signal: a post-hoc partial correlation of weight change with PELVIS BMD change (r=0.62, p=0.01); whole-body, leg, lumbar correlations NS.", "finding": "In a 20-week pilot RCT in older adults (n=20), whole-body and regional BMD and bone-turnover markers did not change significantly, but a post-hoc correlation linked greater weight loss to greater pelvis bone loss (r=0.62) - hypothesis-generating support for weight-loss-mediated loss, not proof.", "population": "Older-adult GLP-1 bone pilot (Trejo/Cortes et al., Front Aging 2025, NCT05786521); 20 community-dwelling adults aged 65+ with prediabetes/T2D + overweight/obesity, UT Health San Antonio.", "comparators": "lifestyle counselling alone", "endpointType": "imaging/physiological surrogate", "notes": "VERY LOW/LOW grade (audit-downgraded from the open-label-RCT rule grade): n=20, pilot, unblinded assessors, whole-body BMD NS, the directional bone-loss trend did not reach significance, and the supportive r=0.62 is a single post-hoc regional correlation. Supports the weight-mediated reading WITHOUT establishing it; do not over-read the r=0.62. Note the paper itself REPEATS the unverified '~5-fold hip/pelvic fracture in 75+ (SELECT)' figure in its discussion - that magnitude is NOT encoded here (open question OQ-BMD-B).", "crossRef": "C-CLASS-BONE-MECH-RCT-01", "grade": "low", "source": { "citation": "Dinkla L, Beavers KM, Robbins R, ... Trejo J, Stepanenko A, Cortes TM, et al. Bone mineral density and turnover response to GLP-1 receptor agonists in older adults with overweight/obesity and prediabetes/type 2 diabetes: a 20-week pilot trial analysis. Front Aging 2025;6:1691007 (PMID 41393101 / PMC12695752).", "url": "https://doi.org/10.3389/fragi.2025.1691007", "identifiers": "DOI:10.3389/fragi.2025.1691007", "date": 2025, "design": "open-label RCT", "maturity": "human-primary", "funding": "academic/government (NIH/NIA + San Antonio VA GRECC + Colorado CCTSI; no industry sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-BONE-TURNOVER-01", "sourceId": "PMID39985672", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Same 25-RCT meta (T2D): beta-CTX (resorption) reported down and P1NP/osteocalcin (formation) up - a favourable-LOOKING turnover profile in T2D. CONTESTED/refuted as a generalisable bone-building effect: the direct double-blind weight-loss RCT shows the opposite (CTX UP, P1NP null).", "finding": "In T2D, the meta reports a favourable-looking turnover shift (beta-CTX down, formation markers up), but this is CONTESTED as a generalisable bone-building effect - likely low-turnover diabetic-bone normalisation. It is directly contradicted by the Hansen double-blind RCT in weight-losing adults (CTX UP, P1NP null) and so must NOT be read as a class anabolic effect.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "REMEDIATED (WI-BMD-01): the favourable-turnover reading is re-scoped to a CONTESTED T2D-specific pole and explicitly REFUTED as a generalisable anabolic effect by the WI-BMD-01 deep-research pass. Most plausibly normalising low-turnover diabetic bone, NOT bone-building; directly OPPOSED by the direct double-blind weight-loss RCT (Hansen, C-CLASS-BONE-MECH-RCT-01: resorption marker CTX UP, formation marker P1NP null, BMD down) and the obesity BMD-loss cohorts. Do NOT transfer to the rapid-weight-loss obesity setting.", "crossRef": "C-CLASS-SAFETY-BONE16; C-CLASS-BONE-MECH-RCT-01", "grade": "moderate", "source": { "citation": "GLP-1 RA bone density and turnover (25-RCT meta-analysis), Acta Diabetol 2025", "url": "https://doi.org/10.1007/s00592-025-02468-5", "identifiers": "DOI:10.1007/s00592-025-02468-5", "date": 2025, "design": "meta-analysis", "maturity": "review", "funding": "academic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CARDIO-01", "sourceId": "PMID34425083", "drug": "GLP-1 receptor agonist class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class meta-analysis)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.86 (95% CI 0.80-0.93; P<0.0001); all-cause death HR 0.88 (0.82-0.94); HF hospitalisation HR 0.89 (0.82-0.98); kidney composite HR 0.79 (0.73-0.87). 8 trials, 60,080 patients. No heterogeneity by structural homology.", "finding": "Class-level meta-analysis of 8 GLP-1RA CVOTs in T2D: ~14% MACE reduction, with consistent reductions in each MACE component, all-cause mortality, HF hospitalisation and a kidney composite; no significant heterogeneity by structural homology or eight other subgroups.", "population": "Systematic review and random-effects meta-analysis of 8 placebo-controlled GLP-1RA CVOTs (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, REWIND, PIONEER-6, AMPLITUDE-O); PROSPERO CRD42021259711.", "comparators": "placebo (pooled across constituent trials)", "endpointType": "hard-outcome", "notes": "Class anchor: the ~14% MACE RRR headline. Graded MODERATE per the meta-analysis default rule even though constituents are pivotal CVOTs. STALE-ANCHOR caveat (Council): this is a 2021-vintage pool that pre-dates SELECT (2023), FLOW (2024) and SOUL (2025), so it excludes the non-diabetic-obesity trial most relevant to retatrutide; the 0.86 should NOT be cited as the current class figure. LUMP-NOT-SPLIT caveat: 'no significant heterogeneity by structural homology' is a power statement over sparse-event trials, NOT proof the two null constituents (ELIXA, EXSCEL) are noise; pooling is a value choice. TRANSFER caveat: homology homogeneity is WITHIN the GLP-1RA class and says nothing about molecules adding GIP or glucagon agonism; do not use the 14% RRR as a retatrutide expectation. Per-study COI not individually audited.", "crossRef": "C-LIXI-CARDIO-01; C-EXEN-CARDIO-01; C-ALBI-CARDIO-01; C-EFPE-CARDIO-01", "grade": "moderate", "source": { "citation": "Sattar N, Lee MMY, Kristensen SL et al., Lancet Diabetes Endocrinol, 2021", "url": "https://doi.org/10.1016/S2213-8587(21)00203-5", "identifiers": "PMID34425083", "date": "2021-10-01", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent - no funding (Funding: None)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-01", "sourceId": "PMID41058240", "drug": "tirzepatide / semaglutide (target-trial emulation)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 and GIP/GLP-1 receptor agonists", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "mixed", "magnitude": "Incident AUD vs DPP4i: tirzepatide HR 0.47 (0.29-0.75); semaglutide HR 0.68 (0.52-0.89); liraglutide and dulaglutide NOT significant. Head-to-head tirzepatide vs liraglutide HR 0.47 (0.24-0.92).", "finding": "ADDICTION (alcohol) - a within-class gradient: in a target-trial-emulation EHR study, tirzepatide and semaglutide (but NOT liraglutide or dulaglutide) were associated with lower incident AUD vs DPP-4 inhibitors, suggesting potency or GIP co-agonism may matter (an open question, not a verdict).", "population": "Henney target-trial-emulation observational cohort (US EHR >120M): T2D without prior AUD, propensity-matched vs DPP4i; tirz n=7165, sema n=20198, lira n=6565, dula n=19061; 18 months.", "comparators": "DPP-4 inhibitors; semaglutide; liraglutide; dulaglutide", "endpointType": "other", "notes": "The only tirzepatide alcohol signal + a within-class ordering (newer/more-potent agents significant, older not). Target-trial emulation strengthens design but does NOT remove confounding-by-indication -> LOW. NOTE the species/substrate discrepancy: liraglutide is NULL for human ALCOHOL use disorder here but reduces rodent NICOTINE self-administration (mechanism row) - flag, do not resolve. CHANNELLING (Council): the within-class ordering CO-VARIES with drug recency/channelling (newer tirz/sema prescribed to systematically different patients), so the GIP-co-agonism vs potency vs residual-confounding explanations are NOT separable here - hypothesis only, NOT a GIP attribution, and must NOT pre-position reta's GIP arm as protective. Direction tagged 'mixed' (two of four agents null). VALIDATOR: confirm PMID 41058240.", "crossRef": "C-SEMAGLUTIDE-CNS-02; C-CLASS-CNS-03", "grade": "low", "source": { "citation": "Henney AE, Riley DR, Heague M et al., Diabetes Obes Metab, 2025", "url": "https://doi.org/10.1111/dom.70169", "identifiers": "PMID41058240", "date": "2025-10-07", "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator-initiated (Henney et al., University of Liverpool; EHR target-trial emulation)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-02", "sourceId": "PMID39415416", "drug": "GLP-1 / GIP receptor agonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 and GIP/GLP-1 receptor agonists", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "In OUD: opioid overdose adjusted IRR 0.60 (95% CI 0.43-0.83); in AUD: alcohol intoxication aIRR 0.50 (0.40-0.63) [these two verified against PMID 39415416]. A SEPARATE same-group exploratory OUD+AUD-comorbid cohort (Commun Med 2026) reported lower all-drug overdose (aHR ~0.61) - folded as corroborating, NOT part of this PMID.", "finding": "ADDICTION (opioid/cross-substance): in large EHR cohorts of patients with opioid or alcohol use disorder, GIP/GLP-1 receptor agonist prescriptions were associated with lower rates of opioid overdose and alcohol intoxication. The opioid evidence is OBSERVATIONAL-ONLY (no OUD RCT exists).", "population": "Qeadan EHR cohorts (Oracle/Cerner, >100M): N=503,747 OUD + 817,309 AUD (2014-2022); plus an exploratory N=107,217 OUD+AUD-comorbid cohort.", "comparators": "no GIP/GLP-1 RA prescription", "endpointType": "other", "notes": "Extends the signal to OPIOID overdose - but observational-only (no OUD RCT), LOW (confounding-by-indication, coded events, mixed-agonist exposure, some wide CIs). Two further same-group cohorts (overdose/hospitalisation; methadone-OUD remission + lower depression/anxiety/suicidality) folded here as corroborating low-grade observational. VALIDATOR: confirm PMID 39415416.", "crossRef": "C-CLASS-CNS-01; C-CLASS-CNS-05", "grade": "low", "source": { "citation": "Qeadan F, McCunn A, Tingey B, Addiction, 2025 (+ exploratory OUD+AUD cohort, Commun Med 2026)", "url": "https://doi.org/10.1111/add.16679", "identifiers": "PMID39415416", "date": "2024-10-16", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "few events/wide CI; possible confounding by indication; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-03", "sourceId": "PMID37295046", "drug": "GLP-1 RA class (rodent reward-circuit mechanism)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (preclinical)", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Rodent (qualitative): semaglutide reduced alcohol intake + relapse-like drinking, reached the nucleus accumbens, and blunted alcohol-evoked NAcc dopamine release + hyperlocomotion; liraglutide attenuated nicotine self-administration and cue/priming-induced reinstatement.", "finding": "ADDICTION MECHANISM (RODENT, not human): GLP-1RAs act on the mesolimbic reward circuit - semaglutide reaches the nucleus accumbens and reduces alcohol-evoked dopamine release (the canonical reward signal) and intake/relapse; liraglutide reduces nicotine self-administration and relapse-like reinstatement. A biologically-plausible substrate (in rodents) for the human craving/consumption signals - plausibility only, NOT shown to be the operative human mechanism, and it does NOT raise the grade of the human observational rows it is cross-referenced from.", "population": "Rats and mice (Aranas semaglutide-alcohol; Herman liraglutide-nicotine); self-administration / microdialysis / locomotion models.", "comparators": "vehicle/saline", "endpointType": "other", "notes": "RODENT PRIMARY - NOT a human result (flagged). SOURCE PRECISION (validation): the semaglutide/alcohol/NAcc-dopamine content is verified against PMID 37295046 (Aranas); the liraglutide/nicotine self-administration content is a SEPARATE paper (Herman RJ et al., Psychopharmacology 2023, PMID 37129617), folded here. The reward-circuit mechanism (NAcc dopamine) convergent with the human exenatide fMRI/DAT data. Species/endpoint discrepancy: liraglutide reduces rodent nicotine self-administration yet is NULL for human AUD (C-CLASS-CNS-01) - flag, do not resolve. VALIDATOR: confirm PMID 37295046 is rodent semaglutide-alcohol.", "crossRef": "C-EXENATIDE-CNS-01; C-CLASS-CNS-01", "grade": "very-low", "source": { "citation": "Aranas C et al., EBioMedicine, 2023 (semaglutide/alcohol/NAcc dopamine); Herman RJ et al., Psychopharmacology, 2023 (liraglutide/nicotine)", "url": "https://doi.org/10.1016/j.ebiom.2023.104642", "identifiers": "PMID37295046", "date": "2023-06-07", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic (Aranas/Herman rodent neuroscience groups; no sponsor disclosure extracted)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-04", "sourceId": "PMID41994910", "drug": "GLP-1 receptor agonist (class, epidemiology + mechanism)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Incident Parkinson's: 5.2 (GLP-1RA) vs 8.0 (sulfonylurea) per 10,000 person-years; adjusted HR 0.81 (95% CI 0.68-0.96); 2-year lag HR 0.84 (0.70-1.02); DPP4i-censored HR 0.74 (0.60-0.93).", "finding": "NEURODEGENERATION - the EPIDEMIOLOGY pole (in tension with the negative RCTs): in a Scandinavian active-comparator cohort, GLP-1RA use was associated with lower incident Parkinson's than sulfonylurea use. This is a lower-INCIDENCE association in diabetics (exposure 73% liraglutide), NOT disease modification - the randomised tests (exenatide PD ph3, EVOKE) were NEGATIVE, and reverse causation (prodromal disease reducing drug initiation) is a MATERIAL threat. The mechanistic rationale (brain GLP-1 receptors; reduced amyloid/tau, neuroinflammation; improved central insulin signalling in rodent models) is preclinical and did NOT translate to disease modification in the human RCTs.", "population": "Engstrom Scandinavian cohort (DK/NO/SE registers): N=158,961 new GLP-1RA vs 188,065 new sulfonylurea users, age >=45; exposure dominated by liraglutide (73%).", "comparators": "sulfonylureas", "endpointType": "other", "notes": "THE EPIDEMIOLOGY POLE. Honest read: lower PD/dementia incidence in DIABETIC GLP-1 users (a prevention/risk signal) does NOT imply disease modification once disease is established (the RCTs - exenatide PD ph3, EVOKE - were negative). Observational -> LOW (confounding-by-indication, reverse causation, exposure liraglutide-dominated). The rodent neuroprotection mechanism is folded here, flagged rodent-only/not-human. VALIDATOR: confirm PMID 41994910.", "crossRef": "C-EXENATIDE-CNS-04; C-SEMAGLUTIDE-CNS-04", "grade": "low", "source": { "citation": "Engstrom A, Svanstrom H, Hviid A et al., Diabetes Obes Metab, 2026 (Scandinavian PD cohort)", "url": "https://doi.org/10.1111/dom.70760", "identifiers": "PMID41994910", "date": "2026-04-17", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-05", "sourceId": "PMID40105856", "drug": "GLP-1 / incretin class (psychiatric-safety consolidation)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 / GIP-GLP-1 / incretin receptor agonists", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "no-change", "magnitude": "Pooled RCT suicide/self-harm RR 0.76 (95% CI 0.48-1.21); FDA 91-trial meta-analysis no increase; EMA PRAC no causal link; a 2026 synthesis: observational suicidality OR 0.34 vs RCT RR 1.13 (NS, the confounding-by-indication illustration); RCT depression/anxiety did not worsen.", "finding": "PSYCHIATRIC SAFETY - consolidated verdict (cross-refs the existing safety-other MH rows, not re-gathered): the suicidality/self-harm signal was INVESTIGATED by regulators (EMA PRAC, FDA) and LARGELY CLEARED in RCT and meta-analytic data (FDA removed the suicidal-ideation warning from liraglutide/semaglutide-2.4/tirzepatide labels), with residual pharmacovigilance (FAERS/VigiBase) noise and confounding-by-indication in observational data; RCT depression/anxiety symptoms did not increase.", "population": "Adults with T2D/obesity across the class; regulatory reviews, the STEP/SURMOUNT RCT programmes, RCT + observational meta-analyses (27-RCT pool; 82-study synthesis), pharmacovigilance databases.", "comparators": "placebo; active comparators; non-GLP-1 anti-obesity medications", "endpointType": "other", "notes": "NEUTRAL consolidation; cross-refs (does NOT re-mint) the existing MH rows. Reassuring pole: EMA PRAC C-CLASS-SAFETY-MH01, FDA label-removal MH02, STEP PHQ-9 MH09, SURMOUNT C-SSRS MH08, FAERS nulls MH05/06/07, + the new 27-RCT null (RR 0.76). Cautionary/noise pole: VigiBase increased ROR for ideation MH04, per-agent FAERS ROR MH06, the cohort body MH10. The observational-vs-RCT suicidality gap (OR 0.34 vs RR 1.13) is itself a confounding-by-indication demonstration. Retatrutide NOT covered (see reta gap). VALIDATOR: confirm PMID 40105856 (RR 0.76) and 41862354.", "crossRef": "C-CLASS-SAFETY-MH01; C-CLASS-SAFETY-MH02; C-CLASS-SAFETY-MH04; C-CLASS-SAFETY-MH05; C-TIRZ-SAFETY-MH08; C-SEMA-SAFETY-MH09; C-CLASS-SAFETY-MH10; C-RETATRUTIDE-CNS-01", "grade": "very-low", "source": { "citation": "Consolidation of existing safety-other MH rows; new RCT-pooled suicidality meta-analysis Ebrahimi et al., JAMA Psychiatry 2025; broad neuropsychiatric synthesis Choudhury et al., Clin Ther 2026 (PMID 41862354)", "url": "https://doi.org/10.1001/jamapsychiatry.2025.0091", "identifiers": "PMID40105856", "date": "2025-09-01", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-ALCOHOL-ACUTE-01", "sourceId": "PMID41093891", "drug": "GLP-1-based class (acute-alcohol folk-claim verdict; reta-emphasised)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "n/a", "magnitude": "The ONLY human alcohol-challenge study (Quddos 2025, n=20 pilot, non-randomised, 1:1 GLP-1RA users vs controls) found GLP-1 users had LOWER and DELAYED breath alcohol and reduced subjective intoxication (abstract-confirmed direction; the specific breath-alcohol figures e.g. ~0.021 vs ~0.037 are from the full text) and rated themselves LESS intoxicated per drink - the OPPOSITE of 'hits like three'. Classic physiology: delayed gastric emptying LOWERS peak blood-alcohol (aspirin, dietary fat). A rat interoception study (Windram 2025, incl. retatrutide) found alcohol felt LESS like alcohol.", "finding": "FOLK-CLAIM VERDICT ('one drink hits like three' / wrecked alcohol tolerance, described as near-universal for retatrutide): NOT SUPPORTED, likely FALSE as stated - and DISTINCT from the real, separately-evidenced reduced-craving effect. The only human alcohol-challenge data show LOWER blood-alcohol and LESS intoxication per drink, and the gastric-emptying physiology points the same way. The lived experience is better explained by drinking on a near-empty stomach, far lower desire (stopping at one), GI upset making a drink unpleasant fast, and (chronically) a smaller body-water volume from weight loss - none of which is 'higher blood alcohol per drink'. NO retatrutide-specific human alcohol data exist; the reta-specificity is a community-reporting artefact.", "population": "One human alcohol-challenge PK pilot (n=20, non-randomised); gastric-emptying/alcohol-PK physiology literature; one rat alcohol-interoception study (incl. retatrutide).", "comparators": "non-GLP-1 controls", "endpointType": "other", "notes": "GRADE low/very-low (single small non-randomised human pilot + physiology + rat data) - but the verdict is a DEBUNK: the only direct measurement contradicts the folk claim. Keep DISTINCT from the reduced-alcohol-CRAVING evidence (C-SEMAGLUTIDE-CNS-01 Hendershot RCT; C-EXENATIDE-CNS-01; C-SEMAGLUTIDE-CNS-02 Wang EHR), which is real-but-emerging and points the SAME way behaviourally (people drink less) but for a different (reward) reason. Folk-claim frequency: EXTREMELY COMMON (Part-1 craving) + near-universal-for-reta (Part-2 acute, the false part).", "crossRef": "C-SEMAGLUTIDE-CNS-01; C-EXENATIDE-CNS-01; C-SEMAGLUTIDE-CNS-02", "grade": "low", "source": { "citation": "Quddos F et al. GLP-1 receptor agonists and acute alcohol pharmacokinetics/subjective effects (alcohol-challenge pilot). Sci Rep 2025 (PMID 41093891); + Windram J et al., Psychopharmacology 2025 (PMID 40699363, rat interoception incl. retatrutide).", "url": "https://doi.org/10.1038/s41598-025-17927-w", "identifiers": "PMID41093891", "date": "2025-10-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator-initiated (Quddos et al., alcohol-challenge pilot)", "scopeLimits": "animal data; human relevance uncertain; small sample (N~20)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-COMPULSIONS-01", "sourceId": "PMID36066977", "drug": "GLP-1-based class (non-food compulsions folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "The food/alcohol reward base is real (mesolimbic dopamine; the exenatide AUD RCT reduced heavy-drinking days + striatal reward reactivity in the obese subgroup). For gambling, compulsive buying and body-focused repetitive behaviours (nail-biting, skin-picking, hair-pulling): NO completed RCT with any such primary endpoint; a skin-picking pharmacology scoping review (13 studies) does not list GLP-1s at all. Supporting evidence is social-media/self-report only.", "finding": "FOLK-CLAIM VERDICT ('reduces compulsive behaviours - shopping, gambling, nail-biting, skin-picking, hair-pulling'): MIXED - the food/alcohol reward base is real and mechanistically grounded (MATCHED to D5), but the GENERALISATION to non-consummatory compulsions (gambling, shopping, BFRBs) is UNPROVEN: zero RCTs, social-media/self-report only, plausible shared mesolimbic substrate but not demonstrated. This is belief running ahead of the evidence - and there is a counter-pole (a semaglutide-associated manic-episode case report), so the neuropsychiatric effect is not uniformly 'calming'.", "population": "Exenatide AUD RCT (reward base) + a Reddit/social-media compulsive-behaviour study + a skin-picking pharmacology review (GLP-1 absent); no controlled trial in gambling/shopping/BFRBs.", "comparators": "placebo", "endpointType": "other", "notes": "GRADE: reward base moderate (RCT, though primary-negative with a subgroup signal); the generalisation is very-low (social-media only). Belief-vs-reality: drug-driven reduction is demonstrated only for CONSUMMATORY reward (food; partially alcohol); for gambling/shopping/BFRBs it is anecdote + a credible-but-untested mechanism. Do NOT present the non-food generalisation as established. Cross-ref the alcohol/addiction rows (D5).", "crossRef": "C-SEMAGLUTIDE-CNS-01; C-EXENATIDE-CNS-01; C-CLASS-CNS-ALCOHOL-ACUTE-01", "grade": "low", "source": { "citation": "Klausen MK, Jensen ME, Moller M et al., JCI Insight, 2022", "url": "https://doi.org/10.1172/jci.insight.159863", "identifiers": "PMID36066977", "date": "2022-10-10", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-DREAMS-01", "sourceId": "PMID39226070", "drug": "GLP-1-based class (vivid-dreams folk claim; semaglutide-named)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "incretin / GLP-1-based", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "n/a", "magnitude": "'Abnormal dreams' is not a reported endpoint/notable AE in the semaglutide phase-3 programme; the pooled STEP 1/2/3/5 psychiatric-safety post-hoc (Wadden 2024) tracking psychiatric + nervous-system AEs does not surface it. A targeted search for GLP-1 + polysomnography/REM/parasomnia/nightmares returned zero drug-specific studies. A post-marketing spontaneous-report-database screen of oral semaglutide (Xiong 2024, 93 preferred terms) shows no dream/parasomnia signal. Manufacturer (Novo): 'abnormal dreams' reports <0.1 per 100 patient-years, with no cause-effect relationship established.", "finding": "FOLK-CLAIM VERDICT ('vivid/bizarre Ozempic dreams'): UNPROVEN / essentially anecdotal. There is no randomised-trial endpoint, no sleep-architecture (PSG) study, and only a sub-0.1/100-patient-year uncoded spontaneous-report trickle with an explicit no-causation caveat; post-marketing spontaneous-report screening is dream-silent. More parsimonious benign explanations (REM rebound from improved sleep/OSA resolution, nocturnal hypoglycaemia in the diabetic subset, recall/attention bias and social contagion around a viral named phenomenon) are unproven but more likely than a direct dream-generating drug effect.", "population": "Pooled STEP 1/2/3/5 semaglutide psychiatric-safety post-hoc analysis (Wadden 2024, the anchor source); corroborated by a post-marketing spontaneous-report screen and the manufacturer spontaneous-report rate.", "comparators": "placebo", "endpointType": "other", "notes": "GRADE floored to low via robustness_override (absence-of-signal verdict; the author's working note read very-low, but a one-tier override below the moderate post-hoc source is the permitted structural floor). Anchored on ABSENCE of signal in controlled + post-marketing data and a sub-0.1/100-PY uncoded rate. Belief-vs-reality: the experience is real for some, but the causal story ('the drug makes you dream vividly') is unsupported - no trial endpoint, no PSG study, no causal attribution. A genuine GAP recorded as UNPROVEN/anecdotal. Cross-ref the mood verdict (Thread 13 / D5 covers the suicidality/depression question, which is MATCHED and net-reassuring).", "crossRef": "C-CLASS-CNS-05", "grade": "moderate", "source": { "citation": "Wadden TA et al., JAMA Intern Med 2024 (STEP 1/2/3/5 psychiatric post hoc)", "url": "https://doi.org/10.1001/jamainternmed.2024.4346", "identifiers": "PMID 39226070; DOI 10.1001/jamainternmed.2024.4346", "date": "2024-08-26", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-CNS-SMOKING-FOLK-01", "sourceId": "PMID33831213", "drug": "GLP-1-based class (smoking-cessation folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Pilot RCT (Yammine 2021): extended-release exenatide + nicotine patch vs patch alone (n=84): abstinence 46.3% vs 26.8% (RR 1.70; Bayesian PP 96.5%, credible interval crossing 1), reduced craving/withdrawal and less post-cessation weight gain. EHR target-trial emulation (Wang 2024, n=222,942 T2D): semaglutide initiators had lower tobacco-use-disorder healthcare encounters vs other antidiabetics (HR 0.88 vs other GLP-1RAs; 0.68 vs insulin), emerging within 30 days. A larger confirmatory exenatide RCT (NCT05610800, n=216) is ongoing.", "finding": "FOLK-CLAIM VERDICT ('smoking/nicotine cessation or reduction'): UNPROVEN-but-PROMISING (do not call it TRUE). One small positive pilot RCT (exenatide) + a consistent semaglutide EHR signal + preclinical nicotine-reward data make it biologically coherent and encouraging, but there is no adequately powered confirmatory trial (one is ongoing). Likely a class effect but unproven as such; the EHR data are observational (no actual smoking-status data).", "population": "Pilot exenatide+patch RCT (n=84) + semaglutide EHR target-trial emulation (n=222,942); confirmatory RCT pending.", "comparators": "placebo; nicotine patch alone", "endpointType": "other", "notes": "GRADE moderate for the pilot RCT (small, 6-wk endpoint, CI crossing 1); the EHR signal is low (observational). Partly MATCHED (the exenatide addiction RCTs are in D5); this adds the smoking-cessation verdict + the semaglutide TUD EHR. Belief-vs-reality: genuinely promising and biologically coherent, but confirmatory RCTs are pending - promising, not proven.", "crossRef": "C-EXENATIDE-CNS-02; C-SEMAGLUTIDE-CNS-02", "grade": "high", "source": { "citation": "Yammine L, Green CE, Kosten TR et al., Nicotine Tob Res, 2021", "url": "https://doi.org/10.1093/ntr/ntab066", "identifiers": "PMID33831213", "date": "2021-08-29", "design": "double-blind RCT", "maturity": "human-primary", "funding": "academic / NIH - UTHealth Center for Clinical and Translational Sciences (NIH CTSA) + PARTNERS Research Awards; no industry sponsor (prior 'AstraZeneca' inference was WRONG)", "scopeLimits": "small sample (N~84)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-COMPARE-STRENGTH-FOLK-01", "sourceId": "PMID40353578", "drug": "comparative (reta vs tirzepatide vs semaglutide strength hierarchy)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 mono vs GIP/GLP-1 dual vs triple", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "n/a", "magnitude": "Best mean weight loss: retatrutide -24.2% (12 mg, phase-2, 48 wk, STILL DESCENDING); tirzepatide -20.9% (SURMOUNT-1, phase-3, 72 wk); semaglutide -14.9% (STEP-1, phase-3, 68 wk). The ONLY head-to-head, SURMOUNT-5: tirzepatide -20.2% vs semaglutide -13.7% (P<0.001).", "finding": "FOLK-CLAIM VERDICTS (strength hierarchy): (1) 'reta > tirz > sema' = TRUE directionally, OVERSTATED on certainty - the tirz>sema rung is head-to-head proven (SURMOUNT-5), but reta's #1 rank rests entirely on CROSS-TRIAL inference from a single phase-2 trial (no reta-vs-tirz head-to-head exists); the direction is very likely right, the certainty is not established (TRIUMPH phase-3 will settle it). (2) 'tirz is stronger than sema' = TRUE (SURMOUNT-5). (3) 'sema stopped working' = FALSE as a mechanism - it is a sustained plateau + a lower efficacy ceiling than tirzepatide, not tachyphylaxis; switching benefit is real but is ceiling-access, not tolerance-escape. (4) 'reta is DIFFERENT, not just stronger' = TRUE - it is a TRIPLE agonist; the glucagon arm adds effects the dual/mono agents lack (liver-fat clearance, energy expenditure, the HR rise, dysesthesia), so it is not 'tirzepatide at a higher dose'.", "population": "Cross-trial comparison of the pivotal weight-loss trials + the one head-to-head (SURMOUNT-5).", "comparators": "semaglutide; tirzepatide; retatrutide", "endpointType": "other", "notes": "GRADE: high for tirz>sema (head-to-head RCT); moderate-to-low for reta>tirz (phase-2 single-trial cross-trial inference - carries the standing reta phase-2/cross-trial confidence discount). Belief-vs-reality: the community states all three rungs as settled; only the bottom rung is head-to-head proven, reta's top rank is confident-but-unproven inference, and the 'sema stopped working' framing mislabels a ceiling/plateau as tolerance. The 'reta is different not just stronger' intuition is correct. MATCHED to comparative-efficacy + the per-mechanism threads.", "crossRef": "C-COMPARE-12; C-TIRZ-VS-SEMA-TOLGI-01; C-RETATRUTIDE-SAFETY-DYSESTHESIA-01", "grade": "moderate", "source": { "citation": "Aronne LJ, et al. N Engl J Med 2025 (SURMOUNT-5); presented ECO 2025", "url": "https://doi.org/10.1056/NEJMoa2416394", "identifiers": "PMID 40353578; DOI 10.1056/NEJMoa2416394; NCT05822830", "date": "2025-07-03", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-FERTILITY-PCOS-CONCEPTION-01", "sourceId": "PMID40713699", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "increase", "magnitude": "PCOS open-label RCT (n=100): semaglutide+metformin natural pregnancy 35% vs 15% (metformin alone), with menstrual recovery and testosterone reduction.", "finding": "In a PCOS RCT, adding semaglutide to metformin raised the natural pregnancy rate (35% vs 15%) in anovulatory women.", "population": "PCOS open-label RCT (NCT not stated; Reprod Biol Endocrinol 2025): 100 overweight/obese women with PCOS (Rotterdam criteria), prospective randomised controlled open-label trial of semaglutide 1 mg weekly plus metformin vs metformin alone, 16 weeks.", "comparators": "", "endpointType": "womens-health", "notes": "WEIGHT/OVULATION-MEDIATED in a PCOS-anovulatory population (a channel absent in already-ovulatory women); open-label, small. Context-distinct from the general fertility-care cohort - the honest compendium statement is that the effect on fertility is context-dependent, not one-way.", "crossRef": "C-CLASS-FERTILITY-SEMA-IVFPRETREAT-01", "grade": "moderate", "source": { "citation": "Semaglutide+metformin in PCOS (open-label RCT, n=100), Reprod Biol Endocrinol 2025", "url": "https://doi.org/10.1186/s12958-025-01447-3", "identifiers": "DOI:10.1186/s12958-025-01447-3", "date": 2025, "design": "open-label RCT", "maturity": "human-primary", "funding": "academic/government - Chinese government and institutional grants (Chongqing Health Commission/Science & Technology Bureau; NSFC; not industry)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-FERTILITY-SEMA-IVFPRETREAT-01", "sourceId": "PMID42001071", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "Retrospective PSM cohort (n=1936): semaglutide pretreatment before fertility care associated with LOWER/delayed clinical-pregnancy and live-birth; miscarriage unchanged.", "finding": "In a matched real-world cohort, semaglutide pretreatment before fertility care was associated with reduced and delayed conception, with miscarriage unchanged.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "CONTEXT-DISTINCT, both-poled with the PCOS conception-up RCT (different population). This cohort signal is confounded by required washout/discontinuation timing and indication - NOT a demonstrated direct anti-fertility drug effect. Do not state a one-way 'GLP-1 harms fertility'.", "crossRef": "C-CLASS-FERTILITY-PCOS-CONCEPTION-01", "grade": "low", "source": { "citation": "Semaglutide pretreatment and fertility-care outcomes (PSM cohort), Reprod Biol Endocrinol 2026", "url": "https://doi.org/10.1186/s12958-026-01549-6", "identifiers": "DOI:10.1186/s12958-026-01549-6", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-FRACTURE-NMA-01", "sourceId": "PMID30083774", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Bayesian network meta-analysis (54 RCTs, 49,602 patients with T2D, 28,353 GLP-1-RA-treated): GLP-1 RAs associated with DECREASED fracture risk vs placebo; exenatide had the lowest point estimate (RR 0.17, 95% CI 0.03-0.67). Statistically significant inconsistency observed in some comparisons.", "finding": "A 2018 Bayesian network meta-analysis of 54 RCTs (49,602 T2D patients) found GLP-1 RAs were associated with decreased fracture risk versus placebo - an independent net-neutral-to-protective fracture pole, separate from the contested anabolic-BMD claim.", "population": "GLP-1 RA fracture network meta-analysis (Zhang et al., Osteoporos Int 2018; 54 RCTs, T2D, PROSPERO CRD42018094433).", "comparators": "placebo; other anti-hyperglycaemic drugs", "endpointType": "safety-event/signal", "notes": "SCOPE LIMIT: T2D RCTs, PREDATES the high-dose obesity agents (semaglutide 2.4 mg / tirzepatide / retatrutide) - does not speak to rapid-weight-loss bone effects. The 'exenatide ranked safest' sub-claim (and the agent ranking generally) is NOT established - encoded is only the NET protective direction, not the ranking (which rests on sparse fracture events and acknowledged network inconsistency). Provides an INDEPENDENT fracture pole so the net-neutral/protective read no longer rests solely on the contested PMID39985672. Opposes the older-adult-harm pole (C-CLASS-BONE-FRAC-ELDERLY-01) and the unverified SELECT 75+ concern (OQ-BMD-B).", "crossRef": "C-CLASS-BONE-FRAC-ELDERLY-01", "grade": "moderate", "source": { "citation": "Zhang YS, Weng WY, Xie BC, et al. Glucagon-like peptide-1 receptor agonists and fracture risk: a network meta-analysis of randomized clinical trials. Osteoporos Int 2018;29(12):2639-2644.", "url": "https://doi.org/10.1007/s00198-018-4649-8", "identifiers": "DOI:10.1007/s00198-018-4649-8", "date": 2018, "design": "network meta-analysis", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-HAIRLOSS-SEXSKEW-01", "sourceId": "PMID41914454", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Cross-sectional (n=254 users, 71% female): males adjusted OR 0.36 (p=0.003) vs females for reporting hair loss; severe worse with tirzepatide (Mounjaro aOR 3.02).", "finding": "GLP-1 RA-associated hair loss is markedly female-predominant (men about two-thirds less likely to report it), and more severe with tirzepatide.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Self-report, single-country; the female predominance is partly adjusted for the cohort skew. Quantifies the sex-skew beyond the SURMOUNT-1 ~7% vs ~0.5% datum. DEEPENS the alopecia row.", "crossRef": "C-CLASS-SAFETY-HAIRLOSS-01", "grade": "low", "source": { "citation": "GLP-1 RA hair-loss sex-skew (cross-sectional, n=254), J Cosmet Dermatol 2026", "url": "https://doi.org/10.1111/jocd.70835", "identifiers": "DOI:10.1111/jocd.70835", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-01", "sourceId": "PMID37328273", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "~30% per year of GLP-1 RA exposure lower serum ferritin (95% CI 20-40% simple model; 10-40% non-linear model) in T2D + hereditary haemochromatosis; effect largely independent of HH duration.", "finding": "In a Danish nationwide register of people with type-2 diabetes and hereditary haemochromatosis, each year of GLP-1 receptor agonist exposure was associated with roughly 30% lower serum ferritin - i.e. GLP-1 RAs are associated with LOWER iron stores, not higher.", "population": "Danish nationwide register (observational cohort), 439 people with hereditary haemochromatosis + type-2 diabetes, 6,529 ferritin measurements 2008-2021; only ~36 GLP-1-exposed contributing ~366 samples.", "comparators": "no GLP-1 RA treatment; SGLT-2 inhibitor", "endpointType": "safety-event/signal", "notes": "Single Danish nationwide register, ~36 GLP-1-exposed individuals; explicitly hypothesis-generating; 5 of 7 authors Novo Nordisk-affiliated. Direction (down) robust; magnitude fragile. Observational; possible confounding by indication.", "crossRef": "", "grade": "low", "source": { "citation": "Bain SC, Hansen TK et al. Glucose-lowering drugs and serum ferritin in haemochromatosis and type-2 diabetes: a Danish nationwide register study. BMJ Open Diabetes Res Care 2023.", "url": "https://doi.org/10.1136/bmjdrc-2022-003300", "identifiers": "PMID 37328273 / DOI 10.1136/bmjdrc-2022-003300 / PMC10277078", "date": "2023-06", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-02", "sourceId": "PMID37328273", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "SGLT-2 inhibitors RAISED ferritin (+23%/yr, 95% CI 13.1-33.7%) in the same register; GLP-1-vs-SGLT-2 reduction up to ~40% at year 4 of HH duration.", "finding": "In the same register, SGLT-2 inhibitors RAISED serum ferritin, so the headline GLP-1-vs-SGLT-2 gap (~40% at HH year 4) is partly a comparator artefact: part of the apparent GLP-1 'lowering' is relative to a drug that raises ferritin, which overstates GLP-1 lowering versus no treatment.", "population": "Danish nationwide register (observational cohort), people with hereditary haemochromatosis + type-2 diabetes; SGLT-2 inhibitor exposure arm.", "comparators": "GLP-1 RA; no treatment", "endpointType": "safety-event/signal", "notes": "The increase direction here is for SGLT-2i, not GLP-1; it bounds the magnitude of the GLP-1 lowering claim. Same single register; observational; hypothesis-generating.", "crossRef": "C-CLASS-IRON-01", "grade": "low", "source": { "citation": "Bain SC, Hansen TK et al. Glucose-lowering drugs and serum ferritin in haemochromatosis and type-2 diabetes: a Danish nationwide register study. BMJ Open Diabetes Res Care 2023.", "url": "https://doi.org/10.1136/bmjdrc-2022-003300", "identifiers": "PMID 37328273 / DOI 10.1136/bmjdrc-2022-003300 / PMC10277078", "date": "2023-06", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-03", "sourceId": "PMID37328273", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Mechanism not established; authors flag possible mediation via glycaemic control and body weight; model not adjusted for weight loss, CRP/inflammation, or HbA1c.", "finding": "The register study did NOT establish a mechanism for the lower ferritin; the authors flag possible mediation via glycaemic control and body weight, and the model did not adjust for weight loss, CRP/inflammation or HbA1c - so the association cannot yet be attributed to a direct iron-handling effect.", "population": "Danish nationwide register (observational cohort), people with hereditary haemochromatosis + type-2 diabetes.", "comparators": "no treatment", "endpointType": "safety-event/signal", "notes": "Mechanism unestablished; unadjusted for weight/CRP/HbA1c. Observational; hypothesis-generating.", "crossRef": "C-CLASS-IRON-01", "grade": "low", "source": { "citation": "Bain SC, Hansen TK et al. Glucose-lowering drugs and serum ferritin in haemochromatosis and type-2 diabetes: a Danish nationwide register study. BMJ Open Diabetes Res Care 2023.", "url": "https://doi.org/10.1136/bmjdrc-2022-003300", "identifiers": "PMID 37328273 / DOI 10.1136/bmjdrc-2022-003300 / PMC10277078", "date": "2023-06", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-04", "sourceId": "PMID41549912", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Narrative review: GLP-1 RA users 26-30% lower ferritin vs SGLT2i comparators; frequent iron depletion (>60% below DRI for iron); attributed to appetite suppression / delayed gastric emptying / altered absorption.", "finding": "A narrative review reports that GLP-1 RA users have 26-30% lower ferritin than SGLT2i comparators with frequent iron depletion, attributing it to appetite suppression, delayed gastric emptying and altered absorption.", "population": "Narrative review (Urbina et al., Clin Obes 2026) summarising GLP-1 RA iron-status literature.", "comparators": "SGLT-2 inhibitor", "endpointType": "safety-event/signal", "notes": "Secondary / narrative source; rests largely on the single Bain register. Confidence medium. Review, not primary data.", "crossRef": "C-CLASS-IRON-01", "grade": "low", "source": { "citation": "Urbina et al., GLP-1 receptor agonists and iron status, Clin Obes 2026;16:e70070", "url": "https://doi.org/10.1111/cob.70070", "identifiers": "PMID 41549912 / DOI 10.1111/cob.70070", "date": 2026, "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-05", "sourceId": "PMID40840939", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Counter-evidence: a 700-patient retrospective GLP-1 analogue cohort found NO significant ferritin change (haemoglobin fell 0.2 g/dL; 8.4% developed anaemia).", "finding": "The lowering effect is NOT universal: a 700-patient retrospective GLP-1 analogue cohort found no significant change in ferritin (haemoglobin fell 0.2 g/dL and 8.4% developed anaemia), which is counter-evidence to the class-wide ferritin-lowering claim.", "population": "700-patient retrospective observational cohort of GLP-1 analogue users (Saudi Med J 2025); ferritin a secondary endpoint.", "comparators": "baseline", "endpointType": "safety-event/signal", "notes": "Ferritin was a secondary endpoint with no p-value or magnitude reported; possible underpowering. Counter-evidence to C-CLASS-IRON-01. Observational cohort.", "crossRef": "C-CLASS-IRON-01", "grade": "low", "source": { "citation": "Effect of GLP-1 receptor agonists on haematological and iron indices: a retrospective cohort. Saudi Med J 2025;46(8):907-912.", "url": "https://pubmed.ncbi.nlm.nih.gov/40840939/", "identifiers": "PMID 40840939 / DOI 10.15537/smj.2025.46.8.20240100", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-IRON-06", "sourceId": "PMID41549912", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Interpretive key: ferritin is a positive acute-phase reactant; an elevated value may reflect inflammation rather than iron stores, and a FALL on these drugs may partly reflect resolving inflammation/steatosis rather than only iron depletion.", "finding": "Interpretive key bounding all direction findings: ferritin is a positive acute-phase reactant, so an elevated value may reflect inflammation not iron stores, and a fall during weight loss / reduced steatosis on these drugs may partly reflect resolving inflammation rather than only true iron depletion.", "population": "Narrative review (Urbina et al., Clin Obes 2026) plus acute-phase-reactant physiology (AASLD Liver Fellow Network; PMC2893236/PMC5878890/PMC5223018).", "comparators": "not applicable", "endpointType": "safety-event/signal", "notes": "Interpretive key; bounds the meaning of every direction finding in this cluster. Note AASLD Liver Fellow Network and PMC2893236/PMC5878890/PMC5223018. Review-level.", "crossRef": "", "grade": "low", "source": { "citation": "Urbina et al., GLP-1 receptor agonists and iron status, Clin Obes 2026;16:e70070", "url": "https://doi.org/10.1111/cob.70070", "identifiers": "PMID 41549912 / DOI 10.1111/cob.70070", "date": 2026, "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LACTATION-MILKTRANSFER-01", "sourceId": "PMID39275201", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "Semaglutide UNDETECTABLE in human milk (n=8, LC-MS); worst-case relative infant dose 1.26%, below the 10% threshold.", "finding": "A measured human-milk PK study found subcutaneous semaglutide undetectable in breast milk, with a worst-case relative infant dose of 1.26% - converting the lactation question from never-measured to measured-negligible FOR SEMAGLUTIDE.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "UPGRADES the label-only lactation rows. Caveats: n=8, single-dose sampling, no infant plasma levels or long-term outcomes. Non-semaglutide agents (tirz, lira, reta) remain never-measured for milk transfer.", "crossRef": "C-SEMA-LACTATION-US-01; C-TIRZ-LACTATION-US-01", "grade": "low", "source": { "citation": "Semaglutide human breast-milk transfer study (n=8), Nutrients 2024", "url": "https://doi.org/10.3390/nu16172886", "identifiers": "DOI:10.3390/nu16172886", "date": 2024, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LIBIDO-DULA-NULL-01", "sourceId": "PMID39232425", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "RCT (healthy lean eugonadal men, 4-wk crossover): dulaglutide null on sexual desire (MGH-SFQ +0.58, NS); testosterone/FSH/LH/sperm unchanged.", "finding": "Short-term dulaglutide did not alter sexual desire or the reproductive axis in healthy lean men.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "A counter-pole AGAINST a direct libido effect (no weight-loss confound in lean men). Narrow: lean, eugonadal, 4 weeks. Pairs with the existing libido verdict.", "crossRef": "C-CLASS-SAFETY-LIBIDO-01", "grade": "high", "source": { "citation": "Dulaglutide on male sexual function and HPG axis (RCT), EBioMedicine 2024", "url": "https://doi.org/10.1016/j.ebiom.2024.105284", "identifiers": "DOI:10.1016/j.ebiom.2024.105284", "date": 2024, "design": "double-blind RCT", "maturity": "human-primary", "funding": "academic-Swiss National Science Foundation and Swiss foundations", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LIBIDO-GLP1-INFUSION-NULL-01", "sourceId": "PMID32052032", "drug": "GLP-1 (native; physiology)", "drugRoot": "GLP-1 (native; physiology)", "drugSlug": "glp-1-native-physiology", "drugLabel": "GLP-1 (native; Physiology)", "drugClass": "native GLP-1", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Crossover RCT (acute 8-h GLP-1 infusion, healthy men): LH pulses, LH/FSH/testosterone all NS - contradicts rodent data.", "finding": "Acute GLP-1 infusion did not affect reproductive-hormone secretion in healthy men, contradicting rodent findings.", "population": "Acute single-blind randomised placebo-controlled crossover RCT (8-h GLP-1 infusion, healthy men; small acute mechanistic study).", "comparators": "placebo infusion", "endpointType": "womens-health", "notes": "Acute-only (not chronic agonist therapy); small mechanistic crossover; species-translation note (rodent-positive, human-null). A second counter-pole against a direct effect on the male axis.", "crossRef": "", "grade": "low", "source": { "citation": "Acute GLP-1 infusion on the male reproductive axis (crossover RCT), J Clin Endocrinol Metab 2020", "url": "https://doi.org/10.1210/clinem/dgaa072", "identifiers": "DOI:10.1210/clinem/dgaa072", "date": 2020, "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic-UK public (NIHR / MRC / Wellcome Trust / BBSRC / Imperial)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LIBIDO-LIRA-HYPOGONAD-01", "sourceId": "PMID30707677", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "increase", "magnitude": "Open-label RCT (n=30, obese hypogonadal men, 16 wk): liraglutide reversed obesity-related functional hypogonadism via HPG-axis (gonadotropin rise), unlike testosterone replacement; far greater weight loss.", "finding": "Liraglutide reversed obesity-related functional hypogonadism by restoring the HPG axis, unlike exogenous testosterone which suppresses it.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "WEIGHT/HPG-MEDIATED (the most mechanistically interesting male signal, but still in an obesity-weight context); small, open-label.", "crossRef": "", "grade": "moderate", "source": { "citation": "Liraglutide vs testosterone for obesity hypogonadism (open-label RCT, n=30), Endocr Connect 2019", "url": "https://doi.org/10.1530/EC-18-0514", "identifiers": "DOI:10.1530/EC-18-0514", "date": 2019, "design": "open-label RCT", "maturity": "human-primary", "funding": "academic / investigator - University Medical Centre Ljubljana grant P3-0298", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LIBIDO-TIRZ-ED-01", "sourceId": "PMID40604795", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "increase", "magnitude": "Controlled NON-randomised pilot (n=83, obese men, 2 mo): tirzepatide raised IIEF-5 and LH/FSH/SHBG/testosterone vs no-drug and transdermal-T arms.", "finding": "In obese men with metabolic hypogonadism, tirzepatide improved erectile function and raised testosterone, outperforming testosterone replacement on axis recovery.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "WEIGHT/TESTOSTERONE-CONFOUNDED and NON-randomised with baseline imbalances and self-report IIEF-5 - NOT a demonstrated direct drug effect; contradicted by the null RCT/infusion data. Graded low (non-randomised; not high).", "crossRef": "", "grade": "low", "source": { "citation": "Tirzepatide on erectile function and hypogonadism (controlled non-randomised pilot, n=83), Reprod Biol Endocrinol 2025", "url": "https://doi.org/10.1186/s12958-025-01425-9", "identifiers": "DOI:10.1186/s12958-025-01425-9", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-LIBIDO-TIRZ-ED-COHORT-01", "sourceId": "PMID40614622", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "TriNetX cohort (T2D men): lower incident ED with tirzepatide vs sitagliptin (RR 0.70), injectable semaglutide (0.67), dulaglutide (0.55).", "finding": "Tirzepatide was associated with lower incident erectile dysfunction than several comparators in T2D men.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Relative-to-comparator (not vs placebo); confounded by indication/weight; coding-based outcome. Weight/testosterone-mediated, consistent with the other male signals.", "crossRef": "", "grade": "low", "source": { "citation": "Tirzepatide and incident erectile dysfunction (TriNetX cohort), J Diabetes Complications 2025", "url": "https://doi.org/10.1016/j.jdiacomp.2025.109116", "identifiers": "DOI:10.1016/j.jdiacomp.2025.109116", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-01", "sourceId": "PMID22029981", "drug": "weight-loss physiology (diet-induced, drug-agnostic)", "drugRoot": "weight-loss physiology (drug-agnostic)", "drugSlug": "weight-loss-physiology-drug-agnostic", "drugLabel": "Weight-loss Physiology (drug-agnostic)", "drugClass": "weight-loss physiology (drug-agnostic mechanism)", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "After ~13.5 kg diet-induced loss, at 1 year significant persistent shifts from baseline: leptin down, PYY down, CCK down, insulin down, ghrelin up, plus increased subjective hunger (P 0.04 to <0.001).", "finding": "MECHANISM (set-point / why regain happens): one year after diet-induced weight loss, circulating appetite-regulating hormones remained shifted in a direction that favours regain (ghrelin up; leptin/PYY/CCK/insulin down) and had NOT reverted, with persistently increased hunger. The foundational human evidence that the body defends a higher weight via a durable orexigenic state.", "population": "Sumithran/Proietto (NCT00870259): N=50 overweight/obese adults without diabetes; 10-week very-low-energy diet; hormones at baseline, 10 wk, 62 wk.", "comparators": "within-subject baseline", "endpointType": "other", "notes": "Landmark human mechanistic study. CAVEAT: DIET-induced loss, NOT a drug result - the relevance to stopping a GLP-1 drug is that exogenous agonism is removed ON TOP of this endogenous orexigenic state. Small N=50, single-arm within-subject. Graded low (mechanistic context, drug-agnostic). VALIDATOR: confirm PMID 22029981.", "crossRef": "C-CLASS-MAINT-02; C-CLASS-MAINT-03", "grade": "moderate", "source": { "citation": "Sumithran P, Prendergast LA, Delbridge E et al., N Engl J Med, 2011", "url": "https://doi.org/10.1056/NEJMoa1105816", "identifiers": "PMID22029981", "date": "2011-10-27", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic/government - Australian NHMRC and others (not industry)", "scopeLimits": "small sample (N~50)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-02", "sourceId": "PMID27136388", "drug": "weight-loss physiology (diet/exercise-induced, drug-agnostic)", "drugRoot": "weight-loss physiology (drug-agnostic)", "drugSlug": "weight-loss-physiology-drug-agnostic", "drugLabel": "Weight-loss Physiology (drug-agnostic)", "drugClass": "weight-loss physiology (drug-agnostic mechanism)", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "decrease", "magnitude": "End of 30-wk competition: -58.3 kg, RMR fell 610 kcal/day. At 6 years: 41.0 kg regained, yet RMR still 704 kcal/day below baseline; metabolic adaptation -499 kcal/day; greater maintained loss correlated with greater metabolic slowing (r=0.59, P=0.025).", "finding": "MECHANISM (adaptive thermogenesis / set-point): six years after large weight loss, resting metabolic rate remained suppressed below baseline and metabolic adaptation persisted DESPITE substantial regain - direct human DXA-plus-calorimetry evidence that adaptive thermogenesis is durable and proportional to ongoing weight suppression.", "population": "Fothergill/Hall ('Biggest Loser'): N=14 of 16 competitors; DXA + indirect calorimetry at baseline, 30 wk, 6 yr.", "comparators": "within-subject baseline", "endpointType": "imaging/physiological surrogate", "notes": "The closest located human body-composition-across-a-loss-then-regain-cycle dataset (DXA at all three timepoints) and the durable-adaptive-thermogenesis evidence. CAVEAT: extreme-lifestyle cohort, very small N=14, diet/exercise NOT drug - the mechanistic analogue, not a drug result. A candidate rodent molecular mechanism (Ferrara, Life Metab 2023, PMID 37206438: post-loss skeletal-muscle mitochondrial efficiency rises ~50% via cardiolipin remodelling) is noted here as rodent-only, NOT human, NOT drug. Graded low. VALIDATOR: confirm PMID 27136388.", "crossRef": "C-CLASS-MAINT-01; C-CLASS-MAINT-04", "grade": "low", "source": { "citation": "Fothergill E, Guo J, Howard L et al., Obesity (Silver Spring), 2016", "url": "https://doi.org/10.1002/oby.21538", "identifiers": "PMID27136388", "date": "2016-05-02", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; small sample (N~14)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-03", "sourceId": "PMID41889156", "drug": "GLP-1 / incretin class (review)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA / dual incretin agonists (review)", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "Weight regain 60-90% within 1 year of stopping; cardiometabolic parameters return towards baseline by ~12-18 months. SEPARATELY (hypothesis-only, carries NO hard-CV-outcome weight): early discontinuation (<1 yr) was OBSERVATIONALLY associated with increased CAD and HF risk in real-world cohorts - high risk of confounding by indication AND reverse causation (sicker patients, or those developing events, stop early); no effect estimate or adjustment reported in this narrative synthesis.", "finding": "Class-level synthesis: a narrative review of randomised-withdrawal trials, meta-analyses and real-world cohorts (>289,000 patients) concludes that GLP-1RA discontinuation is followed by substantial weight regain (60-90% within a year) and parallel reversal of cardiometabolic benefits, attributed to reactivation of orexigenic pathways and adaptive thermogenesis. It also notes the absence of validated tapering strategies.", "population": "Narrative review of randomised-withdrawal trials, systematic reviews/meta-analyses and observational cohorts (>289,000 patients).", "comparators": "continued therapy", "endpointType": "other", "notes": "Class-level regain synthesis + mechanism framing, and the bridge to the metabolic-adaptation rows. Narrative (not systematic) review -> low; the early-discontinuation CAD/HF association is observational and ring-fenced as hypothesis-only (confounding by indication + reverse causation). DIET-vs-DRUG firewall (Council Species seat): the review's mechanistic attribution (orexigenic reactivation + adaptive thermogenesis) is largely extrapolated from DIET-induced human physiology (Sumithran/Fothergill); the drug-discontinuation case ALSO involves withdrawal of an exogenous agonist signal, so the diet-derived mechanism is suggestive, not established, for post-drug regain. Validation: PMID 41889156 confirmed (2026 GLP-1RA-discontinuation review, 60-90% regain).", "crossRef": "C-CLASS-MAINT-01; C-CLASS-MAINT-05", "grade": "low", "source": { "citation": "Shah E, AlShiab R, Abdo A et al., Diabetes Obes Metab, 2026", "url": "https://doi.org/10.1111/dom.70713", "identifiers": "PMID41889156", "date": "2026-03-26", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-04", "sourceId": "CIT:gap-synthesis-across-the-confirmed-d4-withdrawal", "drug": "GLP-1 / incretin class (evidence-gap)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA / dual / triple incretin agonists", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "n/a", "magnitude": "No drug-specific fat-vs-lean regain data located. Adjacent: incretin-class lean-mass loss during the LOSS phase ~25-40% of weight lost (D2 records); Biggest Loser shows DXA composition change across a non-drug cycle.", "finding": "EMERGING CONCERN / GAP: no published study measured body composition (DXA/MRI fat vs lean) across a complete loss-then-regain cycle ON a GLP-1/incretin drug, so whether regained weight is disproportionately FAT with lean mass incompletely restored is untested. The withdrawal trials report TOTAL weight regain only; the human composition-across-cycle evidence (Biggest Loser) is diet/exercise, not drug. The worry is biologically plausible and reinforced by documented incretin-class lean-mass loss during the loss phase (D2), but direct drug-specific data are absent.", "population": "Cross-study gap assessment across STEP-1 extension, STEP-4, SURMOUNT-4 (total weight only) and the metabolic-adaptation cohort.", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "DELIBERATE GAP-FLAG. Captures the 'a weight cycle worsens fat:lean ratio' concern as EMERGING with thin/absent direct human drug data. Anchors the open question; cross-ref D2 lean-mass loss (loss phase documented; regain-phase composition NOT). NOT a positive finding - records an absence. COUNCIL: rule whether a sourceless gap row belongs or should be an OQ only.", "crossRef": "C-CLASS-MAINT-02; D2 body-composition (C-CLASS-BODYCOMP-08)", "grade": "low", "source": { "citation": "Gap synthesis across the confirmed D4 withdrawal records (no single source reports drug-specific regain body composition)", "url": "", "identifiers": "n/a-gap-bodycomp-regain", "date": "2026-06-21", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-05", "sourceId": "CIT:gap-synthesis-corroborated-by-shah-e-et-al-diabe", "drug": "GLP-1 / incretin class (dosing-strategy gap)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA / dual / triple incretin agonists", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "n/a", "magnitude": "No data (documented absence). Available maintenance trials (STEP-4, SURMOUNT-4) test continued FULL maintenance dose vs placebo only.", "finding": "EVIDENCE GAP: no randomised trial of a LOWER maintenance dose or an INTERMITTENT / reduced-frequency incretin dosing schedule for sustaining weight loss was located. The maintenance trials prove FULL-dose continuation works but say nothing about whether a reduced or intermittent dose can hold weight off; the class discontinuation review explicitly notes no validated tapering strategies exist.", "population": "Gap assessment across STEP-4, SURMOUNT-4 and the GLP-1RA discontinuation review.", "comparators": "", "endpointType": "other", "notes": "DELIBERATE GAP-FLAG. Answers the decision-relevant 'can you taper / dose intermittently to maintain?' - NO published RCT evidence located (absence of evidence, not evidence of absence; such trials may be ongoing). Distinguish from STEP-4/SURMOUNT-4 (full-dose continuation works). COUNCIL: rule keep-as-row vs OQ-only.", "crossRef": "C-CLASS-MAINT-03; C-SEMAGLUTIDE-MAINT-01", "grade": "very-low", "source": { "citation": "Gap synthesis; corroborated by Shah E et al., Diabetes Obes Metab, 2026 (no validated tapering strategies)", "url": "", "identifiers": "n/a-gap-maintenance-dose", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "review", "funding": "not-stated", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-06", "sourceId": "PMID28489290", "drug": "obesity disease-framing (position statements)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "interpretive / position statement", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "n/a", "magnitude": "n/a (consensus/position statements).", "finding": "INTERPRETIVE NOTE (neutral framing): authoritative bodies frame obesity as a chronic, relapsing, progressive disease (World Obesity Federation; joint World Heart Federation / World Obesity Federation). This is the backdrop the withdrawal trials are read against: if obesity is chronic and relapsing, regain on stopping is the expected disease course and indefinite MAINTENANCE of some kind is implied (which could be pharmacological, surgical or intensive behavioural). The trials evidence only that DRUG continuation maintains DRUG-induced loss - NOT that lifelong drug therapy specifically is required or net-beneficial over a decade scale. Recorded as framing context, NOT a verdict on whether any individual should be on lifelong therapy.", "population": "World Obesity Federation position statement (2017) and joint WHF/WOF position paper (2022).", "comparators": "", "endpointType": "other", "notes": "Neutral interpretive note. The 'chronic relapsing disease' framing reframes regain-on-stopping as expected disease relapse rather than treatment failure. Graded low (position/consensus, not primary data). COI / INDEPENDENCE (Council Evidence-grader + Red-team): the WOF (2017) and WHF/WOF (2022) are obesity-medicine field bodies with substantial pharmaceutical-industry funding ties, and the position-statement authors OVERLAP with the sponsored withdrawal-trial author lists (e.g. Wilding, also lead author of STEP-1 / C-SEMAGLUTIDE-MAINT-02). The 'chronic disease -> continued therapy' framing is CONCORDANT with the manufacturers' commercial interest in continued treatment; treat as an interpretive stance, NOT independent evidence. Validation: PMID 28489290 + 36007112 confirmed.", "crossRef": "C-CLASS-MAINT-03", "grade": "low", "source": { "citation": "Bray GA, Kim KK, Wilding JPH (WOF), Obes Rev, 2017; companion WHF/WOF paper, Eur J Prev Cardiol, 2022 (PMID 36007112)", "url": "https://doi.org/10.1111/obr.12551", "identifiers": "PMID28489290", "date": "2017-05-10", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-ADHERENCE-01", "sourceId": "PMID38717042", "drug": "class (liraglutide, semaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (obesity indication)", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "Persistence (no >=60-day gap, switching allowed) 46.3% at 180 days and 32.3% at 1 year (~1 in 3 still on therapy; ~2 in 3 discontinued). Adherence (PDC>=80%) only 27.2%; mean PDC 51.0%. By product at 1 yr: semaglutide (Ozempic, off-label obesity) highest 47.1%, liraglutide (Saxenda) lowest 19.2%. 11.1% switched product. N=4,066.", "finding": "In a real-world US commercially insured cohort of obese adults WITHOUT diabetes newly initiating GLP-1 therapy for weight loss, only 32.3% remained persistent at 1 year and only 27.2% were adherent (PDC>=80%) - far below the >85% adherence reported in pivotal obesity trials. (Note: this is the diabetes-free obesity stratum, which persists worse than type 2 diabetes; cf. ADHERENCE-02.)", "population": "Retrospective cohort, Prime Therapeutics integrated pharmacy + medical claims (~16.5M monthly commercially insured members); 4,066 obese adults WITHOUT type 2 diabetes initiating GLP-1 in 2021; mean age 46, 81% female; obesity (weight-loss) indication; USA.", "comparators": "", "endpointType": "other", "notes": "The canonical 'roughly 1 in 3 still on therapy at 1 yr in obesity' real-world figure. It conditions the D4 maintenance dyad: the trial evidence that 'continuation maintains weight loss' (C-LIRAGLUTIDE-MAINT-01 SCALE Maintenance; C-CLASS-MAINT-03 withdrawal synthesis) presumes a continuation that ~2 in 3 real-world obesity patients do NOT achieve - so for the real-world majority the dyad plays out as the REGAIN-on-stopping arm. Distinguish PERSISTENCE (still filling, 32.3%) from ADHERENCE (PDC>=80%, 27.2%) - both poor. GRADE low (claims-based, single PBM, single initiation year, confounding-by-indication; PBM-employed authors). Reta relevance: no reta real-world data (not marketed); as the most potent agent the regain consequence of the same non-persistence would be larger - expectation, not data. [WI-3 RE-DOMAIN 2026-06-24: moved from effect_domain 'weight-maintenance-regain' to 'health-economics-adherence' (domain 18, context-only); this record is a real-world persistence/adherence/discontinuation observation, not regain KINETICS, so it belongs in the economics/adherence column. Grade, validation history and all other fields preserved unchanged.]", "crossRef": "C-CLASS-MAINT-01; C-CLASS-MAINT-02; C-LIRAGLUTIDE-MAINT-01; C-CLASS-MAINT-03; C-CLASS-MAINT-ADHERENCE-02; C-CLASS-MAINT-ADHERENCE-03", "grade": "low", "source": { "citation": "Gleason PP, Urick BY, Marshall LZ, Friedlander N, Qiu Y, Leslie RS. Real-world persistence and adherence to GLP-1 RAs for obesity. J Manag Care Spec Pharm 2024;30(8):860-867 (Prime Therapeutics).", "url": "https://doi.org/10.18553/jmcp.2024.23332", "identifiers": "PMID38717042", "date": "2024-05-08", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-ADHERENCE-02", "sourceId": "PMID39888616", "drug": "class (liraglutide, semaglutide, tirzepatide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1 receptor agonist", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "1-year discontinuation (Kaplan-Meier): 64.8% (95% CI 64.4-65.2) in overweight/obesity WITHOUT T2D vs 46.5% (46.2-46.9) WITH T2D. Among discontinuers, 1-yr reinitiation 36.3% (no T2D) vs 47.3% (T2D). Drivers: lower income raised discontinuation (higher income protective, T2D HR 0.72 for >$80k), moderate/severe incident GI AEs raised it (HR up to 1.38); each 1% weight loss lowered discontinuation hazard ~3%; each 1% weight regain after stopping raised reinitiation hazard ~2-3%. N=125,474.", "finding": "In the largest US real-world EHR cohort, MOST patients with overweight/obesity discontinued GLP-1 RA within 1 year, with discontinuation substantially higher in obesity-without-diabetes (64.8%) than in type 2 diabetes (46.5%); discontinuation was associated with cost/coverage proxies (income) and GI adverse events, while greater weight loss protected against stopping.", "population": "Retrospective cohort, Truveta EHR (collective of US health systems); 125,474 adults (BMI>=27) newly initiating liraglutide, semaglutide or tirzepatide 2018-2023; mean age 54.4, 65.4% women; 61.0% with T2D; obesity vs T2D strata; followed up to 2 yr; USA.", "comparators": "", "endpointType": "other", "notes": "KEY SYNTHESIS ROW. Three things at once: (1) real-world persistence is far below pivotal trials - most obesity patients stop within 1 yr; (2) large, reproducible heterogeneity - T2D persistence > obesity (discontinuation 46.5% vs 64.8%), so the maintenance story is population-dependent; (3) dominant DRIVERS are cost/coverage (income gradient) and GI tolerability. The weight-regain link is EMPIRICAL in this dataset: greater on-treatment weight loss protected against stopping and weight REGAIN after stopping predicted reinitiation - tying real-world non-persistence to the D4 regain mechanism (set-point, C-CLASS-MAINT-01/02). GRADE low (EHR ascertainment, observational associations not causal, agents pooled, KM-vs-claims definitions not comparable across studies). Reta relevance: not marketed, no data; same access/tolerability pressures, larger regain stakes given potency. [WI-3 RE-DOMAIN 2026-06-24: moved from effect_domain 'weight-maintenance-regain' to 'health-economics-adherence' (domain 18, context-only); this record is a real-world persistence/adherence/discontinuation observation, not regain KINETICS, so it belongs in the economics/adherence column. Grade, validation history and all other fields preserved unchanged.]", "crossRef": "C-CLASS-MAINT-01; C-CLASS-MAINT-02; C-CLASS-MAINT-03; C-LIRAGLUTIDE-MAINT-01; C-CLASS-MAINT-ADHERENCE-01; C-CLASS-MAINT-ADHERENCE-03", "grade": "low", "source": { "citation": "Rodriguez PJ, Zhang V, Gratzl S, Do D, Goodwin Cartwright B, Baker C, Gluckman TJ, Stucky N, Emanuel EJ. Discontinuation and reinitiation of GLP-1 RAs. JAMA Netw Open 2025;8(1):e2457349 (Truveta).", "url": "https://doi.org/10.1001/jamanetworkopen.2024.57349", "identifiers": "PMID39888616", "date": "2025-01-02", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MAINT-ADHERENCE-03", "sourceId": "PMID39109455", "drug": "class (semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (type 2 diabetes indication)", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "Good adherence (PDC>=80%) significantly higher for once-weekly than daily GLP-1 RA: OR 1.25 (95% CI 1.21-1.28). Once-weekly initiators also more persistent and achieved larger HbA1c reduction. Good adherence further associated with older age, female sex and higher socio-economic status. N=70,654.", "finding": "In a nationwide T2D real-world database, adherence and persistence to GLP-1 RA were significantly higher for once-weekly than daily formulations and were socio-economically patterned (better adherence with higher socio-economic status), showing real-world persistence varies markedly by agent/dosing schedule and by access, even within type 2 diabetes.", "population": "Retrospective cohort, Clalit Health Services EMR (Israel, nationwide HMO); 70,654 adults with T2D purchasing any GLP-1 RA 2009-2021; 51% female; T2D indication.", "comparators": "once-weekly vs daily GLP-1 RA", "endpointType": "other", "notes": "Anchors the HETEROGENEITY caveat: real-world persistence is NOT a single number - within T2D it is higher for once-weekly than daily agents (adherence OR 1.25) and is socio-economically patterned, echoing the cost/access driver in the obesity cohorts. Read as the T2D end of the gradient (cf. ADHERENCE-02: T2D discontinuation 46.5% vs obesity 64.8%). Distinguish persistence (still purchasing) from adherence (PDC>=80%). GRADE low (purchase-based, T2D only, wide 2009-2021 accrual spanning older agents, single health system, socio-economic confounding). Reta is once-weekly, which on this evidence would favour persistence vs daily agents - but no reta real-world data exist; expectation, not data. [WI-3 RE-DOMAIN 2026-06-24: moved from effect_domain 'weight-maintenance-regain' to 'health-economics-adherence' (domain 18, context-only); this record is a real-world persistence/adherence/discontinuation observation, not regain KINETICS, so it belongs in the economics/adherence column. Grade, validation history and all other fields preserved unchanged.]", "crossRef": "C-CLASS-MAINT-ADHERENCE-01; C-CLASS-MAINT-ADHERENCE-02; C-CLASS-MAINT-03; C-LIRAGLUTIDE-MAINT-01", "grade": "low", "source": { "citation": "Kassem S, Khalaila B, Stein N, Saliba W, Zaina A. Efficacy, adherence and persistence of various glucagon-like peptide-1 agonists: nationwide real-life data. Diabetes Obes Metab 2024;26(10):4646-4652 (Clalit Health Services).", "url": "https://doi.org/10.1111/dom.15828", "identifiers": "PMID39109455", "date": "2024-08-07", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MASH-SURROGATE-GAP", "sourceId": "PMID40489581", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1 / GIP-GLP-1 / GLP-1-glucagon / triple agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "Class meta-analysis (25 RCTs, n=2600): significant histological improvement in steatosis, ballooning and lobular inflammation but NON-significant fibrosis improvement across the class; median ~24-wk follow-up. NO incretin has hard clinical liver-outcome data.", "finding": "FIELD-WIDE SURROGATE-vs-HARD-OUTCOME GAP (the spine of the outcomes story): every incretin MASH approval or positive trial to date rests on 1-2 yr HISTOLOGICAL SURROGATES (MASH resolution; >=1-stage fibrosis improvement) accepted by FDA under accelerated approval (subpart H) as REASONABLY LIKELY to predict benefit. NO incretin has yet shown a reduction in HARD clinical liver outcomes (progression to cirrhosis, decompensation, HCC, transplant, liver-related mortality); those readouts are years away (e.g. ESSENCE part 2 ~240 wk). Retatrutide sits one tier below even this: imaging-surrogate (liver-fat) data only, not histological surrogates.", "population": "Class-level (semaglutide, tirzepatide, survodutide, pemvidutide, efinopegdutide; reta liver-fat only).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "The KEY HONESTY CAVEAT of the outcomes story. Histological MASH resolution and >=1-stage fibrosis improvement are validated as REASONABLY LIKELY to predict clinical benefit (the regulatory basis for accelerated approval), NOT as proven clinical-outcome surrogates - the distinction matters and is preserved. The pooled meta shows the class improves steatosis/ballooning/inflammation but did NOT significantly improve fibrosis, reinforcing that even the surrogate fibrosis signal is incomplete. NEUTRAL on the science; judgemental on the EVIDENCE: hard liver outcomes are UNPROVEN class-wide.", "crossRef": "C2-SEMAGLUTIDE-MASH-01; C2-TIRZEPATIDE-MASH-01; C2-SURVODUTIDE-MASH-01; C2-PEMVIDUTIDE-MASH-01; C2-RETATRUTIDE-MASH-01; C-MASH-NATURAL-HISTORY-REGULATORY", "grade": "moderate", "source": { "citation": "Wang Y, Zhou Y et al. Efficacy of GLP-1-based therapies on MASLD and MASH: systematic review and meta-analysis. J Clin Endocrinol Metab 2025;110(10):2964-2979.", "url": "https://doi.org/10.1210/clinem/dgaf336", "identifiers": "PMID40489581", "date": "2025-09-16", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic - Chinese government (Ministry of Science and Technology grant 2017ZX09303001; National Natural Science Foundation of China grant 82370814)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MASH-WEIGHT-MEDIATION-OUTCOMES", "sourceId": "CIT:synthesis-across-class-mash-datasets-reta-sanyal", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1 / GIP-GLP-1 / GLP-1-glucagon / triple agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "Unresolved attribution: whether incretin MASH improvement is fully weight-mediated or carries a weight-independent hepatic increment (esp. for glucagon-containing agents). Reta phase-2a LF reductions were significantly related to weight/abdominal-fat loss.", "finding": "WEIGHT-MEDIATED vs DIRECT-HEPATIC question for OUTCOMES: it remains unresolved whether incretin MASH improvement is fully explained by weight loss or whether there is a weight-INDEPENDENT hepatic increment, particularly for glucagon-receptor-containing agents (whose GCGR arm drives hepatic lipid oxidation and may act partly independently of weight). For reta specifically, the phase-2a substudy reported liver-fat reductions significantly related to weight and abdominal-fat loss, so a weight-independent hepatic effect of its glucagon arm is NOT established for outcomes - it is the open question.", "population": "Class-level mechanistic-attribution question applied to OUTCOMES; reta glucagon arm the specific open case.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Links OQ-F-K / Thread 8 (the mechanism layer). For OUTCOMES the question is deliberately left OPEN: whether class MASH benefit is weight-mediated or carries a direct-hepatic component (esp. glucagon-containing agents) is not resolved, and reta's glucagon arm is the standout open case because its only liver data are imaging-surrogate and correlated with weight loss. NEUTRAL; recorded as an open question, not a verdict.", "crossRef": "C2-RETATRUTIDE-MASH-01; C2-COTADUTIDE-HEP-01; C2-SURVODUTIDE-MASH-01; C-MULTI-MASH-GLUCAGON-FIBROSIS", "grade": "moderate", "source": { "citation": "Synthesis across class MASH datasets (reta Sanyal Nat Med 2024 LF tied to weight; survodutide/cotadutide GCGR mechanistic signals). Attribution unresolved; no weight-matched hard-outcome dataset exists.", "url": "", "identifiers": "CIT:mash-weight-mediation-outcomes-2026", "date": "2026-06-21", "design": "prespecified/exploratory secondary of RCT", "maturity": "review", "funding": "in-house editorial synthesis - no independent sponsor; underlying primaries separately funded", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MENSTRUAL-PCOS-RECOVERY-01", "sourceId": "PMID40713699", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "PCOS RCT: semaglutide+metformin improved menstrual-cycle recovery alongside greater weight loss.", "finding": "In a PCOS RCT, semaglutide improved menstrual-cycle recovery - a weight-loss-mediated effect.", "population": "PCOS open-label RCT (Reprod Biol Endocrinol 2025): 100 overweight/obese women with PCOS (Rotterdam criteria), prospective randomised controlled open-label trial of semaglutide 1 mg weekly plus metformin vs metformin alone, 16 weeks.", "comparators": "", "endpointType": "womens-health", "notes": "WEIGHT-MEDIATED PCOS menstrual recovery; does NOT isolate a drug-intrinsic abnormal-uterine-bleeding mechanism - the drug-intrinsic AUB signal remains spontaneous-report-only. DEEPENS the menstrual signal row.", "crossRef": "C-CLASS-SAFETY-MENSTRUAL-01", "grade": "moderate", "source": { "citation": "Semaglutide+metformin in PCOS (open-label RCT, n=100), Reprod Biol Endocrinol 2025", "url": "https://doi.org/10.1186/s12958-025-01447-3", "identifiers": "DOI:10.1186/s12958-025-01447-3", "date": 2025, "design": "open-label RCT", "maturity": "human-primary", "funding": "academic/government - Chinese government and institutional grants (Chongqing Health Commission/Science & Technology Bureau; NSFC; not industry)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICROBIOME-01", "sourceId": "PMID36643973", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "Compositional shifts recur in rodents and broadly in the same DIRECTION: liraglutide markedly enriches Akkermansia (e.g. 1.90->33.18% in HFD mice, Zhao 2022 Front Nutr) plus Bifidobacterium/Lactobacillus and lowers the Firmicutes/Bacteroidetes ratio. Corroborated on the semaglutide side by C-SEMA-MICROBIOME-RODENT-01. Taxa are HETEROGENEOUS and partly contradictory between studies; all are 16S-only with small n.", "finding": "In rodents, liraglutide shifts gut-microbiota composition in a broadly consistent direction (enriching Akkermansia, Bifidobacterium, Lactobacillus), and semaglutide does similarly, but the specific taxa are heterogeneous and the evidence is 16S-only, small, and confounded by reduced food intake.", "population": "High-fat-diet C57BL/6 mice, liraglutide (Zhao 2022 Front Nutr; 16S); semaglutide corroboration encoded separately (Feng 2024 PeerJ mice).", "comparators": "high-fat-diet control; normal-chow control", "endpointType": "mechanistic/physiological", "notes": "RODENT, very-low. Class-DIRECTION reproducibility of compositional change, NOT of a clinical effect. Taxa heterogeneous/contradictory; 16S-only; small n; food-intake confounded. Does NOT establish that the shift mediates anything. Semaglutide pole in C-SEMA-MICROBIOME-RODENT-01.", "crossRef": "C-SEMA-MICROBIOME-RODENT-01", "grade": "very-low", "source": { "citation": "Zhao L, Qiu Y, Zhang P, Wu X, Zhao Z, Deng X, Yang L, Wang D, Yuan G. Gut microbiota mediates positive effects of liraglutide on dyslipidemia in mice fed a high-fat diet. Front Nutr 2022;9:1048693.", "url": "https://doi.org/10.3389/fnut.2022.1048693", "identifiers": "DOI:10.3389/fnut.2022.1048693", "date": "2022-12", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; 16S compositional only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICROBIOME-NOCAUSE-01", "sourceId": "PMID29867765", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "STRUCTURAL: the compositional studies provide NO causal or mediation evidence that the microbiome drives GLP-1-RA WEIGHT LOSS. None uses an FMT, germ-free, antibiotic-knockout, or formal mediation design for weight loss; the shifts are confounded by drug-induced reduced food intake (titles such as 'lowers weight by modulating the microbiota' or 'mediates' overstate what a 16S association can show). Causal weight-loss mediation is NOT established for ANY agent (liraglutide, semaglutide, exenatide, dulaglutide).", "finding": "Across the whole compositional literature, no study demonstrates that the gut-microbiome change CAUSES the weight loss from GLP-1 receptor agonists: the designs are associational (16S only), confounded by reduced food intake, and despite some 'mediates' titles, causal weight-loss mediation is unestablished for every agent.", "population": "Compositional GLP-1-RA microbiome studies reviewed as a body (rodent: Wang 2016, Zhao 2018, Zhao 2022, Feng 2024; human: Chen 2025 n=15) for any weight-loss causal/mediation design - none present.", "comparators": "n/a (structural across the compositional corpus)", "endpointType": "mechanistic/physiological", "notes": "LOAD-BEARING ANTI-OVERCLAIM. direction n/a (this is a no-causation structural statement, not an effect direction). Pinned to a representative rodent compositional source -> very-low container, but the claim is the ABSENCE of causal design, which is well-supported. The dominant confounder is drug-induced reduced food intake. Do NOT let any reader treat compositional shifts as 'the microbiome mediates GLP-1 weight loss'.", "crossRef": "C-LIRA-MICROBIOME-FMT-01", "grade": "very-low", "source": { "citation": "Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, Guo Y, Wang N, Lu Y. A Glucagon-Like Peptide-1 Receptor Agonist Lowers Weight by Modulating the Structure of Gut Microbiota. Front Endocrinol (Lausanne) 2018;9:233.", "url": "https://doi.org/10.3389/fendo.2018.00233", "identifiers": "DOI:10.3389/fendo.2018.00233", "date": "2018-05", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; 16S compositional only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICROBIOME-PREDICT-01", "sourceId": "PMID35095773", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "Reverse direction (microbiome->drug response): in one human pilot (Tsai 2021, 52 type-2-diabetes patients on liraglutide n=22 / dulaglutide n=30), BASELINE microbiome composition differed between glycaemic responders and non-responders (beta-diversity ADONIS P=0.004; alpha-diversity NS, Shannon P=0.832); a 17-feature baseline signature had an IN-SAMPLE AUROC of 0.96 (NOT externally validated; over-fit risk). Bacteroides dorei and Roseburia inulinivorans were positively, Prevotella copri negatively, associated with glycaemic reduction.", "finding": "In a single small human pilot, patients' baseline gut microbiome differed between those who did and did not respond glycaemically to GLP-1 receptor agonists, and an in-sample model predicted response well - but this is correlational, single-centre, not externally validated, and says nothing about GI tolerability.", "population": "52 type-2-diabetes patients on liraglutide (n=22) or dulaglutide (n=30); single-centre Taiwanese pilot; baseline 16S microbiome vs glycaemic response (n=52).", "comparators": "responders vs non-responders (within-cohort)", "endpointType": "mechanistic/physiological", "notes": "HUMAN pilot, n=52, single-centre, correlational -> low (species floor exempted by human-cohort tokens; not inflated). In-sample AUROC 0.96 only (over-fit risk), NOT externally validated. No data on baseline microbiome predicting GI TOLERABILITY (gap -> OQ-MICROBIOME-D). Reverse direction is still a pharmacology question.", "crossRef": "C-CLASS-MICROBIOME-NOCAUSE-01", "grade": "low", "source": { "citation": "Tsai CY, Lu HC, Chou YH, Liu PY, Chen HY, Huang MC, Lin CH, Tsai CN. Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study. Front Endocrinol (Lausanne) 2022;12:814770.", "url": "https://doi.org/10.3389/fendo.2021.814770", "identifiers": "DOI:10.3389/fendo.2021.814770", "date": "2022-01", "design": "unspecified", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (n=52); single-centre pilot; correlational (baseline-predicts-response); in-sample AUROC (not externally validated)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICROBIOME-SCFA-01", "sourceId": "PMID25109781", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "increase", "magnitude": "Short-chain fatty acids causally stimulate the body's OWN (endogenous) incretins: propionate/SCFAs trigger GLP-1 and PYY secretion from colonic L-cells via the SCFA receptors FFAR2/GPR43 (and FFAR3), shown with knockouts - secretion is attenuated in FFA2(-/-) mice both in vitro (primary colonic cultures) and in vivo (intra-colonic propionate raises portal/jugular GLP-1 and PYY in wild-type but not FFA2(-/-) rodents) [Psichas 2015; corroborated by Tolhurst 2012]. CRITICAL: this is the SCFA->OWN-incretin axis (how microbes drive ENDOGENOUS GLP-1), NOT a demonstration that the microbiome mediates INJECTED GLP-1-RA weight loss - a related but DISTINCT question.", "finding": "Gut microbes make short-chain fatty acids that causally stimulate the body's OWN GLP-1 and PYY (proven with FFAR2/FFAR3-knockout rodents) - but this endogenous-incretin pathway is a DISTINCT question from how injected GLP-1 receptor agonists work; it does not show the microbiome mediates the drugs' weight loss.", "population": "FFA2/FFAR2 (and FFAR3) knockout mice + Wistar rats; primary murine colonic crypt cultures and in-vivo intra-colonic propionate infusion (Psichas 2015 Int J Obes; Tolhurst 2012 Diabetes, Gribble/Reimann).", "comparators": "wild-type; FFA2(-/-) / FFAR3(-/-) knockout", "endpointType": "mechanistic/physiological", "notes": "RODENT/knockout mechanism, very-low. R3 conflation guard: the SCFA->ENDOGENOUS-incretin vs INJECTED-drug-mechanism distinction is in the FINDING TEXT. This is foundational endogenous physiology; it must NOT be read as 'the microbiome mechanism of semaglutide'. Corroborated by C-CLASS-MICROBIOME-SCFA-02 (Tolhurst).", "crossRef": "C-CLASS-MICROBIOME-SCFA-02", "grade": "very-low", "source": { "citation": "Psichas A, Sleeth ML, Murphy KG, et al. (Frost G, senior). The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 2015;39(3):424-429.", "url": "https://doi.org/10.1038/ijo.2014.153", "identifiers": "DOI:10.1038/ijo.2014.153", "date": "2015-03", "design": "preclinical (rodent)", "maturity": "in-vitro", "funding": "academic/independent (Imperial College London; MRC/Wellcome; Frost/Bloom lab)", "scopeLimits": "animal data; human relevance uncertain; mechanistic (endogenous-incretin axis, not injected-drug mechanism)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICROBIOME-SCFA-02", "sourceId": "PMID22190648", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "increase", "magnitude": "Corroborating receptor identification: SCFAs trigger GLP-1 secretion from mixed colonic L-cell cultures via FFAR2/GPR43; FFAR2 (ffar2/gpr43) and FFAR3 (gpr41) are enriched in GLP-1-secreting L-cells, SCFAs raise cytosolic Ca2+ in L-cells, and SCFA-triggered GLP-1 secretion is REDUCED in ffar2(-/-) or ffar3(-/-) mice both in vitro and in vivo, with a parallel impairment of glucose tolerance (Tolhurst 2012). AGAIN: this is the SCFA->OWN-incretin axis (endogenous GLP-1), a DISTINCT question from how injected GLP-1-RA drugs produce weight loss.", "finding": "A second knockout study confirms that gut-microbial short-chain fatty acids stimulate the body's own GLP-1 through the FFAR2 receptor - reinforcing the endogenous-incretin pathway, which is distinct from the mechanism of injected GLP-1 receptor agonists.", "population": "ffar2(-/-) and ffar3(-/-) knockout mice + mixed primary murine colonic cultures; in-vitro and in-vivo SCFA-triggered GLP-1 secretion (Tolhurst 2012 Diabetes; Gribble/Reimann, Cambridge).", "comparators": "wild-type; ffar2(-/-) / ffar3(-/-) knockout", "endpointType": "mechanistic/physiological", "notes": "RODENT/knockout mechanism, very-low. Corroborates C-CLASS-MICROBIOME-SCFA-01 (Psichas). Same R3 distinct-axis guard in the finding text: endogenous-incretin physiology, NOT the injected-drug mechanism. Avoids orphaning the Tolhurst source while keeping it honestly scoped.", "crossRef": "C-CLASS-MICROBIOME-SCFA-01", "grade": "very-low", "source": { "citation": "Tolhurst G, Heffron H, Lam YS, et al. (Gribble FM, Reimann F, senior). Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012;61(2):364-371.", "url": "https://doi.org/10.2337/db11-1019", "identifiers": "DOI:10.2337/db11-1019", "date": "2012-02", "design": "preclinical (rodent)", "maturity": "in-vitro", "funding": "academic/independent (Cambridge; Wellcome Trust/MRC; Gribble & Reimann lab)", "scopeLimits": "animal data; human relevance uncertain; mechanistic (endogenous-incretin axis, not injected-drug mechanism)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-MICRONUTRIENT-VITD-01", "sourceId": "PMID41549912", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Narrative review: vitamin-D deficiency reported as the most common micronutrient abnormality on GLP-1 RA therapy (7.5% at 6 months / 13.6% at 12 months in an n=69 deficiency sub-study); >60% of patients below the DRI for calcium and iron. These are INTAKE (and a small deficiency sub-study), NOT serum status across the cohort.", "finding": "The same narrative review reports vitamin-D deficiency as the most common micronutrient abnormality on GLP-1 RA therapy (7.5% at 6 mo / 13.6% at 12 mo in an n=69 sub-study) and intakes below the DRI for calcium and iron in >60% of patients - but these are intake/small-substudy data, not serum status.", "population": "Narrative review (Urbina et al., Clin Obes 2026) summarising GLP-1 RA micronutrient-status literature; the vitamin-D-deficiency rates from an n=69 sub-study.", "comparators": "SGLT-2 inhibitor", "endpointType": "safety-event/signal", "notes": "CONFIDENCE medium; low-grade (narrative review of INTAKE not serum). Same source + domain as the iron finding C-CLASS-IRON-04 (bumps Urbina n_findings to 4). B12, folate and magnesium are NOT verified by this source - explicit gaps (routed to OQ-BMD-C). Do not read the 7.5%/13.6% deficiency rates as a cohort-wide serum prevalence.", "crossRef": "C-CLASS-IRON-04", "grade": "low", "source": { "citation": "Urbina et al., GLP-1 receptor agonists and iron status, Clin Obes 2026;16:e70070", "url": "https://doi.org/10.1111/cob.70070", "identifiers": "PMID 41549912 / DOI 10.1111/cob.70070", "date": 2026, "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-NMA-EFFICACY-01", "sourceId": "PMID41039116", "drug": "multiple (network meta-analysis)", "drugRoot": "multiple (network meta-analysis)", "drugSlug": "multiple-network-meta-analysis", "drugLabel": "Multiple (network Meta-analysis)", "drugClass": "multiple (class synthesis)", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "decrease", "magnitude": "Network meta-analysis (56 RCTs, n=60,307): semaglutide and tirzepatide each >10% total body-weight loss vs placebo; both reduced HF hospitalisation and gave T2D remission; semaglutide reduced MACE; tirzepatide gave OSA and MASH benefit.", "finding": "Across 56 trials, semaglutide and tirzepatide are the leading agents on weight and carry the broadest proven extra-glycaemic benefits.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "comparative", "notes": "Network meta-analysis -> moderate; indirect comparisons. Useful as a class-comparative synthesis anchor.", "crossRef": "", "grade": "moderate", "source": { "citation": "GLP-1-based therapies for obesity: systematic review and network meta-analysis, Nat Med 2025", "url": "https://doi.org/10.1038/s41591-025-03978-z", "identifiers": "DOI:10.1038/s41591-025-03978-z", "date": "2025-10-01", "design": "network meta-analysis", "maturity": "review", "funding": "academic / non-commercial", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-NMA-SURGERY-01", "sourceId": "PMID41326176", "drug": "multiple (network meta-analysis)", "drugRoot": "multiple (network meta-analysis)", "drugSlug": "multiple-network-meta-analysis", "drugLabel": "Multiple (network Meta-analysis)", "drugClass": "multiple (class synthesis)", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "decrease", "magnitude": "Network meta-analysis (30 RCTs, n=20,015): bariatric/metabolic surgery superior to GLP-1 RAs overall for total weight loss (ETD -10.3%, p=0.001); BUT in tirzepatide-only comparisons the difference versus surgery was NOT statistically significant.", "finding": "Bariatric surgery still beats GLP-1 drugs on weight overall, but tirzepatide narrows the gap to non-significance versus surgery.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "comparative", "notes": "Network meta-analysis (indirect) -> moderate. Both-poled: surgery superior overall, tirzepatide-vs-surgery NS.", "crossRef": "", "grade": "moderate", "source": { "citation": "Bariatric surgery versus GLP-1 receptor agonists: network meta-analysis, Obesity 2025", "url": "https://doi.org/10.1002/oby.70100", "identifiers": "DOI:10.1002/oby.70100", "date": "2025-11-01", "design": "network meta-analysis", "maturity": "review", "funding": "academic / non-commercial", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-OSA-LANDSCAPE-01", "sourceId": "PMID41090431", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "incretin class (GIP/GLP-1 dual; GLP-1/GIP/glucagon triple)", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "OSA is now a validated incretin indication PATH: tirzepatide (Zepbound) FDA-approved 20 Dec 2024 for moderate-to-severe OSA in obesity (first drug indication; SURMOUNT-OSA placebo-subtracted AHI -20.0 and -23.8 events/hr). Retatrutide is REGISTERED on the same path (TRIUMPH-1/-2 OSA primary endpoints) but has NO results and NO approval.", "finding": "INDICATION LANDSCAPE / REGULATORY CONTEXT: OSA is now a validated incretin indication path - tirzepatide became the first-ever drug approved for OSA (FDA, Dec 2024) on the SURMOUNT-OSA AHI evidence, and Lilly IS pursuing retatrutide along the same path (TRIUMPH OSA cohorts with AHI as a primary endpoint, named as a registrational complication in the TRIUMPH design paper). Reta's place in the path is signalled-and-registered but as-yet-unproven (no OSA results, no indication).", "population": "Class/regulatory context. Tirzepatide anchor: SURMOUNT-OSA (N=469, 52 wk). Reta pipeline: TRIUMPH-1 (NCT05929066) / TRIUMPH-2 (NCT05929079) OSA subsets (AHI >=15 on PSG).", "comparators": "placebo", "endpointType": "other", "notes": "EVIDENCE judgement: the tirzepatide anchor (SURMOUNT-OSA, FDA label) is HIGH-robustness; the retatrutide portion is registry/no-results (very-low) - NOT level, and this row says so. AHI is a physiological SURROGATE; an OSA approval does not by itself establish hard CV-outcome benefit (cross-ref C-CLASS-OSA-SURROGATE). Honest landscape: OSA is a validated incretin indication PATH, reta is REGISTERED on it but has not produced results or sought an OSA indication to approval.", "crossRef": "C-RETATRUTIDE-OSA-01; C-RETATRUTIDE-OSA-02; C-CLASS-OSA-MECHANISM; C-TIRZEPATIDE-OSA-FDA-2024; C2-RETATRUTIDE-GLY-05", "grade": "low", "source": { "citation": "Giblin K et al. Design of the TRIUMPH phase-3 retatrutide programme. Diabetes Obes Metab 2025;28(1):83-93 (registrational OSA framing); with SURMOUNT-OSA (PMID 38912654) and the FDA Zepbound OSA approval (20 Dec 2024) as the tirzepatide anchor.", "url": "https://doi.org/10.1111/dom.70209", "identifiers": "PMID41090431", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-OSA-MECHANISM", "sourceId": "PMID31918559", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin class (GLP-1, GIP/GLP-1, triple)", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "Weight-loss-AHI relationship strong and consistent (SCALE post-hoc P<0.01; SURMOUNT-OSA AHI reduction tracks weight loss). Upper-airway substrate: tongue-fat reduction strongly correlated with AHI improvement (Pearson r 0.62, P<0.0001) and retained an association after adjusting for weight loss (partial r 0.36, P=0.014) - a weight-independent residual shown for weight loss generally, NOT yet for any incretin drug.", "finding": "MECHANISM (the central question): incretin OSA benefit is WEIGHT-DOMINANT - AHI reduction tracks weight loss across SCALE and SURMOUNT-OSA, and the canonical mediator is reduction in upper-airway / parapharyngeal and especially TONGUE fat. A weight-INDEPENDENT/direct component (residual upper-airway-fat pathway, plus possible rostral fluid shift, lung-volume and ventilatory-control/loop-gain effects) is PLAUSIBLE but NOT PROVEN for incretins: no incretin OSA trial has isolated a weight-independent drug effect. Both poles stand.", "population": "Mechanistic synthesis. Key imaging substrate: 67 adults with obesity + OSA, upper-airway + abdominal MRI and sleep study before/after weight loss (lifestyle or bariatric).", "comparators": "", "endpointType": "other", "notes": "Balanced mechanism row (both poles). WEIGHT-DOMINANT: the simplest reading of SCALE + SURMOUNT-OSA is that AHI falls because weight (and parapharyngeal/tongue fat) falls. DIRECT-COMPONENT-PLAUSIBLE: tongue-fat reduction predicts AHI improvement even after adjusting for weight - but this is from lifestyle/bariatric weight loss, NOT demonstrated for any incretin drug; fluid-shift/loop-gain contributions are hypothesis-level. Attribution deliberately left open. Reta relevance: if weight-mediated, reta (largest weight loss) should lead on AHI; if a direct upper-airway pathway dominates, ranking could differ - untested.", "crossRef": "C-LIRAGLUTIDE-OSA-SCALE; C-TIRZEPATIDE-OSA-SURMOUNT-A1; C-CLASS-OSA-SURROGATE; C-RETATRUTIDE-OSA-02", "grade": "low", "source": { "citation": "Wang SH, Keenan BT, Wiemken A, ... Schwab RJ. Effect of Weight Loss on Upper Airway Anatomy and the AHI: The Importance of Tongue Fat. Am J Respir Crit Care Med 2020;201(6):718-727.", "url": "https://doi.org/10.1164/rccm.201903-0692OC", "identifiers": "PMID31918559", "date": "2020-03-15", "design": "observational cohort", "maturity": "human-primary", "funding": "not-stated", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-OSA-SURROGATE", "sourceId": "PMID27571048", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin class (cross-cutting)", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "CPAP RCT precedent (both NULL for the CV primary despite reducing apnoea severity): SAVE (McEvoy, NEJM 2016; N=2717, moderate-severe OSA + established CV disease, mean 3.7 yr) - CV composite HR 1.10 (95% CI 0.91-1.32), P=0.34. ISAACC (Sanchez-de-la-Torre, Lancet Respir Med 2020; N=1264 OSA, post-ACS, median 3.35 yr) - CV events 16% vs 17%, HR 0.89 (0.68-1.17), P=0.40.", "finding": "SURROGATE-vs-HARD-OUTCOME caveat: AHI is the registrational endpoint for incretin OSA trials, but lowering OSA severity does NOT guarantee hard-outcome benefit. The CPAP randomised precedent shows AHI/severity can be reduced without reducing major CV events - SAVE and ISAACC were both NULL for CV outcomes despite effective apnoea-severity reduction. The same caveat applies to drug-induced AHI reduction: the incretin OSA RCTs (SCALE, SURMOUNT-OSA) demonstrate AHI reduction (a surrogate), not reduced CV events, mortality or hard OSA outcomes. BOTH POLES (kept explicit): the CPAP precedent is WEAKENED by low device adherence (~3-4 hr/night) and selection of low-sleepiness populations, so it does not prove drug-induced AHI reduction is futile; but the narrow claim stands - AHI reduction alone is not established proof of hard-outcome benefit.", "population": "Cross-cutting surrogate note. SAVE (N=2717, CV-disease population) and ISAACC (N=1264, post-ACS); both tested CPAP (not an incretin) and were academically led.", "comparators": "usual care; sham/no CPAP", "endpointType": "other", "notes": "Judgemental-on-evidence safeguard (HIGH-robustness hard-outcome RCTs). The point is NOT that incretins fail to help OSA - the SURMOUNT-OSA AHI signal is large and high-quality - but that AHI is a SURROGATE and hard OSA outcomes are not established. COUNTER-BALANCE (kept honest): the CPAP trials had low device adherence (~3-4 hr/night) and selected low-sleepiness populations, weakening the analogy, and incretins independently lower weight/CV risk via other pathways (cf. SELECT) - so an incretin could still benefit hard outcomes for reasons unrelated to AHI. Narrow defensible claim: AHI reduction alone is not proof of hard-outcome benefit.", "crossRef": "C-CLASS-OSA-MECHANISM; C-LIRAGLUTIDE-OSA-SCALE; C-TIRZEPATIDE-OSA-SURMOUNT-A1; C-TIRZEPATIDE-OSA-SURMOUNT-A2", "grade": "high", "source": { "citation": "McEvoy RD et al. CPAP for Prevention of Cardiovascular Events in OSA (SAVE). N Engl J Med 2016;375:919-931; and Sanchez-de-la-Torre M et al. (ISAACC). Lancet Respir Med 2020;8:359-367 (PMID31839558, DOI 10.1016/S2213-2600(19)30271-1).", "url": "https://doi.org/10.1056/NEJMoa1606599", "identifiers": "PMID27571048", "date": "2016-08-28", "design": "double-blind RCT", "maturity": "human-primary", "funding": "mixed-NHMRC (Australia) and Philips Respironics/device industry", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-PCOS-ANDROGEN-META-01", "sourceId": "PMID39178623", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "Meta of 4 RCTs (n=176, mostly liraglutide): total testosterone reduced (MD -1.33, p=0.03) with BMI reduction; HOMA-IR NS.", "finding": "Pooled RCT data found GLP-1 RAs modestly lower total testosterone and BMI in obese PCOS women.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Small/fragile pool (p=0.03, mostly liraglutide, total-T only); any drop is plausibly SHBG/weight-mediated, not a demonstrated direct anti-androgen effect. CONTESTED by a broader meta finding androgens unchanged - both poles stand.", "crossRef": "C-CLASS-PCOS-ANDROGEN-NULL-META-01", "grade": "moderate", "source": { "citation": "GLP-1 RA and androgens in PCOS (meta-analysis, 4 RCTs), J Diabetes Complications 2024", "url": "https://doi.org/10.1016/j.jdiacomp.2024.108834", "identifiers": "DOI:10.1016/j.jdiacomp.2024.108834", "date": 2024, "design": "meta-analysis", "maturity": "review", "funding": "academic / investigator - no industry sponsor disclosed", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-PCOS-ANDROGEN-NULL-META-01", "sourceId": "PMID40360648", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "no-change", "magnitude": "Meta of PCOS RCTs: DHEAS, SHBG, total and free testosterone and FAI all UNCHANGED while weight and insulin resistance improved.", "finding": "A broader PCOS RCT meta-analysis found GLP-1 RAs improve weight and insulin resistance but do NOT change circulating androgens.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Net verdict across the two metas: metabolic improvement yes; androgen effect uncertain/small and at most SHBG/weight-mediated. Both-poled with the androgen-down meta.", "crossRef": "C-CLASS-PCOS-ANDROGEN-META-01", "grade": "moderate", "source": { "citation": "GLP-1 RA in PCOS, broad androgen panel (meta-analysis), Sci Rep 2025", "url": "https://doi.org/10.1038/s41598-025-99622-4", "identifiers": "DOI:10.1038/s41598-025-99622-4", "date": 2025, "design": "meta-analysis", "maturity": "review", "funding": "academic-Guangxi colleges teacher research grant (2023KY0576)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-PREG-PERICONCEPTION-DANISH-01", "sourceId": "PMID41852577", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist class", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Danish nationwide cohort (n=756,636; 529 periconceptionally exposed): preterm birth raised ONLY in diabetes-indication users (lira aOR 1.70, sema 1.84), NOT in weight-management users.", "finding": "In a large nationwide cohort, periconceptional GLP-1 exposure raised preterm-birth risk only among diabetes-indication users, not weight-management users - implicating the underlying disease rather than the drug.", "population": "Peer-reviewed primary (women's-health wave)", "comparators": "", "endpointType": "womens-health", "notes": "Fills the non-diabetic-obese pregnancy gap the prior T2D-only cohort missed. Observational, 529 exposed, residual confounding by glycaemic control; preterm birth not malformation. DEEPENS the class pregnancy rows.", "crossRef": "C-CLASS-SAFETY-PREG01", "grade": "low", "source": { "citation": "Periconceptional GLP-1 exposure and pregnancy outcomes (Danish nationwide cohort), Hum Reprod Open 2026", "url": "https://doi.org/10.1093/hropen/hoag015", "identifiers": "DOI:10.1093/hropen/hoag015", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic / investigator (not separately extracted)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-RODENT-EEDEFENCE-01", "sourceId": "PMID39067024", "drug": "GLP-1 / FGF21 (rodent)", "drugRoot": "GLP-1 (native; physiology)", "drugSlug": "glp-1-native-physiology", "drugLabel": "GLP-1 (native; Physiology)", "drugClass": "GLP-1 receptor agonist / FGF21 (preclinical)", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "no-change", "magnitude": "independent of ambient temperature, GLP-1 and FGF21 PREVENTED the weight-loss-associated reduction in metabolic rate (EE-defence, not EE-elevation); GLP-1 weight loss temperature-robust across 22C vs thermoneutral 30C", "finding": "Rodent EE-defence reframe (Jacobsen Cell Rep 2024): standard ~22C mouse housing is a cold stress inflating energy expenditure, but independent of ambient temperature GLP-1 and FGF21 prevented the FALL in metabolic rate caused by weight loss. This reframes the question from EE-elevation to EE-DEFENCE during deficit. It is a rodent, hypothesis-tier finding - NOT retatrutide-direct - and its human translation is indeterminate.", "population": "Mice across 22C vs thermoneutral 30C housing, GLP-1/FGF21 (and MC4R/PYY/GDF15) weight-loss models (Cell Rep 2024;43(8):114501)", "comparators": "vehicle / weight-loss control; thermoneutral vs 22C housing", "endpointType": "preclinical-mechanistic", "notes": "Promoted from sweep SW-REG-09 (2026-06-21). Audit caveats: VERY-LOW (rodent); survives only as a REFRAMING (EE-defence not elevation); not retatrutide-direct; hypothesis tier; retatrutide-specific human translation indeterminate. The key reframe motivating the EE-defence-during-active-weight-loss open question.", "crossRef": "C-TIRZ-RODENT-METRATE-01", "grade": "very-low", "source": { "citation": "Jacobsen JM, Petersen N, Torz L, et al. GLP-1 and FGF21 prevent the reduction in metabolic rate caused by weight loss. Cell Rep 2024;43(8):114501", "url": "https://doi.org/10.1016/j.celrep.2024.114501", "identifiers": "PMID39067024; DOI 10.1016/j.celrep.2024.114501", "date": "2024-08-27", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "industry - Novo Nordisk (study performed by Novo Nordisk; authors are Novo Nordisk employees, paper funding/affiliation line)", "scopeLimits": "animal data; human relevance uncertain; thermoneutrality vs 22C housing reframe; not retatrutide-direct", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-AKI-CONS01", "sourceId": "CIT:consolidation-of-glp-1ra-aki-pharmacovigilance-v", "drug": "incretin class consolidation (acute kidney injury)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "FAERS: AKI/renal disorders the second-largest AE category after GI in one analysis; tirzepatide AKI reported LESS than semaglutide (comparative FAERS). No incidence rate established.", "finding": "NET VERDICT (acute kidney injury) - a LOW/very-low-grade pharmacovigilance signal that is mostly VOLUME-DEPLETION-mediated, i.e. secondary to dehydration from GI adverse events (vomiting/diarrhoea/poor intake), NOT a primary nephrotoxic effect. Tirzepatide reported less than semaglutide (reporting, not incidence). Higher risk in pre-existing renal impairment. This is the AE signal; longer-term renal OUTCOMES are favourable and live in the renal domain.", "population": "FAERS pharmacovigilance + case literature; comparative tirz-vs-sema FAERS.", "comparators": "semaglutide (for tirzepatide comparison); background FAERS reporting", "endpointType": "safety-event/signal", "notes": "Mostly single-direction with a comparator nuance. Class pole = GLP-1RA AKI signal, dehydration mechanism (AKI12, FAERS, very-low). Comparator nuance = tirzepatide reported LESS (AKI13, PMID/DOI still to confirm - carry the flag). KEY FRAMING: volume-depletion-mediated -> cross-links GI tolerability (manage nausea/hydration); NOT intrinsic nephrotoxicity, and CONTRASTS with the FAVOURABLE long-term renal outcomes in the renal domain. GRADE: very-low (FAERS reporting != incidence). RETA POSITION: class-transfer - reta's GI AE burden is the relevant driver; manage hydration during titration. Consolidation row (CIT synthesis id).", "crossRef": "C-CLASS-SAFETY-AKI12; C-TIRZ-SAFETY-AKI13", "grade": "very-low", "source": { "citation": "Consolidation of GLP-1RA AKI pharmacovigilance (volume-depletion mechanism) + comparative tirz-vs-sema FAERS (cross-refs AKI12/AKI13)", "url": "", "identifiers": "CIT:safety-aki-consolidation-2026", "date": "2026-06-21", "design": "pharmacovigilance / disproportionality", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-AKI12", "sourceId": "PMID36583004", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "FAERS: 2670 AKI reports; liraglutide highest ROR 1.50 (1.41-1.60); hospitalisation 45.3%, fatality 4.23%", "finding": "GLP-1RA-associated acute kidney injury reported in pharmacovigilance/case literature, proposed mechanism dehydration from vomiting/diarrhoea/poor intake; renal disorders the second-largest AE category after GI in one case series.", "population": "Post-marketing pharmacovigilance + case reports/review", "comparators": "", "endpointType": "safety-event/signal", "notes": "AKI largely secondary to GI tolerability (vomiting/dehydration) - cross-links GI domain. Higher risk in pre-existing renal impairment. PMCID confirmed; primary journal/PMID to confirm. [VERIFIED 2026-06-20]: cited PMCID resolved to a FAERS disproportionality study (PMID 36583004), NOT the 120-case series originally described; magnitude corrected and re-graded very-low (reporting != incidence).", "crossRef": "C-TIRZ-SAFETY-AKI13", "grade": "very-low", "source": { "citation": "Dong & Sun, Front Endocrinol 2022 (GLP-1RA AKI FAERS disproportionality)", "url": "https://doi.org/10.3389/fendo.2022.1032199", "identifiers": "PMID 36583004; DOI 10.3389/fendo.2022.1032199", "date": "2022-12-15", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ANAES17", "sourceId": "PMID40230298", "drug": "GLP-1 receptor agonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Residual gastric contents OR 5.96 (3.96-8.98; 165,522 patients); pulmonary aspiration OR 1.04 (0.87-1.25; 471 cases); dose-withholding OR 0.51 (0.33-0.81)", "finding": "Peri-operative aspiration meta-analysis: GLP-1 RA use associated with sharply increased residual gastric contents despite appropriate fasting, but NOT with increased pulmonary aspiration; withholding at least one dose lowered residual-contents odds.", "population": "Meta-analysis, 28 observational studies, fasted patients undergoing anaesthesia/sedation", "comparators": "non-GLP-1 RA exposure", "endpointType": "safety-event/signal", "notes": "Central anaesthesia tension: retained contents up ~6-fold yet no measurable rise in actual aspiration (low/very-low GRADE). Underlies ASA/multi-society pre-procedure hold guidance.", "crossRef": "C-CLASS-SAFETY-ANAES18; C-CLASS-SAFETY-ANAES19", "grade": "moderate", "source": { "citation": "Elkin J et al., Anaesthesia 2025", "url": "https://doi.org/10.1111/anae.16601", "identifiers": "PMID:40230298 / DOI:10.1111/anae.16601", "date": "2025-04-15", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent - investigator (Australian Government Research Training Program Scholarship); no industry study sponsor", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ANAES18", "sourceId": "PMID39039540", "drug": "GLP-1 receptor agonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Pre-procedural GI symptoms OR 7.66 (3.42-17.17); residual gastric content OR 6.08 (2.86-12.94); PONV OR 1.35 (NS); 30-day mortality OR 0.54 (NS)", "finding": "Peri-procedural meta-analysis: pre-procedural GLP-1 RA increased pre-procedural GI symptoms and elevated residual gastric content vs control, with no significant difference in PONV or 30-day mortality.", "population": "Meta-analysis, 14 RCTs/observational, 2143 adults, elective surgery/procedures", "comparators": "control (no GLP-1 RA)", "endpointType": "safety-event/signal", "notes": "Concordant with Elkin on residual gastric content; also reports peri-procedural glycaemic benefit.", "crossRef": "C-CLASS-SAFETY-ANAES17", "grade": "moderate", "source": { "citation": "do Nascimento TS et al., Perioper Med (Lond) 2024", "url": "https://doi.org/10.1186/s13741-024-00439-y", "identifiers": "PMID:39039540 / DOI:10.1186/s13741-024-00439-y", "date": "2024-07-22", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent - self-funded (no external sponsorship)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ANAES19", "sourceId": "PMID40995652", "drug": "GLP-1 RA / tirzepatide (class, peri-operative)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GLP-1 RA and GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Qualitative; delayed gastric emptying and residual-content risk; recommendations expert-consensus-based", "finding": "Anaesthesia narrative reviews: GLP-1 RAs and tirzepatide delay gastric emptying and raise aspiration considerations; data preliminary/conflicting; gastric ultrasound recommended; guidance is multi-society expert consensus.", "population": "Narrative reviews of peri-operative management of novel antidiabetic/anti-obesity drugs", "comparators": "SGLT2 inhibitors (contrast)", "endpointType": "safety-event/signal", "notes": "Kwak 2026 also flags a 'misidentification trap' (AOM adverse effects mistaken for surgical/anaesthetic complications), citing semaglutide NAION HR 7.64 and a WHO 2025 alert. Two DOIs bundled.", "crossRef": "C-CLASS-SAFETY-ANAES17; C-SEMA-SAFETY-EYE01; C-SEMA-SAFETY-EYE08", "grade": "low", "source": { "citation": "Doroba O et al., Anaesthesiol Intensive Ther 2025; Kwak HJ et al., Korean J Anesthesiol 2026", "url": "https://doi.org/10.5114/ait/208895", "identifiers": "PMID:40995652 / DOI:10.5114/ait/208895 ; PMID:42046446 / DOI:10.4097/kja.26375", "date": "2025-09-17", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ANTIINFLAM-JOINT-SKIN-01", "sourceId": "PMID39476339", "drug": "GLP-1-based class (anti-inflammatory / joint / skin folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Knee OA: semaglutide STEP-9 RCT (Bliddal, NEJM 2024, n=407): WOMAC pain -41.7 vs -27.5 placebo, weight -13.7% vs -3.2% (benefit tracks weight loss; placebo also improved). Reta TRIUMPH-4 phase-3 TOPLINE: 12 mg ~28.7% weight loss, WOMAC pain ~-75.8%, >1 in 8 pain-free at 68 wk (company-reported, not peer-reviewed). CRP: semaglutide reduces hs-CRP (SELECT - fell early, somewhat beyond what weight loss alone explains). Skin (psoriasis/hidradenitis): small open-label/case reports only, inconsistent, weight-confounded.", "finding": "FOLK-CLAIM VERDICT ('reduced inflammation / joint pain relief / skin improvements'): MIXED, and the mechanism-split is the whole story. (1) Knee-OA pain relief = TRUE but predominantly WEIGHT-LOSS-mediated (less joint load; STEP-9 real and large, but tracks weight and the placebo arm also improved - not proven direct chondroprotection). (2) Systemic inflammation / CRP reduction = TRUE and PARTLY DIRECT (CRP falls somewhat beyond weight loss in SELECT), though magnitude still mostly adiposity-coupled. (3) Skin (psoriasis, hidradenitis) = UNPROVEN (small/uncontrolled, weight-confounded).", "population": "Semaglutide knee-OA RCT (STEP-9) + reta knee-OA phase-3 topline (TRIUMPH-4) + CRP data (SELECT/HFpEF) + small skin series.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "GRADE: knee-OA moderate-high (STEP-9 RCT); CRP moderate; skin very-low. The reta TRIUMPH-4 knee-OA figures are PRESS/TOPLINE - NON-GRADUATING until peer-reviewed publication (the same trial that surfaced the dysesthesia signal). Belief-vs-reality: 'it's an anti-inflammatory that fixes joints and skin' - knee-OA pain relief is robust but mostly because you weigh less; CRP genuinely drops with a small direct component; skin benefit is anecdotal. Distinguish weight-mediated (joint load, adiposity-driven inflammation) from direct effect. GAP filled (OA/CRP/skin not previously covered). Cross-ref C-RETATRUTIDE-SAFETY-DYSESTHESIA-01 (same TRIUMPH-4 readout).", "crossRef": "C-RETATRUTIDE-SAFETY-DYSESTHESIA-01", "grade": "high", "source": { "citation": "Bliddal H et al. Semaglutide in knee osteoarthritis with obesity (STEP-9). N Engl J Med 2024 (PMID 39476339; phase-3 double-blind placebo-controlled RCT, NCT05064735); CRP review PMID 40115122; reta TRIUMPH-4 knee-OA is an Eli Lilly 2025 topline (not peer-reviewed).", "url": "https://doi.org/10.1056/NEJMoa2403664", "identifiers": "PMID39476339", "date": "2024-10-30", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; disclosed)", "scopeLimits": "knee-OA / obesity population; composite finding also carries press-topline (TRIUMPH-4) and small-series strands separately graded", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ASP-CONS01", "sourceId": "PMID40230298", "drug": "incretin class consolidation (peri-operative aspiration)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Residual gastric contents markedly elevated (~6-fold higher odds on meta-analysis) despite appropriate fasting; withholding >=1 dose lowered it; NO significant increase in actual pulmonary aspiration, PONV or 30-day mortality. Multi-society guidance recommends individualised hold/precaution.", "finding": "NET VERDICT (peri-operative aspiration) - the most clinically live procedural signal: by delaying gastric emptying these agents leave residual gastric contents despite guideline fasting, raising a theoretical aspiration risk under anaesthesia/sedation. Meta-analysis robustly demonstrates the RETAINED-CONTENTS surrogate but does NOT demonstrate increased actual pulmonary aspiration. Operationally live because multi-society/ASA guidance now recommends mitigation.", "population": "Patients on GLP-1RAs undergoing anaesthesia/endoscopy/sedation; meta-analyses of peri-procedural cohorts + gastric-ultrasound studies; semaglutide/liraglutide-era data; no reta-direct.", "comparators": "non-GLP-1-RA controls; fasted controls; dose-withheld vs continued", "endpointType": "safety-event/signal", "notes": "GRADE SPLIT: retained-gastric-contents surrogate = moderate (consistent, ~6-fold); actual pulmonary-aspiration hard outcome = low/very-low and NOT demonstrated to increase; guidance pole = expert multi-society consensus (moderate, not an agency label). Both poles: ANCHOR = Elkin (ANAES17) + do Nascimento (ANAES18) + Wu (ASP09); GUIDANCE = the new Kindel row; CAVEAT = narrative reviews call data preliminary, recommend gastric ultrasound (ANAES19), flag the drug-AE-vs-surgical-complication misidentification trap. RETA POSITION: reta is GI-dominant and shares the delayed-gastric-emptying mechanism, so the retained-contents class-transfer expectation applies; no reta-direct peri-operative data. VALIDATOR: confirm PMID 40230298 (retained contents ~6-fold, no aspiration increase).", "crossRef": "C-CLASS-SAFETY-ANAES17; C-CLASS-SAFETY-ANAES18; C-CLASS-SAFETY-ANAES19; C-CLASS-SAFETY-ASP09; C-CLASS-SAFETY-ASP-GUID01", "grade": "moderate", "source": { "citation": "Elkin J et al., Anaesthesia 2025", "url": "https://doi.org/10.1111/anae.16601", "identifiers": "PMID:40230298 / DOI:10.1111/anae.16601", "date": "2025-04-15", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent - investigator (Australian Government Research Training Program Scholarship); no industry study sponsor", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ASP-GUID01", "sourceId": "PMID39480373", "drug": "incretin class guidance (peri-operative)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Qualitative multi-society guidance (no effect size). Recommends individualised, risk-stratified management (consider holding pre-procedure and/or treating as 'full stomach' with point-of-care gastric ultrasound) rather than mandatory blanket cessation.", "finding": "Multi-society clinical practice guidance for safe peri-operative use of GLP-1 RAs: individualised risk-stratified management rather than fixed cessation, balancing aspiration-risk mitigation against the harms of interrupting therapy. Operationalises the earlier ASA October-2023 consensus (which advised holding GLP-1 RAs pre-procedure).", "population": "Adults on GLP-1 RAs presenting for elective procedures/anaesthesia/endoscopy.", "comparators": "", "endpointType": "safety-event/signal", "notes": "NEW gap row (no guidance-document row existed). PMID 39480373 confirmed by gather (Practice Guideline). Graded moderate: multi-society consensus, NOT an agency label/EPAR. The earlier ASA Oct-2023 consensus could not be resolved to a PMID and is referenced in-note only, NOT minted. RETA POSITION: class-level guidance; reta inherits by class-transfer pending drug-specific labelling. VALIDATOR: confirm PMID 39480373 is the multi-society GLP-1 peri-operative guidance.", "crossRef": "C-CLASS-SAFETY-ASP-CONS01; C-CLASS-SAFETY-ANAES17; C-CLASS-SAFETY-ANAES19", "grade": "moderate", "source": { "citation": "Kindel TL, Wang AY, Wadhwa A et al. (multisociety), Clin Gastroenterol Hepatol, 2024", "url": "https://doi.org/10.1016/j.cgh.2024.10.003", "identifiers": "PMID39480373", "date": "2024-10-29", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "professional-society guidance - no external/commercial funding (AGA and co-sponsoring societies; author consulting COIs disclosed)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ASP09", "sourceId": "PMID38485835", "drug": "GLP-1 RA class (semaglutide, liraglutide, dulaglutide etc.)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Visible gastric content 19% (17/90) GLP-1RA vs 5% (5/102) control; adjusted OR 5.8 (1.7-19.3); 5 emergent intubations vs 1; 1 pulmonary aspiration vs 0", "finding": "In fasting patients undergoing endoscopy under anaesthesia, GLP-1RA therapy associated with markedly higher residual gastric contents, posing additional pulmonary-aspiration risk.", "population": "Retrospective cohort, single US institution (MGH) 2019-2023, EGD under anaesthesia, 90 vs 102", "comparators": "patients starting GLP-1RA after procedure (control)", "endpointType": "imaging/physiological surrogate", "notes": "Per PubMed. Underpins ASA peri-procedural hold guidance. Small N, wide CI.", "crossRef": "C-CLASS-SAFETY-ANAES17", "grade": "low", "source": { "citation": "Wu F et al., Can J Anaesth 2024", "url": "https://doi.org/10.1007/s12630-024-02719-z", "identifiers": "PMID:38485835 / DOI:10.1007/s12630-024-02719-z", "date": "2024-03-14", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "few events/wide CI", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-BIL-CONS01", "sourceId": "PMID35344001", "drug": "incretin class consolidation (biliary)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Composite gallbladder/biliary disease RR ~1.37 (+37%; 95% CI 1.23-1.52) vs control (He 2022 RCT-meta; cholelithiasis sub-component RR ~1.27, cholecystitis also raised; dose interaction RR 1.56 high vs 0.99 low, steeper weight-loss-trial gradient RR ~2.29); concordant +26% gallbladder disorders in a CV-outcomes RCT-meta with no pancreatitis/neoplasm difference; in obesity-without-diabetes semaglutide raised gallbladder disorders >2.6-fold whereas tirzepatide showed no significant biliary excess.", "finding": "NET VERDICT (gallbladder / biliary) - one of the FEW high-confidence real GI safety signals: randomised-trial meta-analysis shows GLP-1-based therapy increases the composite of gallbladder/biliary disease, concentrated at higher doses, longer durations and in weight-loss trials. Leading mechanism is rapid weight loss + reduced gallbladder motility, so it is expected to track with weight-loss magnitude.", "population": "Pooled randomised participants across GLP-1RA trials (T2D and obesity) + CV-outcomes RCT-meta + obesity head-to-head meta. No retatrutide-direct biliary endpoint.", "comparators": "placebo; active comparators; semaglutide; tirzepatide", "endpointType": "safety-event/signal", "notes": "GRADE: high-confidence real (RCT-meta, multiple concordant). STRONG pole = He composite RR ~1.37 (+37%) with dose/weight-loss gradient (BIL01) + Galli (BIL04) + Zeng (BIL02); NUANCE/BRAKE = tirzepatide showed NO significant biliary excess in obesity-only (BIL03) - a genuine brake on the reta-amplification expectation, since reta is mechanistically closer to the dual/triple agents than to semaglutide; a semaglutide bile-duct-cancer VigiBase signal is very-low/contested (BIL15). RETA POSITION: reta is the most weight-loss-potent agent and the signal scales with weight loss, so shared (plausibly greater) biliary risk is a reasonable class-transfer expectation - expectation, NOT observation (no reta-direct endpoint). VALIDATED: PMID 35344001 (He JAMA Intern Med 2022) confirms composite RR 1.37 (95% CI 1.23-1.52); the ~1.27/+26% figure is the cholelithiasis sub-component, corrected.", "crossRef": "C-CLASS-SAFETY-BIL01; C-CLASS-SAFETY-BIL04; C-TIRZ-SAFETY-BIL02; C-SEMA-SAFETY-BIL03; C-SEMA-SAFETY-BIL15", "grade": "moderate", "source": { "citation": "He L et al., JAMA Intern Med 2022", "url": "https://doi.org/10.1001/jamainternmed.2022.0338", "identifiers": "PMID:35344001 / DOI:10.1001/jamainternmed.2022.0338", "date": "2022-05-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic-Chinese public (NSFC / Beijing NSF / CAMS)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-BIL01", "sourceId": "PMID35344001", "drug": "GLP-1 RA class (liraglutide, exenatide, dulaglutide, semaglutide, lixisenatide, albiglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Composite RR 1.37 (1.23-1.52); cholelithiasis 1.27; cholecystitis 1.36; biliary 1.55; weight-loss trials RR 2.29 vs T2D 1.27; higher dose 1.56 vs lower 0.99", "finding": "GLP-1 RA randomisation associated with increased composite of gallbladder/biliary disease (cholelithiasis, cholecystitis, biliary disease); higher at higher doses, longer durations, and in weight-loss trials.", "population": "76 RCTs, 103,371 patients; meta-analysis", "comparators": "placebo; non-GLP-1 RA drugs", "endpointType": "safety-event/signal", "notes": "Cartographic anchor for class biliary signal; dose/duration/weight-loss interaction reported.", "crossRef": "C-TIRZ-SAFETY-BIL02; C-SEMA-SAFETY-BIL03", "grade": "moderate", "source": { "citation": "He L et al., JAMA Intern Med 2022", "url": "https://doi.org/10.1001/jamainternmed.2022.0338", "identifiers": "PMID:35344001 / DOI:10.1001/jamainternmed.2022.0338", "date": "2022-05-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic-Chinese public (NSFC / Beijing NSF / CAMS)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-BIL04", "sourceId": "PMID40892610", "drug": "GLP-1 RA class (8 agents incl. efpeglenatide, tirzepatide)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GLP-1 RA / GIP-GLP-1 dual", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Gallbladder +26%; GI +63%; no difference in stroke, pancreatitis or neoplasm", "finding": "In a CV-outcomes meta-analysis, GLP-1 RAs increased gallbladder disorders by 26% but showed no difference in pancreatitis or neoplasm.", "population": "21 RCTs, 99,599 patients, mean follow-up 2.4 yr; meta-analysis", "comparators": "placebo; controls", "endpointType": "safety-event/signal", "notes": "Null pole for pancreatitis/neoplasm; gallbladder concordant with class signal.", "crossRef": "C-CLASS-SAFETY-BIL01; C-CLASS-SAFETY-PANC05", "grade": "moderate", "source": { "citation": "Galli M et al., J Am Coll Cardiol 2025", "url": "https://doi.org/10.1016/j.jacc.2025.08.027", "identifiers": "PMID:40892610 / DOI:10.1016/j.jacc.2025.08.027", "date": "2025-08-27", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic / independent - no industry sponsor (investigator grant: Sapienza University of Rome)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-BONE-CONS01", "sourceId": "CIT:consolidation-of-glp-1ra-incretin-bone-health-ap", "drug": "incretin class consolidation (bone/fracture)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Neutral-to-mildly-negative non-significant BMD/turnover effect; fracture risk NOT increased at clinical doses; pharmacological weight loss distinguished from larger post-bariatric bone loss/fracture rise.", "finding": "NET VERDICT (bone / fracture) - NEUTRAL-to-mildly-negative and LOW-grade: GLP-1R agonists show neutral-to-mildly-negative (non-significant) BMD/turnover effects, but fracture risk does NOT appear increased at clinically relevant doses; dual/triple incretin/amylin analogues may even be bone-positive (mostly preclinical). The live concern is RAPID weight loss driving sarcopenia and downstream fracture risk, not a direct osteotoxic drug effect.", "population": "Bone-health appraisal/review across GLP-1RA + incretin analogues; preclinical for dual/triple bone-positive signals.", "comparators": "placebo; post-bariatric-surgery populations; lifestyle weight loss", "endpointType": "safety-event/signal", "notes": "Single consolidated pole (genuinely neutral, not a both-poles tension). Bone appraisal (BONE16) + concurring reviews agree neutral-to-mildly-negative BMD, no clinical fracture excess. Residual concern is downstream: rapid pharmacological weight loss -> lean-mass/sarcopenia -> fall/fracture risk (cross-ref the D2 sarcopenia thread). GRADE: low (review + surrogate; fracture under-powered). RETA POSITION: class-transfer with a quantitative caveat - reta produces the LARGEST weight loss, so the rapid-weight-loss/lean-mass pathway is the most relevant reta-direct concern even though direct osteotoxicity looks neutral; no reta-direct fracture/BMD data. Consolidation row (CIT synthesis id).", "crossRef": "C-CLASS-SAFETY-BONE16; C-CLASS-BODYCOMP-08", "grade": "low", "source": { "citation": "Consolidation of GLP-1RA/incretin bone-health appraisal with the rapid-weight-loss/sarcopenia fracture concern (cross-refs BONE16)", "url": "", "identifiers": "CIT:safety-bone-consolidation-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-BONE16", "sourceId": "PMID40555693", "drug": "GLP-1 receptor agonists / incretin analogues (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 RA and incretin co-agonists", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Fracture risk not increased at clinical doses; BMD/bone-turnover neutral-to-mildly-negative, non-significant", "finding": "Bone-health appraisal: GLP-1R agonists show neutral-to-mildly-negative (non-significant) effects on bone turnover/BMD, but fracture risk does NOT appear increased at clinically relevant doses; dual/triple incretin and amylin analogues may be bone-positive (mostly preclinical).", "population": "Critical-appraisal review of anti-obesity medications and bone metabolism (clinical + preclinical)", "comparators": "", "endpointType": "safety-event/signal", "notes": "Distinguishes pharmacological weight loss from post-bariatric bone loss/fracture increase. Concurring earlier review: Herrou/Paccou PMID:37999750.", "crossRef": "C-CLASS-SAFETY-MUSCLE14", "grade": "low", "source": { "citation": "Anastasilakis AD et al., Diabetes Obes Metab 2025", "url": "https://doi.org/10.1111/dom.16541", "identifiers": "PMID:40555693 / DOI:10.1111/dom.16541", "date": "2025-06-24", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-CANC05", "sourceId": "PMID41749007", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Liver cancer HR 0.47 (0.27-0.82); pancreatic cancer HR 0.23 (0.11-0.51); all other cancers p>0.05", "finding": "Vs insulin, GLP-1RA initiation associated with LOWER liver and pancreatic cancer risk and no increased risk for most other major cancers, in a large T2D cohort.", "population": "Retrospective cohort, IBM-MarketScan, T2D 2013-2021, N=106,088, weighted vs insulin", "comparators": "insulin", "endpointType": "safety-event/signal", "notes": "Per PubMed. Observational; confounding-by-indication caveats.", "crossRef": "C-CLASS-SAFETY-CANC06; C-CLASS-SAFETY-CANC07", "grade": "low", "source": { "citation": "Rashid Z et al., J Gen Intern Med 2026", "url": "https://doi.org/10.1007/s11606-026-10300-1", "identifiers": "PMID:41749007 / DOI:10.1007/s11606-026-10300-1 / PMC13176436", "date": "2026-02-26", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-CANC06", "sourceId": "PMID40839273", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Overall 14-cancer HR 0.83 (0.76-0.91); endometrial 0.75; ovarian 0.53; meningioma 0.69; kidney HR 1.38 (0.99-1.93, p=0.04)", "finding": "In obesity, GLP-1RA use associated with LOWER overall cancer risk and reduced endometrial/ovarian/meningioma cancer, but a marginally non-significant INCREASED kidney cancer risk.", "population": "Target-trial emulation, OneFlorida+ EHR 2014-2024, 86,632 matched adults with obesity", "comparators": "non-users eligible for anti-obesity medication", "endpointType": "safety-event/signal", "notes": "Per PubMed. Kidney-cancer signal echoes Wang 2024 (HR 1.54 vs metformin); recorded as emerging/contested, not a verdict.", "crossRef": "C-CLASS-SAFETY-CANC07", "grade": "low", "source": { "citation": "Dai H et al., JAMA Oncol 2025", "url": "https://doi.org/10.1001/jamaoncol.2025.2681", "identifiers": "PMID:40839273 / DOI:10.1001/jamaoncol.2025.2681 / PMC12371547", "date": "2025-10-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-CANC07", "sourceId": "PMID38967919", "drug": "GLP-1 RA class (semaglutide, liraglutide, dulaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "vs insulin: gallbladder HR 0.35, pancreatic 0.41, hepatocellular 0.47, colorectal 0.54, endometrial 0.74, kidney 0.76; breast/thyroid NOT reduced. vs metformin: kidney HR 1.54 (1.27-1.87)", "finding": "In T2D, GLP-1RAs associated with lower risk of 10/13 obesity-associated cancers vs insulin; NO reduction for postmenopausal breast or thyroid cancer; vs metformin, INCREASED kidney cancer.", "population": "Retrospective cohort, US nationwide EHR (113M), 1,651,452 T2D, 2005-2018, 15-yr follow-up, matched", "comparators": "insulin; metformin", "endpointType": "safety-event/signal", "notes": "Per PubMed. Breast/thyroid 'no reduction' and metformin-comparator kidney-cancer increase are the contested poles. Note pancreatic/gallbladder CANCER (distinct from pancreatitis/cholecystitis) lower vs insulin.", "crossRef": "C-CLASS-SAFETY-CANC05; C-CLASS-SAFETY-CANC06; C-CLASS-SAFETY-MTC14", "grade": "low", "source": { "citation": "Wang L, Xu R, Kaelber DC, Berger NA. JAMA Netw Open 2024", "url": "https://doi.org/10.1001/jamanetworkopen.2024.21305", "identifiers": "PMID:38967919 / DOI:10.1001/jamanetworkopen.2024.21305 / PMC11227080", "date": "2024-07-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-CANC08", "sourceId": "PMID41023473", "drug": "incretin / GLP-1 + GIP based therapies", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin-based therapy", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Qualitative (mechanism-focused, no pooled estimate)", "finding": "Mechanistic 'double-edged sword' review: incretin therapies linked in some studies to increased pancreatic/thyroid/cholangiocarcinoma/colorectal cancer (esp. genetically predisposed), while showing anticancer effects in prostate, breast, ovarian and others.", "population": "Narrative review of clinical cohorts + in vivo/in vitro", "comparators": "", "endpointType": "safety-event/signal", "notes": "Per PubMed. Opposing-direction hypotheses (beta-cell proliferation concern vs antitumour mechanisms); both poles.", "crossRef": "C-CLASS-SAFETY-CANC05; C-CLASS-SAFETY-CANC07", "grade": "low", "source": { "citation": "Mavaddat H et al., Mol Biol Rep 2025", "url": "https://doi.org/10.1007/s11033-025-11062-5", "identifiers": "PMID:41023473 / DOI:10.1007/s11033-025-11062-5", "date": "2025-09-29", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-CANCER-CONS01", "sourceId": "CIT:consolidation-of-glp-1ra-cancer-association-coho", "drug": "incretin class consolidation (broader cancer)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Lower risk of liver and pancreatic cancer vs insulin; lower overall + endometrial/ovarian/meningioma in obesity; 10/13 obesity-associated cancers reduced vs insulin in T2D. Counter-poles: marginally non-significant INCREASED kidney cancer (HR ~1.54 vs metformin in an earlier study); NO reduction for postmenopausal breast or thyroid cancer; FAERS pancreatic/islet-cell disproportionality.", "finding": "NET VERDICT (broader cancer) - observational cohorts (confounded by indication) lean reassuring, with a protective pattern for obesity-associated malignancies vs insulin (lower liver/pancreatic and 10/13 obesity-associated cancers; lower overall incl. endometrial/ovarian/meningioma in obesity). This is NOT a protective claim and NOT a net-harm verdict: it sits against a contested marginal kidney-cancer signal, no reduction for postmenopausal breast/thyroid, residual pancreatic pharmacovigilance noise, and a mechanistic double-edged-sword hypothesis.", "population": "Large T2D and obesity observational cohorts + FAERS + mechanistic review.", "comparators": "insulin; metformin; DPP-4 inhibitors; non-users", "endpointType": "safety-event/signal", "notes": "BOTH POLES. Protective = lower liver+pancreatic vs insulin (CANC05), lower overall + endometrial/ovarian/meningioma in obesity (CANC06), 10/13 obesity cancers reduced (CANC07). Caution = marginal kidney-cancer increase (CANC06), no reduction for breast/thyroid (CANC07), the double-edged-sword review (CANC08). Distinguish pancreatic CANCER (lower vs insulin) from pancreatitis (separate signal). GRADE: cohorts low (confounding-by-indication); FAERS very-low; mechanistic review low. NET: reassuring-to-protective for obesity-driven cancers, with the obesity-cancer reduction the dominant pattern; residual pancreatic+kidney pharmacovigilance noise recorded not resolved. RETA POSITION: class-transfer - reta's greater weight loss could amplify any obesity-cancer reduction, but inference only; no reta-direct cancer data. Consolidation row (CIT synthesis id; basis = cross-ref'd rows).", "crossRef": "C-CLASS-SAFETY-CANC05; C-CLASS-SAFETY-CANC06; C-CLASS-SAFETY-CANC07; C-CLASS-SAFETY-CANC08; C-CLASS-SAFETY-MTC-CONS01", "grade": "very-low", "source": { "citation": "Consolidation of GLP-1RA cancer-association cohorts (vs insulin/metformin) with FAERS tumour disproportionality + a mechanistic review (cross-refs the verified CANC rows)", "url": "", "identifiers": "CIT:safety-cancer-consolidation-2026", "date": "2026-06-21", "design": "pharmacovigilance / disproportionality", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-EYE03", "sourceId": "PMID41104517", "drug": "semaglutide (GLP-1 RA class)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "HR 1.85 (1.51-2.27); rate difference 0.29/1000 PY; semaglutide-specific meta-analytic HR 2.78 (1.39-5.56)", "finding": "Multi-database active-comparator emulation (GLP-1RA vs SGLT2i): GLP-1RA associated with ~85% higher presumed-NAION risk, absolute risk small.", "population": "482,912 propensity-matched pairs GLP-1RA vs SGLT2i, three US claims databases 2016-2024", "comparators": "SGLT2 inhibitors", "endpointType": "safety-event/signal", "notes": "Target-trial emulation; signal-confirming but small absolute risk.", "crossRef": "C-SEMA-SAFETY-EYE01; C-SEMA-SAFETY-EYE08", "grade": "low", "source": { "citation": "Tesfaye H, Patorno E et al., Diabetes Obes Metab 2025", "url": "https://doi.org/10.1111/dom.70200", "identifiers": "PMID:41104517 / DOI:10.1111/dom.70200", "date": "2025-10-17", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-EYE06", "sourceId": "PMID42311413", "drug": "GLP-1 receptor agonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-level)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "NAION RR 1.01 (0.62-1.64, I2 89%); glaucoma HR 0.84 (0.71-1.00); retinopathy new-onset HR 0.96, progression HR 0.97", "finding": "REFUTING/NULL pole at class level: meta-analysis of 28 observational studies found GLP-1 RAs did NOT increase NAION, glaucoma, or retinopathy vs other antidiabetics.", "population": "Meta-analysis, 28 observational studies (6 semaglutide, 22 all GLP-1 RA) in T2D, 2006-2025", "comparators": "other antidiabetic treatments", "endpointType": "safety-event/signal", "notes": "High heterogeneity (I2 ~89%); pooled estimate null. Counterpole to signal records.", "crossRef": "C-SEMA-SAFETY-EYE01; C-SEMA-SAFETY-EYE08; C-SEMA-SAFETY-EYE07", "grade": "moderate", "source": { "citation": "Anatriello A et al., Front Pharmacol 2026", "url": "https://doi.org/10.3389/fphar.2026.1808359", "identifiers": "PMID:42311413 / DOI:10.3389/fphar.2026.1808359", "date": "2026-06-02", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent - no financial support received", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-EYE09", "sourceId": "PMID42259643", "drug": "semaglutide; tirzepatide; liraglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Semaglutide 355 reports ROR 94.45 (83.02-107.45); tirzepatide 49 reports ROR 2.94 (2.20-3.93); liraglutide 13 reports ROR 4.58 (2.65-7.91); other three no signal", "finding": "FAERS disproportionality: strong post-marketing reporting signal for optic ischaemic neuropathy with semaglutide; weaker but significant for tirzepatide and liraglutide; none for dulaglutide/exenatide/lixisenatide.", "population": "FAERS via OpenVigil 2.1, approval-Q3 2025; MedDRA 'optic ischaemic neuropathy', primary suspect", "comparators": "tirzepatide; liraglutide; dulaglutide; exenatide; lixisenatide", "endpointType": "safety-event/signal", "notes": "Disproportionality = reporting frequency, not incidence; notoriety bias amplified by publicity. Absence of signal in three agents argues against uniform class effect. Cross-drug record carrying tirzepatide and liraglutide signals.", "crossRef": "C-SEMA-SAFETY-EYE01; C-CLASS-SAFETY-EYE06", "grade": "very-low", "source": { "citation": "Kakkar AK, Payra S, Charaya A, Diabetes Obes Metab 2026", "url": "https://doi.org/10.1111/dom.70952", "identifiers": "PMID:42259643 / DOI:10.1111/dom.70952", "date": "2026-06-08", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-GI12", "sourceId": "CIT:synthesis-jastreboff-2022-jastreboff-2023-attain", "drug": "class-wide (incretin/NuSH)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 / GIP-GLP-1 / triple / glucagon co-agonist / amylin combination", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "decrease", "magnitude": "Qualitative: GI burden concentrated in escalation; lower start dose reduces it", "finding": "Across the roster, GI AEs cluster during dose escalation and are partially mitigated by slower/lower-starting-dose titration; explicit titration-mitigation evidence strongest for retatrutide (2 vs 4 mg start), stated for orforglipron and survodutide.", "population": "Synthesis across SURMOUNT-1, retatrutide phase 2, ATTAIN-1, survodutide phase 2", "comparators": "placebo", "endpointType": "other", "notes": "Cross-cutting observation, not a single-trial result. 'Decrease' denotes mitigation of GI burden, not a drug-effect direction.", "crossRef": "C-RETA-SAFETY-GI03; C-ORF-SAFETY-GI05; C-SURVO-SAFETY-GI08", "grade": "moderate", "source": { "citation": "Synthesis: Jastreboff 2022, Jastreboff 2023, ATTAIN-1, survodutide phase 2", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMIDs 35658024, 37366315", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - multiple, each disclosed per component: Eli Lilly / Boehringer Ingelheim", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-HAIRLOSS-01", "sourceId": "PMID42155605", "drug": "GLP-1-based class (hair-loss folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Meta-analysis (Cheng 2026, 9 studies/7 RCTs, n=4,114): pooled RR 3.25 (95% CI 1.44-7.36) for hair loss vs placebo; single-arm event rate ~3.9%. SURMOUNT-1 tirzepatide: dose-dependent alopecia 2.8/4.1/5.7% (5/10/15 mg) vs 1.0% placebo, strongly female-skewed (~7% women vs ~0.5% men); the FDA label notes it was 'associated with weight reduction'. FAERS signals are inconsistent across agents (modest semaglutide aROR ~1.23; non-significant for tirzepatide).", "finding": "FOLK-CLAIM VERDICT ('hair loss/shedding around month 3-4'): TRUE that it happens / OVERSTATED as a drug toxicity. Alopecia is a real, RCT-replicated signal (RR ~3.25), and the month 3-4 timing is textbook TELOGEN EFFLUVIUM. But the weight of evidence attributes it predominantly to RAPID WEIGHT LOSS + caloric/nutritional deficit (the classic trigger), NOT a direct drug-on-follicle toxicity - i.e. the drug is largely the vehicle for rapid weight loss. It is REVERSIBLE, dose-/weight-loss-magnitude-dependent and female-biased. Mitigation overlaps the muscle-loss fix (adequate protein + micronutrients: iron, zinc, B12, vitamin D).", "population": "Meta-analysis (7 RCTs) + SURMOUNT-1 trial alopecia rates + FAERS disproportionality + dermatology systematic reviews.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "GRADE moderate (RCT meta-analysis for the existence of the signal; the attribution to weight loss is review-level). GENUINE GAP filled (was 1 thin prior row). Retatrutide is UNSTUDIED for alopecia - given it produces the largest/fastest weight loss, the telogen-effluvium mechanism predicts at-least-comparable risk, but that is extrapolated, not shown. Belief-vs-reality: real and replicated, but the proximate cause is telogen effluvium from rapid weight loss + undernutrition (with a possible smaller direct semaglutide component); reversible; female-biased.", "crossRef": "C-CLASS-BODYCOMP-MUSCLELOSS-FOLK-01", "grade": "very-low", "source": { "citation": "Cheng & Chang. GLP-1 receptor agonists and hair loss: a meta-analysis. Diabetes Res Clin Pract 2026 (PMID 42155605); + Gupta 2026 systematic review (PMID 41998799, telogen effluvium / weight-loss attribution).", "url": "https://doi.org/10.1016/j.diabres.2026.113333", "identifiers": "PMID42155605", "date": "2026-01-01", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ILEUS-CONS01", "sourceId": "DOI10.3390/DIAGNOSTICS14242829", "drug": "incretin class consolidation (ileus/obstruction)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "FAERS: only WEAK / non-significant intestinal-obstruction signals, no clear class signal; a randomised-trials network meta-analysis did NOT confirm elevated mechanical-obstruction risk (liraglutide possibly protective). Delayed gastric emptying (functional) is real and on-target but distinct from mechanical obstruction.", "finding": "NET VERDICT (gastroparesis / ileus / intestinal obstruction) - a WEAK, low-grade signal: the class delays gastric emptying (on-target, prominent in tolerability) and spontaneous reports surface ileus/obstruction events, but randomised-trial-level evidence does NOT confirm elevated mechanical-obstruction risk and dedicated FAERS work found only weak/non-significant signals. Honest net: low-grade, trial-unconfirmed.", "population": "FAERS spontaneous-report databases + a randomised-trials network meta-analysis for the obstruction endpoint. No reta-direct.", "comparators": "non-GLP-1-RA reports (FAERS reference); placebo/active (network meta-analysis)", "endpointType": "safety-event/signal", "notes": "GRADE: WEAK / very-low (FAERS reporting != incidence) with the trial-level pole NOT confirming elevated mechanical obstruction. NULL/ANCHOR = FAERS weak/non-significant (ILEUS10) + network-meta unconfirmed (ILEUS11); SIGNAL = separate FAERS ileus/obstruction reports (ILEUS11) + semaglutide FAERS (PV06). IDENTIFIER CAVEAT: the FAERS-signal source behind ILEUS11 has an unverified journal/PMID (placeholder) - flagged, NOT fabricated. RETA POSITION: shares delayed-gastric-emptying mechanism (functional), but no reta-direct ileus signal and the mechanical-obstruction signal is unconfirmed even at class level. VALIDATOR: confirm DOI 10.3390/diagnostics14242829 resolves to the FAERS GI disproportionality study.", "crossRef": "C-CLASS-SAFETY-ILEUS10; C-SEMA-SAFETY-ILEUS11; C-SEMA-SAFETY-PV06", "grade": "very-low", "source": { "citation": "GI Safety Assessment of GLP-1 RAs from FAERS, Diagnostics (MDPI) 2024", "url": "https://www.mdpi.com/2075-4418/14/24/2829", "identifiers": "PMC11675942 / DOI:10.3390/diagnostics14242829", "date": "2024-12-16", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-ILEUS10", "sourceId": "DOI10.3390/DIAGNOSTICS14242829", "drug": "GLP-1 RA class (exenatide, liraglutide, dulaglutide, semaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "FAERS GI disproportionality (Osei et al., Diagnostics 2024): intestinal obstruction was an analysed preferred term with no disproportionate/clear class signal for mechanical obstruction. CORRECTION (validation 2026-06-21): the specific per-drug obstruction RORs previously listed here (exenatide 0.856; liraglutide 1.171; dulaglutide 0.962; semaglutide 1.044) were NOT located in the cited source and have been removed; the qualitative weak/non-significant-signal conclusion stands.", "finding": "FAERS disproportionality found only WEAK / non-significant intestinal-obstruction signals across GLP-1RAs; no clear class signal for mechanical obstruction.", "population": "FAERS 2007-2023, US reports, 16,568 GI AE reports (tirzepatide not included)", "comparators": "FAERS background", "endpointType": "safety-event/signal", "notes": "Contrast pole to reports flagging ileus signals (C-SEMA-SAFETY-ILEUS11). Disproportionality != causation. [VALIDATION 2026-06-21: source confirmed as the Osei Diagnostics 2024 FAERS GI study, but the specific obstruction RORs were unsupported by it and removed; status corrected. The D6 ILEUS consolidation that cross-refs this row used the qualitative weak-signal characterisation, which is unaffected.]", "crossRef": "C-SEMA-SAFETY-ILEUS11", "grade": "very-low", "source": { "citation": "GI Safety Assessment of GLP-1 RAs from FAERS, Diagnostics (MDPI) 2024", "url": "https://www.mdpi.com/2075-4418/14/24/2829", "identifiers": "PMC11675942 / DOI:10.3390/diagnostics14242829", "date": "2024-12-16", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-LIBIDO-01", "sourceId": "PMID41870138", "drug": "GLP-1-based class (libido folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Self-report goes both directions (decreased libido ~0.6% online). A randomised double-blind crossover of dulaglutide in healthy lean men showed NO effect on sexual desire, HPG-axis hormones or semen parameters. FAERS disproportionality for decreased libido/ED/orgasmic dysfunction was NON-significant. Preclinical (rodent) GLP-1R activation suppresses sexual motivation, but human data are mixed/limited. Confounder: weight loss raises testosterone/SHBG and improves erectile/sexual function in men.", "finding": "FOLK-CLAIM VERDICT ('libido changes, both up and down'): UNPROVEN / MIXED - no controlled evidence of a direct GLP-1 libido effect in either direction. The only RCT-level human datapoint (dulaglutide crossover) was null; FAERS was non-significant; the plausible 'up' direction is confounded by weight-loss-driven testosterone normalisation and improved body image, and the 'down' direction lacks a significant controlled signal. Bidirectional anecdotes are genuine experiences but do not establish a pharmacological effect.", "population": "One null dulaglutide RCT (lean men) + FAERS disproportionality + rodent data + online self-report; weight-loss/testosterone confound.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "GRADE low (one null RCT + non-significant FAERS + confounded observational). Belief-vs-reality: a genuine bidirectional anecdote set with no controlled signal; any improvement is plausibly weight/testosterone-mediated, not a direct drug action. GAP recorded as UNPROVEN/MIXED.", "crossRef": "C-CLASS-SAFETY-REPRO-CONS01", "grade": "very-low", "source": { "citation": "Narrative review of GLP-1 RAs and sexual function (men and women): dulaglutide crossover RCT null, FAERS non-significant. Sex Med Rev 2026 (PMID 41870138).", "url": "https://doi.org/10.1093/sxmrev/qeag015", "identifiers": "PMID41870138", "date": "2026-01-01", "design": "pharmacovigilance / disproportionality", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MENSTRUAL-01", "sourceId": "PMID41886296", "drug": "GLP-1-based class (menstrual-changes folk claim; semaglutide-emphasised)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Online self-report (Penn/Sehgal): ~4% of users-with-side-effects reported reproductive symptoms (intermenstrual bleeding 0.9%, heavy bleeding 0.9%, irregular cycles 0.7%), flagged as under-recognised. FAERS disproportionality (2022-2025): SEMAGLUTIDE significantly associated with reproductive/hormonal disorders incl. PCOS (aROR 6.59, 3.73-11.64) and menstrual abnormalities; dulaglutide and TIRZEPATIDE showed NEGATIVE/non-significant associations.", "finding": "FOLK-CLAIM VERDICT ('menstrual changes - intermenstrual/heavy/irregular bleeding'): MIXED / EMERGING - no longer pure self-report. Two independent low-grade signals now converge (online self-report + a semaglutide-specific FAERS reproductive signal), but it is NOT trial-grade: FAERS cannot establish incidence/causation (reporting bias, no denominator, and weight loss itself shifts cycles). Notably the pharmacovigilance signal is AGENT-SPECIFIC (semaglutide), with tirzepatide/dulaglutide trending the opposite way.", "population": "Online self-report cohort + FAERS disproportionality; no dedicated RCT endpoint.", "comparators": "", "endpointType": "safety-event/signal", "notes": "GRADE very-low/low (FAERS disproportionality + self-report; reporting != incidence; weight-loss confound). Belief-vs-reality: the 'real and under-recognised' perception is now partly supported by two converging low-grade sources, but causality is unproven and the signal lands on semaglutide specifically (not tirzepatide). Distinct from the contraception/fertility threads (D6 REPRO). Cross-ref C-CLASS-SAFETY-REPRO-CONS01.", "crossRef": "C-CLASS-SAFETY-REPRO-CONS01; C-CLASS-TOLGI-REDDIT-FREQ-01", "grade": "very-low", "source": { "citation": "Lee & Kim. Reproductive/hormonal adverse-event disproportionality of GLP-1 RAs (FAERS): semaglutide PCOS aROR 6.59. Diabetes Metab Res Rev 2026 (PMID 41886296); + Sehgal et al. online self-report (DOI 10.1038/s44360-026-00108-y).", "url": "https://doi.org/10.1002/dmrr.70163", "identifiers": "PMID41886296", "date": "2026-01-01", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH01", "sourceId": "CIT:ema-prac-meeting-highlights-8-11-april-2024", "drug": "semaglutide; liraglutide (GLP-1 RA class)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "~150 reports reviewed; conclusion: no signal, no labelling change", "finding": "EMA PRAC concluded its class review and found no evidence of a causal association with suicidal/self-injurious thoughts/actions; no product-information update warranted. Triggered by Icelandic case reports (initially 3), ~150 reports analysed.", "population": "Regulatory review of non-clinical, clinical-trial, post-marketing and observational data; Jul 2023-Apr 2024", "comparators": "", "endpointType": "safety-event/signal", "notes": "No-signal pole. EMA-commissioned final study report (16 Feb 2024) informed the conclusion.", "crossRef": "C-CLASS-SAFETY-MH04; C-CLASS-SAFETY-MH02", "grade": "high", "source": { "citation": "EMA PRAC, Meeting highlights 8-11 April 2024", "url": "https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-april-2024", "identifiers": "EMA/PRAC-GLP1-2024", "date": "2024-04-12", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH02", "sourceId": "CIT:fda-drug-safety-communication-fda-requests-remov", "drug": "semaglutide; liraglutide; tirzepatide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Meta-analysis of 91 trials, 107,910 participants (60,338 GLP-1, 47,752 placebo); no increased risk; warning removal requested", "finding": "FDA, after a comprehensive review incl. a meta-analysis of 91 trials, found no increased suicidality risk and REQUESTED REMOVAL of the suicidal-behaviour-and-ideation warning from labels for liraglutide, semaglutide 2.4 mg and tirzepatide.", "population": "FDA pooled clinical-trial meta-analysis + post-marketing/observational review", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Strongest regulatory conclusion to date (warning REMOVAL). Began as a 2023 FDA investigation into post-marketing suicidality + aspiration reports; interim Jan-2024 DSC already found no evidence of causation.", "crossRef": "C-CLASS-SAFETY-MH01; C-SEMA-SAFETY-MH03", "grade": "high", "source": { "citation": "FDA Drug Safety Communication, 'FDA Requests Removal of Suicidal Behavior and Ideation Warning from GLP-1 RA Medications'", "url": "https://www.fda.gov/drugs/drug-safety-communications/fda-requests-removal-suicidal-behavior-and-ideation-warning-glucagon-peptide-1-receptor-agonist-glp", "identifiers": "FDA-DSC-GLP1-2026", "date": "2026-01-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH04", "sourceId": "PMID39433133", "drug": "semaglutide; liraglutide; tirzepatide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Ideation ROR: sema 5.82, lira 4.03, tirz 2.25. Depression/suicidal: sema 14.74, lira 5.86. Behaviour: sema 6.52, lira 3.90. Attempts DECREASED (sema 0.11, lira 0.15); completed suicide DECREASED (sema 0.01, lira 0.008)", "finding": "VigiBase (WHO) disproportionality: significantly increased ROR for suicidal IDEATION with semaglutide, liraglutide, tirzepatide, and for 'depression/suicidal' and suicidal behaviour with semaglutide/liraglutide; BUT significantly DECREASED ROR for suicide attempts and completed suicide.", "population": "WHO VigiBase reports, inception-Jan 2024; disproportionality", "comparators": "full database background", "endpointType": "safety-event/signal", "notes": "Per PubMed. Signal-positive pole for IDEATION (replicates the authors' earlier FAERS finding) but signal-negative for completed suicide. Authors: causality not ascertainable from ROR data either direction.", "crossRef": "C-SEMA-SAFETY-MH03; C-CLASS-SAFETY-MH05", "grade": "very-low", "source": { "citation": "McIntyre RS et al., J Affect Disord 2024;369:922-927", "url": "https://doi.org/10.1016/j.jad.2024.10.062", "identifiers": "PMID:39433133 / DOI:10.1016/j.jad.2024.10.062", "date": "2024-10-19", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH05", "sourceId": "PMID38355513", "drug": "semaglutide; liraglutide; dulaglutide; exenatide; albiglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "204 SSIB cases; information-component not elevated; 81/204 on antidepressants/antipsychotics/benzodiazepines", "finding": "FAERS disproportionality (2018-2022): no signal of disproportionate reporting for suicidal/self-injurious behaviours; co-medication analysis flagged psychiatric-comorbidity proxies.", "population": "FAERS 2018-2022; disproportionality (information component)", "comparators": "full database background", "endpointType": "safety-event/signal", "notes": "Per PubMed. No-signal pole within FAERS (contrast with McIntyre ROR). Different window/method (IC vs ROR) partly explains divergence.", "crossRef": "C-CLASS-SAFETY-MH04; C-CLASS-SAFETY-MH06", "grade": "very-low", "source": { "citation": "Zhou J et al., BMC Med 2024;22(1):65", "url": "https://doi.org/10.1186/s12916-024-03274-6", "identifiers": "PMID:38355513 / DOI:10.1186/s12916-024-03274-6", "date": "2024-02-14", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH06", "sourceId": "PMID38508100", "drug": "semaglutide; liraglutide; dulaglutide; exenatide; tirzepatide; albiglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP-GLP-1", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "ROR (psychiatric ADRs): sema 2.03, tirz 1.76, lira 1.64, dula 0.84, exen 0.80, albi 0.04. 271 unmasked GLP-1 cases; 236 ideation cases; 13 completed suicides", "finding": "FAERS unmasking analysis (2005-2023) with metformin/orlistat comparators: per-agent RORs for psychiatric ADRs elevated for semaglutide (2.03), tirzepatide (1.76), liraglutide (1.64) but lower than metformin; 42 deaths incl. 13 completed suicides; no causal link inferable.", "population": "FAERS 2005-2023, psychiatric-disorder ADRs, metformin/orlistat comparators; unmasking + disproportionality", "comparators": "metformin; orlistat", "endpointType": "safety-event/signal", "notes": "Per PubMed. Per-agent RORs elevated vs background but lower than metformin; rapid weight loss hypothesised as a possible trigger. No causality inferable.", "crossRef": "C-CLASS-SAFETY-MH04", "grade": "very-low", "source": { "citation": "Guirguis A et al., Eur Neuropsychopharmacol 2024;82:82-91", "url": "https://doi.org/10.1016/j.euroneuro.2024.02.003", "identifiers": "PMID:38508100 / DOI:10.1016/j.euroneuro.2024.02.003", "date": "2024-03-19", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH07", "sourceId": "PMID38031404", "drug": "GLP-1 RA class (incl. semaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Overall ROR 0.16 (0.15-0.18); children ROR 2.50 (1.02-6.13, p=0.05) but EBGM05 <2 (not confirmed)", "finding": "FAERS disproportionality (2005-2023): no overall disproportionate increase in suicide/self-injury; a marginal ROR elevation in children was NOT confirmed by EBGM05.", "population": "FAERS 2005 Q2-2023 Q2; 534 cases; ROR + EBGM with age/sex stratification", "comparators": "full database background", "endpointType": "safety-event/signal", "notes": "Per PubMed. No-signal overall; paediatric subgroup ROR is the one emerging caveat (unconfirmed by Bayesian method).", "crossRef": "C-CLASS-SAFETY-MH05", "grade": "very-low", "source": { "citation": "Chen C et al., Eur Psychiatry 2023;66(1):e99", "url": "https://doi.org/10.1192/j.eurpsy.2023.2474", "identifiers": "PMID:38031404 / DOI:10.1192/j.eurpsy.2023.2474", "date": "2023-11-30", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MH10", "sourceId": "DOI10.1007/S00125-024-06243-Z", "drug": "GLP-1 RA class (semaglutide, liraglutide, etc.)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Per-protocol HR 1.04 (95% CI 0.35-3.14) for suicidal ideation/self-harm vs SGLT-2i - null (propensity-weighted Spanish cohort).", "finding": "Propensity-weighted population-based cohort (Diabetologia): assessed GLP-1 RA association with suicidal ideation/self-injury in diabetes and obesity; part of the cohort evidence body informing regulators.", "population": "Individuals with diabetes and obesity; propensity-weighted population-based cohort", "comparators": "active comparators", "endpointType": "safety-event/signal", "notes": "Additional cohort-pole data point. Exact HRs not extracted this pass (PMC11519213 available); recorded with confirmed DOI.", "crossRef": "C-SEMA-SAFETY-MH03", "grade": "low", "source": { "citation": "Population-based cohort, Diabetologia 2024", "url": "https://link.springer.com/article/10.1007/s00125-024-06243-z", "identifiers": "DOI:10.1007/s00125-024-06243-z", "date": "2024-09-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MTC-CONS01", "sourceId": "CIT:consolidation-of-the-fda-semaglutide-tirzepatide", "drug": "incretin class consolidation (thyroid C-cell / MTC)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Rodent: dose/duration-dependent C-cell adenomas/carcinomas at clinically relevant exposures (mice, rats). Human: French SNDS raised HR at 1-3 yr (signal); Scandinavian upper CI <=1.31, MTC null on point estimate; Korean MTC null; FAERS specific MTC disproportionality (reporting != incidence); liraglutide calcitonin screening (>5000 subjects, up to 2 yr) showed no between-group difference.", "finding": "NET VERDICT (thyroid C-cell / MTC) - a RODENT-based FDA boxed warning and class contraindication (personal/family MTC history, or MEN 2) coexists with a NULL-to-unconfirmed HUMAN signal. The regulatory contraindication stands as a labelling FACT while no human MTC excess is confirmed - the rodent C-cell tumourigenic effect does NOT translate (human calcitonin screening negative; null cohorts dominate over reporting-driven signal poles).", "population": "Rodent toxicology (mice/rats) underpinning labels; human pharmacovigilance + national active-comparator cohorts (SNDS, Scandinavian, Korean) + FAERS; prospective calcitonin screening (liraglutide programme).", "comparators": "placebo; DPP-4 inhibitors; other antidiabetics; no-treatment cohorts", "endpointType": "safety-event/signal", "notes": "BOTH POLES. Signal = SNDS (MTC11) + FAERS specific MTC (MTC14). Null/refuting = Scandinavian (MTC12) + Korean (MTC13) + the mechanism-killer liraglutide calcitonin screening (MTC08). Regulatory anchor = semaglutide (MTC09) + tirzepatide (MTC10) boxed warnings, both stating human relevance NOT determined. SPECIES CAVEAT (load-bearing): the C-cell tumour finding is RODENT and does NOT translate (rodent C-cells far more GLP-1R-rich/tumour-prone than human). GRADE: boxed warning a regulatory fact (low, rodent-basis); human cohorts low; FAERS/SNDS very-low. NET: rodent warning real -> labelled contraindication retained; human MTC excess NOT confirmed. RETA POSITION: class-transfer - reta expected to carry the same boxed-warning labelling + MEN2/MTC-history contraindication on approval; no reta-direct human MTC data. Consolidation row (id is a CIT synthesis marker; evidentiary basis is the cross-ref'd verified rows).", "crossRef": "C-SEMA-SAFETY-MTC09; C-TIRZ-SAFETY-MTC10; C-LIRA-SAFETY-MTC08; C-CLASS-SAFETY-MTC11; C-CLASS-SAFETY-MTC12; C-CLASS-SAFETY-MTC13; C-CLASS-SAFETY-MTC14", "grade": "low", "source": { "citation": "Consolidation of the FDA semaglutide/tirzepatide boxed warning with human cohort + pharmacovigilance + calcitonin-screening evidence (cross-refs the verified MTC rows)", "url": "", "identifiers": "CIT:safety-mtc-consolidation-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MTC11", "sourceId": "PMID36356111", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "All thyroid cancer adjusted HR 1.58 (1.27-1.95) for 1-3 yr use; MTC adjusted HR 1.78 (1.04-3.05)", "finding": "SIGNAL pole: French SNDS nested case-control found GLP-1 RA use for 1-3 years associated with increased all-thyroid-cancer AND medullary thyroid cancer risk.", "population": "2562 thyroid-cancer cases vs 45,184 controls; T2D on second-line antidiabetics 2006-2018, France", "comparators": "GLP-1 RA non-users among T2D", "endpointType": "safety-event/signal", "notes": "The SIGNAL pole for human thyroid/MTC; debated for residual confounding/surveillance bias.", "crossRef": "C-CLASS-SAFETY-MTC12; C-CLASS-SAFETY-MTC13", "grade": "low", "source": { "citation": "Bezin J et al., Diabetes Care 2023", "url": "https://doi.org/10.2337/dc22-1148", "identifiers": "PMID:36356111 / DOI:10.2337/dc22-1148", "date": "2023-02-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MTC12", "sourceId": "PMID38683947", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "All thyroid cancer HR 0.93 (0.66-1.31); MTC HR 1.19 (0.37-3.86); vs SGLT2i HR 1.16 (0.65-2.05)", "finding": "REFUTING pole: Scandinavian three-country active-comparator cohort found no substantially increased thyroid cancer risk vs DPP-4 inhibitors; MTC estimate imprecise/null on point estimate.", "population": "145,410 GLP-1 RA vs 291,667 DPP-4i initiators; Denmark/Norway/Sweden 2007-2021; mean follow-up 3.9 yr", "comparators": "DPP-4 inhibitors; SGLT2 inhibitors", "endpointType": "safety-event/signal", "notes": "NULL/refuting pole against Bezin; upper CI consistent with no more than 31% relative increase.", "crossRef": "C-CLASS-SAFETY-MTC11; C-CLASS-SAFETY-MTC13", "grade": "low", "source": { "citation": "Pasternak B et al., BMJ 2024", "url": "https://doi.org/10.1136/bmj-2023-078225", "identifiers": "PMID:38683947 / DOI:10.1136/bmj-2023-078225", "date": "2024-04-10", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MTC13", "sourceId": "PMID39443282", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Pancreatic IRR 0.74; thyroid IRR 1.32 (NS); MTC IRR 0.34. (T2D had 73% higher overall cancer risk vs general population)", "finding": "Second NULL pole: Korean nationwide cohort found no association with new-onset cancers incl. pancreatic and MTC; thyroid point estimate >1 but NS.", "population": "7827 propensity-matched (GLP-1 RA / DM control / non-DM control); Korean NHIS 2004-2021; median follow-up 8 yr", "comparators": "DM controls; non-DM controls", "endpointType": "safety-event/signal", "notes": "Longer median follow-up (8 yr).", "crossRef": "C-CLASS-SAFETY-MTC11; C-CLASS-SAFETY-MTC12", "grade": "low", "source": { "citation": "Kim M et al., Diabetes Metab J 2024", "url": "https://doi.org/10.4093/dmj.2024.0105", "identifiers": "PMID:39443282 / DOI:10.4093/dmj.2024.0105", "date": "2024-10-24", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MTC14", "sourceId": "PMID36386208", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "All tumours PRR 0.83; MTC PRR 27.43; papillary thyroid PRR 8.68; pancreatic neoplasms PRR 9.86; islet cell PRR 2.86", "finding": "FAERS tumour disproportionality (2004-2021): NO overall increase at system-organ-class level, but significant signals for MTC, papillary thyroid cancer, malignant pancreatic neoplasms and islet-cell neoplasms.", "population": "8718 GLP-1 RA tumour reports; FAERS Q1 2004-Q2 2021; disproportionality", "comparators": "FAERS background", "endpointType": "safety-event/signal", "notes": "Both poles in one study: overall PRR <1 yet specific high MTC/pancreatic signals. Reporting bias (boxed-warning-driven) possible.", "crossRef": "C-CLASS-SAFETY-MTC11; C-CLASS-SAFETY-MTC12; C-CLASS-SAFETY-MTC13", "grade": "very-low", "source": { "citation": "Yang Z et al., Front Pharmacol 2022", "url": "https://doi.org/10.3389/fphar.2022.925377", "identifiers": "PMID:36386208 / DOI:10.3389/fphar.2022.925377", "date": "2022-10-25", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MUSCLE12", "sourceId": "PMID39719170", "drug": "GLP-1 / GIP receptor agonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 and GLP-1/GIP receptor agonists", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Across GLP-1 RAs: weight MD -3.55 kg, fat mass -2.95 kg, lean mass -0.86 kg (-1.30 to -0.42); lean loss ~25% of total weight loss", "finding": "Network meta-analysis (body composition): potent agents produce greatest fat-mass loss but significant ABSOLUTE lean-mass loss; RELATIVE (% baseline) lean mass unchanged. Tirzepatide/semaglutide most effective for weight/fat, among least effective at preserving lean mass.", "population": "Network meta-analysis, 22 RCTs, 2258 participants (diabetes and/or overweight/obesity), through Nov 2024", "comparators": "placebo; liraglutide; tirzepatide; semaglutide", "endpointType": "safety-event/signal", "notes": "Absolute vs relative lean-mass framings both recorded. Liraglutide was the only GLP-1 RA achieving significant weight loss without significant lean-mass reduction. Cross-links body-composition.", "crossRef": "C-TIRZ-SAFETY-MUSCLE13; C-CLASS-SAFETY-MUSCLE14", "grade": "moderate", "source": { "citation": "Karakasis P et al., Metabolism 2024", "url": "https://doi.org/10.1016/j.metabol.2024.156113", "identifiers": "PMID:39719170 / DOI:10.1016/j.metabol.2024.156113", "date": "2024-12-22", "design": "network meta-analysis", "maturity": "review", "funding": "academic / independent - no specific grant funding", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MUSCLE14", "sourceId": "PMID38687506", "drug": "incretin therapies (liraglutide, semaglutide, tirzepatide, retatrutide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP/GLP-1 / triple agonists", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Lean mass loss ~10% or ~6 kg; supervised resistance training >10 wk can add ~3 kg lean mass and ~25% strength", "finding": "Narrative review framing: incretin agents cause rapid significant lean-mass loss (~10% of body weight, ~6 kg), characterised as comparable to a decade+ of ageing, raising sarcopenia/frailty concern; resistance exercise proposed to preserve muscle.", "population": "Narrative review across liraglutide, semaglutide, tirzepatide, retatrutide (~15-24% weight loss)", "comparators": "", "endpointType": "safety-event/signal", "notes": "'Ageing-equivalent' framing is the authors' characterisation, not a measured endpoint. Includes retatrutide. Counterpoint in C-CLASS-SAFETY-MUSCLE15.", "crossRef": "C-CLASS-SAFETY-MUSCLE12; C-CLASS-SAFETY-MUSCLE15", "grade": "low", "source": { "citation": "Locatelli JC et al., Diabetes Care 2024", "url": "https://doi.org/10.2337/dci23-0100", "identifiers": "PMID:38687506 / DOI:10.2337/dci23-0100", "date": "2024-10-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-MUSCLE15", "sourceId": "PMID41011082", "drug": "incretin therapies (semaglutide, tirzepatide, liraglutide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / GIP/GLP-1 agonists", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Qualitative: clinical trials show proportional fat and lean loss; preclinical data show muscle-quality benefits", "finding": "Opposite-pole mechanistic view: emerging preclinical/translational data suggest possible muscle-specific BENEFICIAL effects (attenuated atrophy, improved myogenesis/mitochondrial function, reduced myosteatosis), alongside clinical proportional fat/lean loss.", "population": "Narrative review of preclinical (animal) and clinical evidence on skeletal muscle", "comparators": "", "endpointType": "safety-event/signal", "notes": "Muscle-QUALITY-may-improve pole vs muscle-MASS-falls pole; tension between mass and quality, rodent and human; why left open.", "crossRef": "C-CLASS-SAFETY-MUSCLE14; C-CLASS-SAFETY-MUSCLE12", "grade": "very-low", "source": { "citation": "Koceva A, Janez A, Jensterle M, Medicina (Kaunas) 2025", "url": "https://doi.org/10.3390/medicina61091691", "identifiers": "PMID:41011082 / DOI:10.3390/medicina61091691", "date": "2025-09-18", "design": "preclinical (rodent)", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-NAION-CONS01", "sourceId": "PMID40810985", "drug": "semaglutide (class-level GLP-1 NAION signal)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "RCT meta NAION Peto OR 3.92 (95% CI 1.02-15.02; 78 RCTs, n=73,640) but trial-sequential analysis judged data INSUFFICIENT for a definitive NAION conclusion; Danish ~2x 5-yr risk; GLP-1RA vs SGLT2i ~+85%; vs null/lower in a Military Health System cohort and a 28-study meta. EMA/PRAC added NAION to the semaglutide label as 'very rare' (~1/10,000).", "finding": "NET VERDICT (NAION, non-arteritic anterior ischaemic optic neuropathy) - a REAL but DEBATED and rare class signal: observational cohorts split (some ~doubled risk, others null/protective); the 2025 RCT-level meta-analysis found a significant NAION Peto OR 3.92 but TSA judged the data insufficient for a definitive conclusion; EMA/PRAC added NAION to the semaglutide label (frequency 'unknown'/very rare). Absolute incidence is small throughout.", "population": "Adults with T2D and overweight/obesity; signal strongest in T2D, longer follow-up (>=2 yr) and with hypertension. RCT meta n=73,640; observational cohorts range single-centre to nationwide.", "comparators": "placebo; non-GLP-1RA antidiabetics; SGLT2i; active comparators", "endpointType": "imaging/physiological surrogate", "notes": "NET: real-but-debated, rare. SIGNAL = EYE01/02/03/04(late)/07 + spontaneous-report screen EYE09 + the RCT meta NAION OR 3.92. NULL = EYE05/06 + the same RCT meta CLEARING eye-disorders/retinopathy. REGULATORY = EYE08 (EMA/PRAC label 'very rare'). GRADE: NAION-positive evidence largely observational (low) tensioned by one RCT-level meta (moderate but TSA-insufficient for NAION) + the FACT of labelling. RETA POSITION: UNSTUDIED for NAION; reta IS a GLP-1 agonist so the class concern transfers by expectation - flag in any reta dossier, do not assert as observed. Sits ABOVE EYE01-09, does not duplicate them. VALIDATOR: confirm PMID 40810985 (Natividade JAMA Ophthalmol 2025, NAION Peto OR 3.92, TSA-insufficient, DR null).", "crossRef": "C-SEMA-SAFETY-EYE01; C-SEMA-SAFETY-EYE02; C-CLASS-SAFETY-EYE03; C-SEMA-SAFETY-EYE04; C-SEMA-SAFETY-EYE05; C-CLASS-SAFETY-EYE06; C-SEMA-SAFETY-EYE07; C-SEMA-SAFETY-EYE08; C-CLASS-SAFETY-EYE09", "grade": "moderate", "source": { "citation": "Natividade GR et al., JAMA Ophthalmol, 2025 (RCT-level ocular meta) consolidating observational cohorts EYE01-EYE07 + EMA/PRAC label EYE08", "url": "https://doi.org/10.1001/jamaophthalmol.2025.2489", "identifiers": "PMID40810985", "date": "2025-09-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty); full JAMA COI disclosures paywalled", "scopeLimits": "single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PANC-CONS01", "sourceId": "PMID40988099", "drug": "incretin class consolidation (pancreatitis)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "RCT/meta: pancreatitis nominally raised overall but NOT significant once stratified by background medication; pancreatic cancer not associated overall (a signal only in the with-background-medication stratum). CV-outcomes RCT-meta: NO difference in pancreatitis or neoplasm. Counter-pole FAERS: liraglutide greatest pancreatitis reporting signal; semaglutide unexpected pancreatic-cancer reports (reporting != incidence).", "finding": "NET VERDICT (pancreatitis / pancreatic cancer) - largely REASSURED at trial level: randomised and meta-analytic evidence shows no clear increase in pancreatitis (any nominal excess attenuates on stratification) and no overall pancreatic-cancer association. Against this sits a persistent FAERS reporting signal (reporting != incidence). Net: not a confirmed real signal at trial level, with the FAERS pole retained as a low-grade caveat.", "population": "Pooled randomised trial participants (the Wen 2025 meta reportedly INCLUDES retatrutide); CV-outcomes trial populations; FAERS.", "comparators": "placebo; active comparators; background-medication strata", "endpointType": "safety-event/signal", "notes": "GRADE: REASSURING at RCT-meta (moderate evidence of no clear increase) vs very-low FAERS reporting signal. NULL pole = Wen (PANC05) + Galli (BIL04); SIGNAL pole = FAERS liraglutide pancreatitis (PV07), semaglutide pancreatic-cancer (PV06), + the residual with-background-medication pancreatic-cancer stratum in Wen - all reporting != incidence. RETA POSITION: reta is reportedly INCLUDED in Wen's pooled trials, so it shares the reassuring trial-level pole DIRECTLY (not merely class-transfer); no reta-specific pancreatitis excess. VALIDATOR: confirm PMID 40988099 (Wen 2025) + whether it includes retatrutide.", "crossRef": "C-CLASS-SAFETY-PANC05; C-CLASS-SAFETY-BIL04; C-CLASS-SAFETY-PV07; C-SEMA-SAFETY-PV06", "grade": "moderate", "source": { "citation": "Wen J et al., Endocrinol Diabetes Metab 2025", "url": "https://doi.org/10.1002/edm2.70113", "identifiers": "PMID:40988099 / DOI:10.1002/edm2.70113", "date": "2025-09-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "none-declared (independent meta-analysis)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PANC05", "sourceId": "PMID40988099", "drug": "GLP-1 RA class (incl. retatrutide, tirzepatide, beinaglutide)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1 RA / multi-agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Pancreatitis RR 1.44 (1.09-1.89) overall; stratified NS. Pancreatic cancer RR 1.30 (NS) overall; with background meds 1.85 (1.05-3.26)", "finding": "Significantly increased pancreatitis risk overall, but NOT significant when stratified by background medication; pancreatic cancer not associated overall, but a signal in the with-background-medication stratum.", "population": "62 RCTs, 66,232 patients, mean follow-up 43.5 wk; meta-analysis", "comparators": "placebo; active comparators", "endpointType": "safety-event/signal", "notes": "Includes retatrutide among pooled trials. Contested pancreatitis signal attenuates on stratification - both poles within one study.", "crossRef": "C-TIRZ-SAFETY-BIL02", "grade": "moderate", "source": { "citation": "Wen J et al., Endocrinol Diabetes Metab 2025", "url": "https://doi.org/10.1002/edm2.70113", "identifiers": "PMID:40988099 / DOI:10.1002/edm2.70113", "date": "2025-09-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "none-declared (independent meta-analysis)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PREG01", "sourceId": "PMID38079178", "drug": "GLP-1 RA class (semaglutide, liraglutide, exenatide, dulaglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "MCM 8.3% in GLP-1RA-exposed (n=938) vs 7.8% insulin (n=5078); adjusted RR 0.95 (0.72-1.26)", "finding": "Periconceptional GLP-1 RA exposure NOT associated with a large increased major-congenital-malformation risk vs insulin, in a multinational cohort of pregnant women with T2D.", "population": "Cohort, 4 Nordic + US MarketScan + Israeli Maccabi, 2009-2021; T2D pregnancies, infants to 1 yr", "comparators": "insulin; sulfonylureas; DPP-4i; SGLT2i", "endpointType": "safety-event/signal", "notes": "Per PubMed. Estimates imprecise/confounded by maternal T2D; no glycaemic-control data. Reassuring but not exonerating.", "crossRef": "C-CLASS-SAFETY-PREG02", "grade": "low", "source": { "citation": "Cesta CE et al., JAMA Intern Med 2024", "url": "https://doi.org/10.1001/jamainternmed.2023.6663", "identifiers": "PMID:38079178 / DOI:10.1001/jamainternmed.2023.6663", "date": "2024-02-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PREG02", "sourceId": "PMID39181497", "drug": "GLP-1 RA class (incl. semaglutide, liraglutide, tirzepatide, dulaglutide, exenatide, lixisenatide)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GLP-1 / incretin receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Qualitative (animal teratogenic signal; human signal not consistently demonstrated)", "finding": "Animal reproductive-tox studies show adverse offspring outcomes (decreased fetal growth, skeletal/visceral anomalies, embryonic death); no consistent pattern of human congenital anomalies to date.", "population": "Review of animal repro-tox + human case reports/cohort/population studies", "comparators": "insulin", "endpointType": "safety-event/signal", "notes": "Per PubMed. Animal-vs-human discordance recorded as-is. Authors recommend contraception; fertility improves with weight loss.", "crossRef": "C-CLASS-SAFETY-PREG01; C-CLASS-SAFETY-PREG03", "grade": "low", "source": { "citation": "Drummond RF, Seif KE, Reece EA. Am J Obstet Gynecol 2024", "url": "https://doi.org/10.1016/j.ajog.2024.08.024", "identifiers": "PMID:39181497 / DOI:10.1016/j.ajog.2024.08.024", "date": "2024-08-23", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PREG03", "sourceId": "PMID42122936", "drug": "GLP-1 RA class (semaglutide, liraglutide)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Qualitative (improved ovulation/fertility); pregnancy-exposure data sparse", "finding": "GLP-1 RAs may improve ovulatory function/menstrual regularity (esp. obesity/PCOS), potentially increasing conception and unintended pregnancy; human pregnancy-exposure safety data remain limited.", "population": "Narrative review 2020-2025, reproductive-age women", "comparators": "", "endpointType": "safety-event/signal", "notes": "Per PubMed. 'Fertility-restoration -> unintended pregnancy' mechanism underlies contraception advice.", "crossRef": "C-TIRZ-SAFETY-CONTRA04", "grade": "low", "source": { "citation": "Abedi MM et al., J Clin Med 2026", "url": "https://doi.org/10.3390/jcm15093204", "identifiers": "PMID:42122936 / DOI:10.3390/jcm15093204 / PMC13164487", "date": "2026-04-22", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-PV07", "sourceId": "PMID36568085", "drug": "GLP-1 RA class", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Liraglutide pancreatitis ROR 32.67 (29.44-36.25); class GI ROR 1.46; semaglutide nausea ROR 7.41, vomiting 6.67, diarrhoea 3.55, constipation 6.17", "finding": "FAERS: liraglutide carried the greatest pancreatitis reporting signal of the class; semaglutide greatest for nausea/vomiting/diarrhoea/constipation.", "population": "FAERS Jan 2018-Sep 2022; 21,281 GI reports; disproportionality", "comparators": "FAERS background", "endpointType": "safety-event/signal", "notes": "RORs reflect reporting, not incidence.", "crossRef": "C-SEMA-SAFETY-PV06", "grade": "very-low", "source": { "citation": "Liu L et al., Front Endocrinol 2022", "url": "https://doi.org/10.3389/fendo.2022.1043789", "identifiers": "PMID:36568085 / DOI:10.3389/fendo.2022.1043789", "date": "2022-12-07", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-REPRO-CONS01", "sourceId": "CIT:consolidation-of-the-tirzepatide-oral-contracept", "drug": "incretin class consolidation (reproductive)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Contraception: tirzepatide label advises non-oral or added barrier method for 4 weeks after initiation and each dose escalation (oral only). Fertility: improved ovulation/menstrual regularity esp. obesity/PCOS. Pregnancy: animal decreased fetal growth + skeletal/visceral anomalies + embryonic death; human periconceptional exposure NOT associated with a large major-malformation increase vs insulin (imprecise).", "finding": "NET VERDICT (reproductive) - three threads, distinct grades. (1) ORAL hormonal contraceptive efficacy is REDUCED by tirzepatide (delayed gastric emptying) - a real LABELLED interaction (barrier/non-oral advised), labelled for tirzepatide but not injectable semaglutide. (2) FERTILITY: GLP-1RAs improve ovulatory function in obesity/PCOS ('Ozempic babies'), raising conception/unintended-pregnancy risk. (3) PREGNANCY: contraindicated - animal repro-tox shows adverse offspring outcomes, while human cohorts show NO large major-malformation excess vs insulin (reassuring but confounded, not exonerating).", "population": "Tirzepatide label (PK interaction); GLP-1RA ovulation/PCOS literature; animal reproductive-toxicology + a multinational human pregnancy-exposure cohort (T2D).", "comparators": "insulin (pregnancy cohort); non-oral contraceptive methods; pre-treatment baseline (ovulation)", "endpointType": "safety-event/signal", "notes": "THREE THREADS. (1) Contraception (CONTRA04): tirzepatide reduces ORAL contraceptive efficacy via delayed gastric emptying - LABELLED (firmest, regulatory/PK fact), distinctive vs injectable semaglutide; non-oral methods unaffected. (2) Fertility (PREG03): improved ovulation in obesity/PCOS -> 'Ozempic babies' - the mechanism MOTIVATING the contraception advice (low, observational). (3) Pregnancy BOTH POLES: animal repro-tox adverse outcomes (PREG02; SPECIES CAVEAT) vs human no-large-malformation-excess (PREG01; reassuring but imprecise/confounded). Net: pregnancy contraindicated (precautionary), contraception counselling indicated. GRADE: contraceptive interaction firmest (label/PK); fertility + pregnancy cohort low; animal repro-tox very-low for human inference. RETA POSITION: class-transfer pregnancy contraindication expected; an oral-contraceptive interaction is plausible for any gastric-emptying-delaying drug but is reta-UNCONFIRMED (tirzepatide-specific labelling - do not assume reta carries it without its own label). Consolidation row (CIT synthesis id).", "crossRef": "C-TIRZ-SAFETY-CONTRA04; C-CLASS-SAFETY-PREG01; C-CLASS-SAFETY-PREG02; C-CLASS-SAFETY-PREG03", "grade": "low", "source": { "citation": "Consolidation of the tirzepatide oral-contraceptive labelled interaction with GLP-1RA fertility/ovulation evidence + animal repro-tox + a human pregnancy cohort (cross-refs CONTRA04/PREG01-03)", "url": "", "identifiers": "CIT:safety-repro-consolidation-2026", "date": "2026-06-21", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-RETINOPATHY-CONS01", "sourceId": "PMID27633186", "drug": "semaglutide (rapid-glucose-lowering retinopathy)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "SUSTAIN-6 retinopathy-complication HR 1.76 (95% CI 1.11-2.78), p=0.02; RCT-level pooled diabetic-retinopathy OR 1.04 (95% CI 0.92-1.17), null and TSA-confirmed; post-hoc: central retinal thickness change attenuated on Time-in-Range adjustment (TIR independently associated with increased CRT).", "finding": "NET VERDICT (early-worsening diabetic retinopathy): SUSTAIN-6 found retinopathy complications significantly MORE frequent with semaglutide than placebo (HR 1.76), widely attributed to RAPID glucose-lowering ('early worsening') in those with pre-existing retinopathy - a KNOWN phenomenon, not necessarily a direct drug effect. At RCT level the 2025 meta found NO overall DR increase (OR 1.04, TSA-sufficient), and a post-hoc RCT showed CRT change explained by glycaemic change rather than drug-specific toxicity.", "population": "T2D at high CV risk with variable baseline retinopathy (SUSTAIN-6, n=3297, 104 wk); pooled RCT n=73,640; post-hoc mechanistic substudy n=40.", "comparators": "placebo; empagliflozin; active comparators", "endpointType": "safety-event/signal", "notes": "The recent RCT-level evidence (Natividade PMID 40810985 DR-null; Gullaksen PMID 40239470 CRT explained by glycaemia/TIR) confirms the 'early worsening = rapid glucose-lowering' interpretation rather than direct retinotoxicity. RETA LIVE QUESTION: reta produces the LARGEST, most rapid glucose-lowering (HbA1c -2.02% at 12 mg) + large weight loss, so rapid-large-glycaemic-correction -> early retinopathy worsening is a CLASS-RELEVANT caution for reta in T2D with pre-existing retinopathy - unstudied for reta, flag it. GRADE: SUSTAIN-6 high (CVOT, retinopathy secondary); pooled DR-null moderate; CRT substudy low (n=40, surrogate). FOCUS full magnitude unconfirmed (RETINO11) - carried, not re-minted. VALIDATOR: confirm PMID 27633186 (SUSTAIN-6 retinopathy HR 1.76) + 40810985 + 40239470.", "crossRef": "C-SEMA-SAFETY-RETINO10; C-SEMA-SAFETY-RETINO11; C-RETATRUTIDE-SAFETY-CONS01; C-CLASS-SAFETY-NAION-CONS01", "grade": "high", "source": { "citation": "Marso SP et al. (SUSTAIN-6), NEJM, 2016", "url": "https://doi.org/10.1056/NEJMoa1607141", "identifiers": "PMID 27633186; DOI 10.1056/NEJMoa1607141; NCT01720446", "date": "2016-09-15", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-SAFETY-STRUCTURE01", "sourceId": "CIT:structural-synthesis-over-the-safety-other-corpu", "drug": "incretin class cross-signal structure", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 / GIP-GLP-1 / triple agonists", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Ordinal evidence-grade ranking (not a single effect size): HIGH/REAL = biliary, rapid-glucose-lowering early DR worsening (steady-state pooled DR null), peri-operative retained-gastric-contents surrogate (actual aspiration unproven); CLEARED/NULL in humans = MTC, suicidality; DEBATED = NAION; WEAK/pharmacovigilance-only = pancreatitis, ileus, AKI.", "finding": "CROSS-SIGNAL STRUCTURE (the dossier spine) - the class safety signals ranked by EVIDENCE GRADE, not by alarm. HIGH/REAL (RCT or consistent replication): gallbladder/biliary (weight-loss-coupled); rapid-glucose-lowering early diabetic-retinopathy worsening (SUSTAIN-6 HR 1.76; note steady-state pooled DR is NULL, OR 1.04, TSA-sufficient); peri-operative retained-gastric-contents SURROGATE (the surrogate is robust ~6-fold but actual pulmonary aspiration is unproven). CLEARED/NULL in humans: medullary thyroid carcinoma (rodent-basis boxed warning, no human MTC signal); suicidality (regulatory-cleared). DEBATED: NAION (cohorts split; RCT meta OR 3.92 but TSA-insufficient; label 'very rare'). WEAK/pharmacovigilance-only (reporting != incidence): pancreatitis, ileus, acute kidney injury (mostly volume-depletion-mediated).", "population": "Class-wide across GLP-1 mono, GIP/GLP-1 dual, triple, and amylin co-agonists; strength/population vary by signal.", "comparators": "placebo; other antidiabetics; SGLT2i; non-GLP-1RA", "endpointType": "imaging/physiological surrogate", "notes": "GRADING DISCIPLINE: HIGH bin = RCT/consistent-replication (biliary, SUSTAIN-6 retinopathy + post-hoc, aspiration retained-contents surrogate); CLEARED = signal raised then not borne out in humans (MTC rodent-only; suicidality regulatory-cleared). NOTE suicidality is binned CLEARED on the strength of the D5 thread (Thread 13) and carries NO consolidation row in this D6 set - it is a cross-ref dependency, not a row minted here. DEBATED = NAION; WEAK = pharmacovigilance-only (very-low). RETA MAPPING (cross-ref RETATRUTIDE-SAFETY-CONS01): reta is most exposed on the WEIGHT-LOSS-COUPLED HIGH signals (biliary, amplified) + the T2D rapid-glycaemia retinopathy signal; NAION transfers by GLP-1 class membership; MTC is a labelling inheritance; the HR rise is reta-specific and sits OUTSIDE this taxonomy (thread-7). This row is the spine of Thread 14. Synthesis row (CIT id; no new effect claim - ranks existing graded rows).", "crossRef": "C-CLASS-SAFETY-NAION-CONS01; C-CLASS-SAFETY-RETINOPATHY-CONS01; C-RETATRUTIDE-SAFETY-CONS01; C-CLASS-SAFETY-BIL-CONS01; C-CLASS-SAFETY-MTC-CONS01", "grade": "very-low", "source": { "citation": "Structural synthesis over the safety-other corpus (the per-signal consolidations); the dossier spine for Thread 14", "url": "", "identifiers": "CIT:safety-signal-structure-2026", "date": "2026-06-21", "design": "pharmacovigilance / disproportionality", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; post-hoc (not prespecified); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-01", "sourceId": "PMID40760325", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "Pooled (25 RCTs, 3,224 pts): GLP-1 RA add-on vs placebo lowered HbA1c MD -0.23% (95% CI -0.30,-0.17), body weight -3.93kg (-4.29,-3.56), and total insulin dose -5.74 U/day (-7.30,-4.19); no significant effect on time-in-range; the effect is LIRAGLUTIDE-WEIGHTED (liraglutide dominated the trials).", "finding": "A 2025 meta-analysis of 25 RCTs confirms a modest class-level benefit of GLP-1 RAs added to insulin in T1D (HbA1c about -0.23%, weight -3.9kg, insulin -5.7 U/day), but the pooled estimate is effectively liraglutide.", "population": "GLP-1 RA add-on T1D meta-analysis (Rebelos/Liakos et al., 25 RCTs, 3,224 patients; PMC12678461).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "LIRAGLUTIDE-WEIGHTED: the 'class' estimate is dominated by liraglutide trials - do NOT transfer to other agents (non-liraglutide agents are ineffective on HbA1c, see C-CLASS-T1D-02). The review also found GLP-1 RAs do NOT prevent progressive C-peptide loss and counter-regulatory glucagon stays intact. High heterogeneity for insulin dose/TIR (I2~71%).", "crossRef": "C-CLASS-T1D-02", "grade": "moderate", "source": { "citation": "Rebelos E, Anastasiou IA, Tentolouris N, Karagiannis T, Tsapas A, Ferrannini E, Liakos A. Glucagon-like peptide-1 receptor agonists as add-on therapy to insulin for type 1 diabetes mellitus: a systematic review and meta-analysis. Hormones (Athens) 2025;24(4):1141-1151.", "url": "https://doi.org/10.1007/s42000-025-00704-9", "identifiers": "DOI:10.1007/s42000-025-00704-9", "date": "2025-08", "design": "meta-analysis", "maturity": "review", "funding": "academic/independent (Greek/Italian university authors; no manufacturer sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-02", "sourceId": "PMID38249345", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "Corroborating meta-analysis (11 RCTs, 2,856 pts): overall HbA1c -0.21% (95% CI -0.33,-0.10), weight -4.04kg (-4.8,-3.27), total insulin -5.73 IU (-10.61,-0.86); liraglutide SPECIFICALLY -0.26% HbA1c (-0.38,-0.14), whereas exenatide, exenatide-ER and albiglutide showed NO significant HbA1c effect (full text confirmed).", "finding": "A 2023 meta-analysis corroborates the modest class benefit and shows the HbA1c effect is essentially confined to liraglutide - exenatide, exenatide-ER and albiglutide had no significant glycaemic effect - underlining that 'class' is effectively liraglutide.", "population": "GLP-1 RA add-on T1D meta-analysis (Tan et al., 11 RCTs, 2,856 patients; PMC10797415).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "Liraglutide-specific -0.26% and the exenatide/exenatide-ER/albiglutide NULL were confirmed in the PMC full text (not just abstract). Subgroup: HbA1c effect larger in obese/overweight (-0.43%) than normal-weight (-0.10%, NS) T1D - the only suggestion of phenotype-dependence, against Dejgaard's BMI-null (different cut/method). Reinforces liraglutide-weighting (C-CLASS-T1D-01).", "crossRef": "C-CLASS-T1D-01", "grade": "moderate", "source": { "citation": "Tan X, Pan X, Wu X, Zheng S, Chen Y, Liu D, Zhang X. Glucagon-like peptide-1 receptor agonists as add-on therapy to insulin for type 1 diabetes mellitus. Front Pharmacol 2023;14:975880.", "url": "https://doi.org/10.3389/fphar.2023.975880", "identifiers": "DOI:10.3389/fphar.2023.975880", "date": 2023, "design": "meta-analysis", "maturity": "review", "funding": "academic/government (Central South University, China; Hunan provincial science foundations)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-DOUBLEDIAB-01", "sourceId": "PMID34463425", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "no-change", "magnitude": "'Double diabetes' (overweight/obese T1D): in the pooled ADJUNCT ONE/TWO post-hoc, reductions in HbA1c, body weight and insulin dose did NOT differ significantly (P>.05) by baseline BMI (<27 vs >=27 kg/m2) or baseline HbA1c; risk of hypoglycaemia/hyperglycaemia-with-ketosis also did not differ by BMI. Residual beta-cell function was the only effect-modifier identified.", "finding": "Heavier (overweight/obese) type-1 patients did NOT get greater benefit from liraglutide: in a pooled post-hoc, effects on HbA1c, weight and insulin did not differ by baseline BMI - the 'double diabetes' rationale for targeting obese T1D is not supported by this subgroup.", "population": "Pooled ADJUNCT ONE/TWO post-hoc subgroup analysis (Dejgaard et al., 2021; PMC9292057).", "comparators": "placebo (insulin background)", "endpointType": "safety-event/signal", "notes": "CONFIDENCE MEDIUM: post-hoc subgroup, coarse BMI cut (<27 vs >=27). NB Tan's separate subgroup (C-CLASS-T1D-02 notes) suggested a LARGER HbA1c effect in obese/overweight T1D (different cut/method) - the two are not strictly comparable; encoded as no-change per Dejgaard with that caveat. Only residual beta-cell function modified the effect.", "crossRef": "C-CLASS-T1D-02", "grade": "moderate", "source": { "citation": "Dejgaard TF, von Scholten BJ, Christiansen E, et al. Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials. Diabetes Obes Metab 2021;23(12):2752-2762.", "url": "https://doi.org/10.1111/dom.14532", "identifiers": "DOI:10.1111/dom.14532", "date": "2021-12", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry+academic (Novo Nordisk sponsor; Steno Diabetes Center Copenhagen)", "scopeLimits": "post-hoc (not prespecified); subgroup analysis", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-GI-01", "sourceId": "PMID42105869", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "GI tolerability burden: Kateel 2026 nausea RR 2.89, vomiting RR 3.10, driving a ~2-fold early treatment withdrawal (RR 2.02, MODERATE certainty); Tan 2023 GI adverse-event OR 2.96 (95% CI 2.33-3.77). Subgroup: overall tolerability significantly IMPROVES after ~6 months of therapy.", "finding": "GLP-1 RAs added to insulin in T1D roughly tripled nausea and vomiting and doubled early treatment withdrawal - a substantial early gastrointestinal burden that eases after about six months, requiring slow dose titration and careful patient selection.", "population": "GLP-1 RA T1D safety/tolerability meta-analyses (Kateel et al., 25 studies; corroborated by Tan et al. GI-AE OR 2.96, PMC10797415).", "comparators": "placebo (insulin background)", "endpointType": "safety-event/signal", "notes": "Textbook GLP-1 GI tolerability - kept in tolerability-gi (distinct from the safety-other hypo/ketosis signals). The early-withdrawal RR 2.02 is the clinically meaningful consequence; improves after ~6mo, supporting stepwise titration.", "crossRef": "C-CLASS-T1D-02", "grade": "moderate", "source": { "citation": "Kateel R, Parida A, Chogtu B, Holla SN. Safety of GLP-1 receptor agonists in type 1 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 2026;237:113270.", "url": "https://doi.org/10.1016/j.diabres.2026.113270", "identifiers": "DOI:10.1016/j.diabres.2026.113270", "date": "2026-05", "design": "meta-analysis", "maturity": "review", "funding": "academic/government (Kasturba Medical College, Manipal; Dept of Health Research, India)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-OFFLABEL-01", "sourceId": "PMID27506222", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "OFF-LABEL: no GLP-1 RA (including liraglutide) is approved for type-1 diabetes; all use is off-label. This is INFERRED from the trialists' own 'limiting clinical use' conclusion and the absence of a T1D indication, NOT from a primary regulator citation in this pass.", "finding": "No GLP-1 receptor agonist is approved for type-1 diabetes - every use is off-label, consistent with the pivotal-trial investigators concluding the safety signals limit clinical use. This is inferred from the trial conclusions, not a primary regulator document.", "population": "Liraglutide pivotal T1D RCTs (Mathieu ADJUNCT ONE; Ahren ADJUNCT TWO); regulatory-status inferred, not primary-sourced this pass.", "comparators": "placebo (insulin background)", "endpointType": "other", "notes": "CONFIDENCE MEDIUM / INFERRED: regulator status derived from the trialists' 'limiting clinical use' conclusion and the lack of any T1D indication, NOT a primary ADA/EASD/NICE/EMA/FDA citation. Flagged to OQ-T1D-C (add a primary guideline/regulator doc).", "crossRef": "C-LIRA-T1D-CONCLUSION-01", "grade": "high", "source": { "citation": "Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016;39(10):1702-1710.", "url": "https://doi.org/10.2337/dc16-0691", "identifiers": "DOI:10.2337/dc16-0691", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT01836523)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-PEAK-01", "sourceId": "PMID34463425", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "placebo-adjusted HbA1c reduction -0.30%-points at week 26 (the peak)", "finding": "A pooled post-hoc of the two pivotal trials shows the placebo-adjusted HbA1c reduction peaked near -0.30/-0.35% at week 26 then waned by week 52 - so the larger week-26 figure should not be headlined over the smaller 52-week primary endpoint.", "population": "Pooled ADJUNCT ONE/TWO post-hoc analysis (Dejgaard et al., 2021; PMC9292057).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "TIME-COURSE caveat: the -0.30/-0.35% wk26 peak is LARGER than the -0.20% 52-wk ADJUNCT ONE PRIMARY endpoint (C-LIRA-T1D-01) - do not headline the peak. Efficacy attenuated over time. Novo-sponsored post-hoc (5 author-employees).", "crossRef": "C-LIRA-T1D-01", "grade": "moderate", "source": { "citation": "Dejgaard TF, von Scholten BJ, Christiansen E, et al. Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials. Diabetes Obes Metab 2021;23(12):2752-2762.", "url": "https://doi.org/10.1111/dom.14532", "identifiers": "DOI:10.1111/dom.14532", "date": "2021-12", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry+academic (Novo Nordisk sponsor; Steno Diabetes Center Copenhagen)", "scopeLimits": "post-hoc (not prespecified); subgroup analysis", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-T1D-SAFETY-03", "sourceId": "PMID42105869", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Pooled safety meta (25 studies): NO significant increase in DKA (RR 0.60, VERY LOW certainty), severe hypoglycaemia (RR 0.74, LOW certainty), overall hypoglycaemia (RR 1.01, MODERATE certainty), or serious adverse events (RR 0.89, MODERATE certainty). Corroborated by Tan 2023 (DKA OR 1.38, 95% CI 0.93-2.05, NS; severe-hypo OR 0.86, NS).", "finding": "Pooled meta-analyses found NO significant increase in DKA or severe hypoglycaemia with GLP-1 RAs in T1D - but the DKA estimate is VERY LOW certainty and this null does NOT overturn the dose-dependent ketosis signal in the individual ADJUNCT trials.", "population": "GLP-1 RA T1D safety meta-analysis (Kateel et al., 25 studies [23 RCTs + 2 observational]; corroborated by Tan et al. PMC10797415).", "comparators": "placebo (insulin background)", "endpointType": "safety-event/signal", "notes": "MUST NOT READ AS REASSURANCE: the DKA RR 0.60 is VERY LOW certainty with wide CIs (statistical imprecision); the pool DILUTES the high-dose/liraglutide ketosis signal across lower doses and non-liraglutide agents. It does NOT overturn the dose-dependent hyperglycaemia-with-ketosis seen at liraglutide 1.8mg in the individual trials (C-LIRA-T1D-SAFETY-02). Tan's DKA OR 1.38 is numerically higher but NON-significant. The honest read is UNSETTLED at high dose, not safe. Routed to OQ-T1D-D.", "crossRef": "C-LIRA-T1D-SAFETY-02", "grade": "moderate", "source": { "citation": "Kateel R, Parida A, Chogtu B, Holla SN. Safety of GLP-1 receptor agonists in type 1 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 2026;237:113270.", "url": "https://doi.org/10.1016/j.diabres.2026.113270", "identifiers": "DOI:10.1016/j.diabres.2026.113270", "date": "2026-05", "design": "meta-analysis", "maturity": "review", "funding": "academic/government (Kasturba Medical College, Manipal; Dept of Health Research, India)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-TOLGI-FOLKVERDICT-01", "sourceId": "DOI10.1111/DOM.14551", "drug": "GLP-1-based class (GI-tolerability folk-claim verdicts)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Pooled STEP semaglutide 2.4 mg (Wharton 2022): nausea 43.9% (placebo 16.1%), diarrhoea 29.7%, vomiting 24.5%, constipation 24.2%; 98.1% of GI events mild-to-moderate, clustered at dose escalation. SURMOUNT tirzepatide nausea ~25-33%. Network meta-analysis: semaglutide/liraglutide lean constipation, tirzepatide leans diarrhoea.", "finding": "FOLK-CLAIM VERDICTS (GI cluster): (1) 'Nausea is near-inevitable' = OVERSTATED - real and the top AE but ~25-44% (not inevitable), mostly mild-moderate, concentrated at titration. (2) 'Constipation is more common than diarrhoea' = FALSE/MIXED - for semaglutide diarrhoea (29.7%) >= constipation (24.2%), and the balance is DRUG-SPECIFIC (sema/lira constipation-leaning, tirzepatide diarrhoea-leaning). (3) 'Fatigue, especially after each dose increase' = TRUE as a recognised (labelled) AE, but the per-step-spike mechanism is OVERSTATED - fatigue is largely secondary to reduced intake/dehydration/electrolytes during the nausea-prone escalation window, not a proven per-step pharmacological effect.", "population": "Pooled STEP 1-3 (semaglutide) GI-tolerability analysis + SURMOUNT (tirzepatide) + a class network meta-analysis.", "comparators": "placebo", "endpointType": "other", "notes": "Belief-vs-reality: nausea is a large-minority, mostly-mild, titration-linked event (not inevitable); the 'these drugs back you up' rule is wrong-way-round for semaglutide and is drug-specific; fatigue is real but intake-mediated. Frequency anchors (self-report) are in C-CLASS-TOLGI-REDDIT-FREQ-01. Cross-ref C-TIRZ-VS-SEMA-TOLGI-01 (tirz-gentler) and the existing tolerability-gi rows. [REASONED CAVEAT + OPEN QUESTION (OQ-FOLK-GI-01), 2026-06-22, NOT a settled finding: the constipation-vs-diarrhoea split likely reflects an ASYMMETRY - constipation is the more DRUG-INTRINSIC outcome (slowed transit -> the colon reabsorbs more water -> hard, dry stool; happens largely independent of diet, even on small intake), whereas diarrhoea is the more DIET/BEHAVIOUR-MODULATED one (the drug, especially tirzepatide's GIP-driven effect on fat handling, primes fat and bile to reach the colon where they trigger a secretory/osmotic flush, but it needs a fatty/difficult-to-digest meal to actually fire). The DRUG component of the diarrhoea tilt is REAL (it appears in the SURMOUNT-5 head-to-head and meta-analyses, not only in self-report), but its MAGNITUDE is diet- and population-modulated - and the real-world tirzepatide diarrhoea signal is further confounded as the drug reaches a broader, less-screened, less-diet-coached population (the same confound that grades the self-report rows very-low). Testable prediction: a high-fat-meal challenge or a diet-controlled comparison should move the diarrhoea rate while barely touching the constipation rate.]", "crossRef": "C-CLASS-TOLGI-REDDIT-FREQ-01; C-TIRZ-VS-SEMA-TOLGI-01", "grade": "moderate", "source": { "citation": "Wharton S et al. Gastrointestinal tolerability of semaglutide 2.4 mg (pooled STEP 1-3). Diabetes Obes Metab 2022 (DOI 10.1111/dom.14551); + Ismaiel A et al. network meta-analysis, Int J Obes 2025 (DOI 10.1038/s41366-025-01859-6).", "url": "https://doi.org/10.1111/dom.14551", "identifiers": "DOI10.1111/dom.14551", "date": "2022-01-01", "design": "network meta-analysis", "maturity": "human-primary", "funding": "industry - Novo Nordisk A/S (sponsor of the underlying STEP 1-3 trials and the load-bearing Wharton 2022 pooled GI-tolerability analysis)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-TOLGI-REDDIT-FREQ-01", "sourceId": "DOI10.1038/S44360-026-00108-Y", "drug": "GLP-1-based class (real-world online self-report frequencies)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "n/a", "magnitude": "Sehgal et al. (Nature Health 2026) computational analysis of ~410,198 Reddit posts (67,008 self-reported users, May 2019-Jun 2025): of the 43.5% reporting >=1 side effect - nausea 36.9%, fatigue 16.7%, vomiting 16.3%, constipation 15.3%, diarrhoea 12.6%, eructation/burping 6.9%; a between-subreddit split of nausea 39.4% (semaglutide) vs 28.6% (tirzepatide). Emerging self-report signals: reproductive/menstrual ~4%, thermoregulatory (chills/hot flashes).", "finding": "REAL-WORLD ONLINE SELF-REPORT context for the GI/other folk frequencies. This is a SIGNAL-DETECTION / pharmacovigilance-adjacent dataset, NOT prevalence, NOT incidence, NOT causal - self-selected communities, no denominator, no controls, no titration timing (the authors state they cannot say GLP-1s cause these symptoms). Use it to gauge how COMMON a BELIEF/report is, never to estimate true rates. The sema-vs-tirz nausea split is a text-mining ratio, not a randomised comparison.", "population": "Self-selected online communities (Reddit); semaglutide + tirzepatide users; computational NLP classification.", "comparators": "", "endpointType": "other", "notes": "GRADE very-low (self-selected online self-report; reporting != incidence). Verified to exist (Nature Health 2026) but NOT PubMed-indexed - findable via Nature/medRxiv preprint (10.64898/2026.03.12.26348253)/arXiv 2603.12341. Captured as the frequency-of-belief layer per the Director's instruction; heavily fenced. Anchors the frequency tags throughout the folk-claims register.", "crossRef": "C-CLASS-TOLGI-FOLKVERDICT-01", "grade": "very-low", "source": { "citation": "Sehgal NKR, Tronieri J, Ungar L, Guntuku SC. Self-reported side effects of semaglutide and tirzepatide in online communities. Nature Health 2026 (DOI 10.1038/s44360-026-00108-y; NOT PubMed-indexed - verified via Nature/medRxiv/Penn).", "url": "https://doi.org/10.1038/s44360-026-00108-y", "identifiers": "DOI10.1038/s44360-026-00108-y", "date": "2026-03-01", "design": "pharmacovigilance / disproportionality", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-TOLGI-SULFURBURPS-01", "sourceId": "CIT:no-indexed-literature-on-glp-1-associated-sulfur", "drug": "GLP-1-based class (sulfur-burps folk claim)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / GLP-1-based", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "n/a", "magnitude": "A targeted literature search (eructation/belching/'sulfur burp'/hydrogen-sulfide x GLP-1/incretin) returned NO indexed studies. Eructation appears at ~6.9% in online self-report (Sehgal). Delayed gastric emptying is a well-established class effect; the chain (retained/fermenting gastric contents -> hydrogen sulfide -> rotten-egg belches) is biologically coherent but unstudied.", "finding": "FOLK-CLAIM VERDICT ('sulfur burps' / rotten-egg belches): UNPROVEN - this is the clearest GENUINE EVIDENCE GAP in the GI cluster. The phenomenon is a widespread, recognisable community 'class signal' with a plausible mechanism (delayed gastric emptying -> fermentation -> hydrogen sulfide), but there is NO trial, case series or mechanistic paper formally characterising or quantifying it. Real-world reports + coherent mechanism, but no formal evidence base.", "population": "n/a - documents the absence of formal literature; online self-report (eructation ~6.9%) is the only frequency anchor.", "comparators": "", "endpointType": "other", "notes": "GRADE very-low (no evidence base; verdict is 'unstudied', not 'refuted'). Belief-vs-reality: patients treat sulfur burps as a known class signature; the science has barely looked. A genuine open research question (the one true gap in the GI set). Cross-ref C-CLASS-TOLGI-FOLKVERDICT-01.", "crossRef": "C-CLASS-TOLGI-FOLKVERDICT-01", "grade": "low", "source": { "citation": "No indexed literature on GLP-1-associated sulfur eructation/hydrogen-sulfide belching located (zero-hit PubMed sweep, 2026-06); delayed-gastric-emptying class effect is the proposed mechanism; frequency from Sehgal online self-report.", "url": "", "identifiers": "CIT:sulfur-burps-evidence-gap-2026", "date": "2026-06-21", "design": "observational cohort", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-URATE-01", "sourceId": "PMID35384008", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Meta-analysis (17 studies): GLP-1 RAs lowered SUA pre-to-post (difference in means -0.341, P<.001) but NOT versus placebo (-0.455, P=0.079, NS); active comparators (insulin/metformin/SGLT2i/DPP-4i) outperformed GLP-1 RAs at lowering SUA (+0.250, P<.001).", "finding": "A class-level meta-analysis found GLP-1 RAs reduce serum uric acid before-versus-after treatment but NOT significantly versus placebo, and less than active comparators including SGLT2 inhibitors - so the apparent urate-lowering is not an established placebo-controlled drug effect at the class level.", "population": "GLP-1 RA class meta-analysis (Najafi et al., 17 studies; RCTs, observational and uncontrolled studies pooled).", "comparators": "placebo; insulin; metformin; SGLT-2 inhibitor; DPP-4 inhibitor", "endpointType": "safety-event/signal", "notes": "SCOPE LIMIT: predates high-dose agents (tirzepatide/retatrutide) and the comparator estimate pools four drug classes. The pre-post drop is confounded by weight loss/regression; the placebo-controlled NS result is the honest class verdict. Two-directional (pre-post down vs placebo NS vs comparator-worse) -> mixed.", "crossRef": "", "grade": "moderate", "source": { "citation": "Najafi S, Bahrami M, Butler AE, Sahebkar A. The effect of glucagon-like peptide-1 receptor agonists on serum uric acid concentration: a systematic review and meta-analysis. Br J Clin Pharmacol 2022;88(8):3627-3637.", "url": "https://doi.org/10.1111/bcp.15344", "identifiers": "DOI:10.1111/bcp.15344", "date": 2022, "design": "meta-analysis", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-URATE-02", "sourceId": "PMID39068059", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "TriNetX real-world (T2D): GLP-1 RAs showed NO significant reduction in incident gout vs matched controls, whereas SGLT2i cut gout (HR 0.75 [0.69-0.82] +metformin; HR 0.83 [0.74-0.92] +insulin) and SGLT2i beat GLP-1 RAs head-to-head (HR 0.77 metformin / 0.82 insulin).", "finding": "In a large real-world cohort, GLP-1 RAs were gout-neutral on clinical OUTCOMES while SGLT2 inhibitors reduced incident gout and outperformed GLP-1 RAs head-to-head - the biochemical urate-lowering did not translate into a gout-incidence benefit for GLP-1 RAs.", "population": "TriNetX federated EHR cohort (Preston et al.), T2D on metformin/insulin +/- SGLT2i or GLP-1 RA, propensity-matched, 5-yr gout incidence.", "comparators": "metformin; insulin; SGLT-2 inhibitor", "endpointType": "safety-event/signal", "notes": "Observational/EHR, coding-based gout outcomes, confounding by indication. The gout-NEUTRAL summary sub-claim for GLP-1 RAs was 2-1 (not unanimous) - encoded as no-change with that caveat. SGLT2i contrast pole is the genuinely uricosuric comparator.", "crossRef": "", "grade": "low", "source": { "citation": "Preston FG et al. SGLT2 inhibitors, but not GLP-1 receptor agonists, reduce incidence of gout in people living with type 2 diabetes across the therapeutic spectrum (TriNetX). Clin Ther 2024;46(11):835-840.", "url": "https://doi.org/10.1016/j.clinthera.2024.06.021", "identifiers": "DOI:10.1016/j.clinthera.2024.06.021", "date": 2024, "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-URATE-03", "sourceId": "DOI10.1016/J.AED.2026.04.006", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Case series (n=4, tirzepatide/semaglutide): paradoxical transient hyperuricaemia/gout during rapid weight loss; 2/4 had acute gout flares, one recurrent despite urate-lowering therapy and normal serum uric acid.", "finding": "A 4-patient case series reported paradoxical transient hyperuricaemia and acute gout flares during rapid GLP-1/GIP-driven weight loss, including a recurrent flare despite urate-lowering therapy and normal uric acid - a hypothesis-generating counter-signal to the net urate-lowering RCT data.", "population": "AACE Endocrinology & Diabetes 2026 observational case series / uncontrolled cohort (Chaaya et al.); 4 adults on tirzepatide or semaglutide with substantial weight loss.", "comparators": "none (uncontrolled observational case series)", "endpointType": "safety-event/signal", "notes": "Very low grade: n=4, uncontrolled, hypothesis-generating; proposed mechanism is ketosis-related renal urate retention during rapid loss. EXCLUDED sub-claim: the '3/4 rose within 3-5 months regardless of baseline urate' statement was REFUTED 0-3 in adversarial review and is deliberately NOT encoded. Contrasts with the net urate-lowering RCT pole.", "crossRef": "", "grade": "low", "source": { "citation": "Chaaya JA et al. Transient increase in serum uric acid and gout attacks after weight-loss effect on tirzepatide and semaglutide (case series, n=4). AACE Endocrinol Diabetes 2026.", "url": "https://doi.org/10.1016/j.aed.2026.04.006", "identifiers": "DOI:10.1016/j.aed.2026.04.006", "date": 2026, "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-URATE-04", "sourceId": "DOI10.1002/RAI2.70015", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Observational cohort (TriNetX overweight/obese T2D): GLP-1 users (n=65,489) gout 1.0% vs 0.8% non-users (n=701,728), RR 1.176 [1.041-1.329], p=0.009; higher colchicine use (6.12 vs 3.10 scripts/patient, p<0.001).", "finding": "A real-world cohort found a small but statistically significant HIGHER gout/colchicine signal in GLP-1 users versus non-users - not protective - consistent with a transient-flare or detection-bias effect rather than causal urate-raising.", "population": "TriNetX observational cohort (Lam et al.), overweight/obese T2D, GLP-1 users vs non-users.", "comparators": "non-users", "endpointType": "safety-event/signal", "notes": "Observational, confounding by indication, absolute difference only 0.2 percentage points; colchicine is an indirect flare proxy (the colchicine sub-claim was 2-1). Consistent with the transient-flare phenomenon / detection bias, NOT demonstrated causal urate-raising. Both-poled against the net urate-lowering RCT data.", "crossRef": "C-CLASS-URATE-03", "grade": "low", "source": { "citation": "Lam DCH et al. Assessing gout risk associated with GLP-1 therapy in obese patients with type 2 diabetes (TriNetX cohort). Rheumatol Autoimmun 2025.", "url": "https://doi.org/10.1002/rai2.70015", "identifiers": "DOI:10.1002/rai2.70015", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CLASS-URATE-RENAL-01", "sourceId": "PMID29341461", "drug": "GLP-1 RA class (multi-agent)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1 receptor agonist (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Post hoc of 4 phase-4 trials: no durable plasma-urate change in short/weight-neutral settings; acute IV exenatide was marginally/transiently uricosuric (fractional urate excretion +0.76+/-0.38%, P=0.049) WITHOUT changing plasma urate; 12-wk liraglutide and 8-wk lixisenatide showed no plasma-urate or excretion change.", "finding": "In mechanistic renal-physiology trials, acute exenatide transiently raised renal urate excretion without lowering plasma urate, and prolonged liraglutide/lixisenatide produced no urate change - indicating only a marginal, transient tubular effect, not chronic urate-lowering.", "population": "GLP-1 RA renal-physiology trials (Tonneijck et al., post hoc of 4 controlled phase-4 trials; Study-A n=9 healthy, Study-B n=52, Study-C n=36, Study-D n=35 T2D).", "comparators": "placebo; insulin glulisine", "endpointType": "safety-event/signal", "notes": "Small mechanistic cohorts, normal-urate/low-CV-risk T2D; exploratory (no sample-size calculation). Two-directional: transient uricosuria (excretion up) but plasma urate unchanged/slightly up -> mixed. Authors conclude urate is unlikely to mediate GLP-1 RA cardio-renal benefit. Design = observational cohort -> low (NOT promoted to moderate).", "crossRef": "", "grade": "low", "source": { "citation": "Tonneijck L et al. Effect of immediate and prolonged GLP-1 receptor agonist administration on uric acid and kidney clearance: post-hoc analyses of four clinical trials. Diabetes Obes Metab 2018;20(5):1235-1245.", "url": "https://doi.org/10.1111/dom.13223", "identifiers": "DOI:10.1111/dom.13223", "date": 2018, "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-01", "sourceId": "PMID34170647", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "HbA1c diff -0.15 to -0.45 pp; weight diff -1.9 to -5.5 kg favouring tirzepatide; baseline HbA1c 8.28%, baseline weight 93.7 kg", "finding": "DIRECT head-to-head (SURPASS-2, T2D). Tirzepatide at all three doses (5/10/15 mg) was non-inferior AND superior to semaglutide 1 mg for HbA1c reduction at 40 weeks; weight loss was also greater with tirzepatide. HbA1c change: -2.01 / -2.24 / -2.30 percentage points (tirz 5/10/15) vs -1.86 (sema 1 mg); treatment differences -0.15 (p=0.02), -0.39 (p<0.001), -0.45 (p<0.001). Weight: least-squares mean treatment difference vs sema -1.9 / -3.6 / -5.5 kg (p<0.001 all).", "population": "1879 adults with T2D on metformin, open-label, 40 weeks, randomised 1:1:1:1; comparator semaglutide 1 mg s.c. weekly", "comparators": "semaglutide 1 mg", "endpointType": "other", "notes": "Pivotal direct head-to-head in T2D. NOTE the comparator was semaglutide 1 mg (the highest T2D dose at the time), NOT the 2.4 mg obesity dose - so this is not the obesity ladder comparison. The 'why' of the tirz advantage (GIP component vs higher GLP-1 exposure) is left OPEN. Cross-ref C-COMPARE-02 (obesity head-to-head) and C-COMPARE-03 (post hoc targets).", "crossRef": "C-COMPARE-02, C-COMPARE-03", "grade": "moderate", "source": { "citation": "Frias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2)", "url": "https://doi.org/10.1056/NEJMoa2107519", "identifiers": "PMID 34170647; DOI 10.1056/NEJMoa2107519; NCT03987919", "date": "2021-06-25", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "open-label (unblinded); post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-02", "sourceId": "PMID40353578", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "-20.2% vs -13.7% body weight at 72 weeks (treatment difference ~ -6.5 pp); ~47% greater relative weight loss with tirzepatide", "finding": "DIRECT head-to-head (SURMOUNT-5, obesity without T2D). Tirzepatide (max tolerated 10 or 15 mg) was SUPERIOR to semaglutide (max tolerated 1.7 or 2.4 mg) for weight loss at 72 weeks: mean -20.2% vs -13.7% (a ~47% greater relative reduction). Waist circumference also reduced more with tirzepatide. GI adverse events causing discontinuation were lower with tirzepatide (2.7%) than semaglutide (5.6%).", "population": "Adults with obesity (no T2D), randomised 1:1, open-label, 72 weeks; max tolerated doses; first direct obesity head-to-head of the two leading agents", "comparators": "semaglutide 2.4 mg (max tolerated 1.7 or 2.4 mg)", "endpointType": "other", "notes": "This is the SINGLE definitive obesity-population direct head-to-head as of mid-2026 - the cleanest 'tirz beats sema' datapoint at matched obesity doses. Open-label design is a caveat (recorded, not adjudicated). Responder-rate detail at >=20%/25% thresholds not fully extracted here (abstract paywalled) - flag for follow-up. The 'why' left OPEN.", "crossRef": "C-COMPARE-01, C-COMPARE-12", "grade": "moderate", "source": { "citation": "Aronne LJ, et al. N Engl J Med 2025 (SURMOUNT-5); presented ECO 2025", "url": "https://doi.org/10.1056/NEJMoa2416394", "identifiers": "PMID 40353578; DOI 10.1056/NEJMoa2416394; NCT05822830", "date": "2025-07-03", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-03", "sourceId": "PMID41419618", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "OR weight loss >15% 3.86 (95% CI 2.69-5.55); OR HbA1c <6.5% 1.88 (1.49-2.36) favouring tirzepatide", "finding": "DIRECT head-to-head post hoc (SURPASS-2). Tirzepatide improved attainment of composite therapeutic targets vs semaglutide 1 mg at 40 weeks. For standard targets, >=3 targets met by 34% (sema) vs 42/53/57% (tirz 5/10/15). For intensive targets, 8% (sema) vs 15/20/29% (tirz). Odds ratios favouring tirzepatide: HbA1c <7% OR 1.50; HbA1c <6.5% OR 1.88; weight loss >10% OR 2.72; weight loss >15% OR 3.86.", "population": "Post hoc of 1879 SURPASS-2 participants (T2D), 40 weeks; tirz 5/10/15 vs sema 1 mg", "comparators": "semaglutide 1 mg", "endpointType": "other", "notes": "Independent academic post hoc (Vivli data access), not company-authored - useful provenance contrast. Composite/responder framing of the same SURPASS-2 head-to-head. Open 'why'.", "crossRef": "C-COMPARE-01", "grade": "moderate", "source": { "citation": "Neves JS, Leite AR, Vale C, et al. Diabetologia 2025/2026", "url": "https://doi.org/10.1007/s00125-025-06637-7", "identifiers": "PMID 41419618; DOI 10.1007/s00125-025-06637-7", "date": "2025-12-19", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-04", "sourceId": "PMID29397376", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "HbA1c ETD ~ -0.40 pp; weight ETD -2.26 to -3.55 kg favouring semaglutide", "finding": "DIRECT head-to-head (SUSTAIN 7, T2D). Semaglutide was superior to dulaglutide at matched low and high doses for both HbA1c and weight at 40 weeks. HbA1c: sema 0.5 mg -1.5 pp vs dula 0.75 mg -1.1 pp (ETD -0.40, p<0.0001); sema 1.0 mg -1.8 pp vs dula 1.5 mg -1.4 pp (ETD -0.41, p<0.0001). Weight: sema 0.5 -4.6 kg vs dula 0.75 -2.3 kg (ETD -2.26 kg); sema 1.0 -6.5 kg vs dula 1.5 -3.0 kg (ETD -3.55 kg, p<0.0001).", "population": "1201 adults with T2D on metformin, open-label phase 3b, 40 weeks, randomised 1:1:1:1; 16 countries", "comparators": "dulaglutide 0.75 mg; dulaglutide 1.5 mg", "endpointType": "other", "notes": "Establishes the within-GLP-1-class ordering sema > dula. GI AEs similar across arms (33-48%). 'Why' (structure/PK differences) noted by authors but left OPEN here per neutrality rule.", "crossRef": "C-COMPARE-11", "grade": "moderate", "source": { "citation": "Pratley RE, Aroda VR, Lingvay I, et al. Lancet Diabetes Endocrinol 2018 (SUSTAIN 7)", "url": "https://doi.org/10.1016/S2213-8587(18)30024-X", "identifiers": "PMID 29397376; DOI 10.1016/S2213-8587(18)30024-X; NCT02648204", "date": "2018-02-01", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-05", "sourceId": "PMID40544433", "drug": "cagrilintide-semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "amylin analogue + GLP-1 (CagriSema)", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "CagriSema -20.4% vs placebo -3.0% at 68 weeks; sema-alone and cagri-alone arms present for component comparison", "finding": "ACTIVE-CONTROLLED head-to-head within trial (REDEFINE 1, obesity without T2D). CagriSema (cagri 2.4 mg + sema 2.4 mg) gave -20.4% weight vs placebo -3.0% (difference -17.3 pp) at 68 weeks; trial also contained semaglutide 2.4 mg monotherapy (N=302) and cagrilintide 2.4 mg monotherapy (N=302) arms enabling within-trial comparison of the combination against each component.", "population": "3417 adults with overweight/obesity without diabetes, double-blind placebo- and active-controlled phase 3a, 68 weeks; randomised 21:3:3:7 (combo:sema:cagri:placebo)", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "other", "notes": "Contains a true within-trial comparison of combo vs sema-2.4-alone vs cagri-alone (component arms), though the abstract reports only the combo-vs-placebo headline. The cagri+sema 20.4% sits near tirzepatide territory but in a DIFFERENT trial/population - cross-trial caveat applies vs SURMOUNT-5. 'Why' OPEN. NOTE: CagriSema fell short of some pre-trial expectations (component arms relevant).", "crossRef": "C-COMPARE-06, C-COMPARE-12", "grade": "high", "source": { "citation": "Garvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)", "url": "https://doi.org/10.1056/NEJMoa2502081", "identifiers": "PMID 40544433; DOI 10.1056/NEJMoa2502081; NCT05567796", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-06", "sourceId": "PMID40544432", "drug": "cagrilintide-semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "amylin analogue + GLP-1 (CagriSema)", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "weight -13.7% vs -3.4%; HbA1c <=6.5% in 73.5% vs 15.9%", "finding": "ACTIVE/placebo-controlled (REDEFINE 2, overweight/obesity WITH T2D). CagriSema -13.7% vs placebo -3.4% weight at 68 weeks (difference -10.4 pp). HbA1c <=6.5% reached by 73.5% (CagriSema) vs 15.9% (placebo).", "population": "1206 adults with T2D and BMI >=27, double-blind, 68 weeks, randomised 3:1 vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "T2D companion to REDEFINE 1. Note weight loss in T2D (-13.7%) lower than obesity-only (-20.4%) - the standard T2D weight-loss attenuation pattern, recorded as observation. No active drug comparator (placebo only).", "crossRef": "C-COMPARE-05", "grade": "high", "source": { "citation": "Davies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)", "url": "https://doi.org/10.1056/NEJMoa2502082", "identifiers": "PMID 40544432; DOI 10.1056/NEJMoa2502082; NCT05394519", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-07", "sourceId": "PMID40544435", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1 receptor agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "decrease", "magnitude": "HbA1c -1.07 pp vs placebo (36 mg); weight -7.6% (36 mg) vs -1.7% placebo at 40 weeks", "finding": "PLACEBO-controlled (ACHIEVE-1, early T2D, diet/exercise only). Oral orforglipron 3/12/36 mg gave HbA1c change -1.24/-1.47/-1.48 pp vs placebo -0.41 at 40 weeks; weight -4.5/-5.8/-7.6% vs placebo -1.7%. No direct active comparator in this trial.", "population": "559 adults with early T2D (diet/exercise only), double-blind placebo-controlled phase 3, 40 weeks, 1:1:1:1", "comparators": "placebo", "endpointType": "other", "notes": "Orforglipron weight loss (~7.6% at 40 wk) sits BELOW injectable sema/tirz on the cross-trial ladder; useful for placing the oral small-molecule rung. Placebo-controlled only - any sema/tirz comparison is INDIRECT/cross-trial. 'Why' OPEN.", "crossRef": "C-COMPARE-08, C-COMPARE-11", "grade": "high", "source": { "citation": "Rosenstock J, Hsia S, et al. N Engl J Med 2025 (ACHIEVE-1)", "url": "https://doi.org/10.1056/NEJMoa2505669", "identifiers": "PMID 40544435; DOI 10.1056/NEJMoa2505669; NCT05971940", "date": "2025-06-21", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-08", "sourceId": "PMID42251769", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1 receptor agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "decrease", "magnitude": "HbA1c treatment difference up to -1.08 pp vs placebo; weight -5.4% (36 mg) vs +0.2% placebo", "finding": "PLACEBO-controlled add-on (ACHIEVE-5, T2D on insulin glargine). Orforglipron 3/12/36 mg added to titrated glargine gave HbA1c -1.58/-1.88/-1.82 pp vs placebo -0.79 at 40 weeks; weight -2.6/-4.8/-5.4% vs placebo +0.2%. No active drug comparator.", "population": "546 adults with T2D inadequately controlled on insulin glargine (+/- metformin/SGLT2i), double-blind phase 3, 40 weeks", "comparators": "placebo", "endpointType": "other", "notes": "Insulin-background population - weight loss attenuated vs monotherapy ACHIEVE-1. Placebo-controlled; cross-class comparison remains indirect.", "crossRef": "C-COMPARE-07", "grade": "high", "source": { "citation": "Giorgino F, D'Souza S, et al. JAMA 2026 (ACHIEVE-5)", "url": "https://doi.org/10.1001/jama.2026.9512", "identifiers": "PMID 42251769; DOI 10.1001/jama.2026.9512; NCT06109311", "date": "2026-06-07", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-09", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/GCGR triple agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "-24.2% weight vs placebo -2.1% at 48 weeks", "finding": "Phase 2 obesity, placebo-controlled (no GLP-1/dual active comparator). Retatrutide 48-week weight loss -8.7% (1 mg), -17.1% (4 mg), -22.8% (8 mg), -24.2% (12 mg) vs placebo -2.1%. Responder rates at 12 mg: 100% >=5%, 93% >=10%, 83% >=15%. This is the source of the cited '~24% phase 2' top rung of the efficacy ladder.", "population": "338 adults with obesity (or BMI 27-30 + complication), double-blind placebo-controlled phase 2, 48 weeks", "comparators": "placebo", "endpointType": "other", "notes": "RETATRUTIDE HEAD-TO-HEAD GAP: this pivotal obesity dataset has NO active comparator (placebo only). The '24% reta vs 20-22% tirz vs 15% sema' ladder is therefore CROSS-TRIAL, not a direct comparison - flag explicitly. Phase 3 TRIUMPH-1 (press) reported up to ~30% at 80 wk but still no direct sema/tirz arm. 'Why' OPEN.", "crossRef": "C-COMPARE-10, C-COMPARE-12, C-COMPARE-13", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-10", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/GCGR triple agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "weight -16.94% (reta 12 mg) vs -2.02% (dula 1.5 mg) at 36 weeks; HbA1c -2.02 vs -1.41 pp favouring retatrutide", "finding": "DIRECT head-to-head (phase 2 T2D): retatrutide vs dulaglutide 1.5 mg active comparator. At 36 weeks, retatrutide 8-12 mg gave HbA1c reductions (-1.99 to -2.02 pp at 24 wk) significantly GREATER than dulaglutide 1.5 mg (-1.41 pp; p=0.0019 to 0.0002 for the higher doses). Weight at 36 weeks: reta up to -16.94% (12 mg) vs dulaglutide -2.02% (all reta >=4 mg p<0.0001 vs dula).", "population": "281 adults with T2D (HbA1c 7-10.5%, BMI 25-50), double-blind, placebo- AND active-comparator (dulaglutide 1.5 mg), 36 weeks", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "other", "notes": "This IS a genuine retatrutide direct head-to-head - but vs DULAGLUTIDE 1.5 mg (a weaker GLP-1 RA), NOT vs semaglutide or tirzepatide. So the strongest 'reta beats sema/tirz' claim remains cross-trial. Partly closes the 'no reta head-to-head' gap, but only against dulaglutide. 'Why' OPEN.", "crossRef": "C-COMPARE-09, C-COMPARE-04", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-COMPARE-11", "sourceId": "PMID38286487", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "n/a", "magnitude": "tirz HbA1c -2.10 pp (rank 1, SUCRA 94.2%); weight: CagriSema -14.03 kg > tirzepatide -8.47 kg vs placebo", "finding": "INDIRECT (network meta-analysis, T2D). Across 76 RCTs / 15 GLP-1RA drugs / 39,246 participants, tirzepatide induced the LARGEST HbA1c reduction vs placebo (-2.10 pp, SUCRA 94.2%) and the largest fasting glucose reduction (SUCRA 97.2%), ranking as the single most effective agent for glycaemic control. For WEIGHT, CagriSema ranked highest (-14.03 kg vs placebo) followed by tirzepatide (-8.47 kg).", "population": "Network meta-analysis, 76 RCTs, 39,246 adults with T2D, follow-up >=12 weeks; all estimates vs placebo", "comparators": "placebo; semaglutide; dulaglutide; CagriSema; all GLP-1RAs", "endpointType": "other", "notes": "INDIRECT ranking - confirms tirz #1 for glycaemia and CagriSema #1 for weight in the T2D evidence base as of Aug 2023 (predates retatrutide phase 3 and SURMOUNT-5). Open full text. Useful as the Bayesian-ranking anchor record. 'Why' OPEN.", "crossRef": "C-COMPARE-01, C-COMPARE-05", "grade": "moderate", "source": { "citation": "Yao H, Zhang A, Li D, et al. BMJ 2024", "url": "https://doi.org/10.1136/bmj-2023-076410", "identifiers": "PMID 38286487; DOI 10.1136/bmj-2023-076410; PROSPERO CRD42022342845", "date": "2024-01-29", "design": "network meta-analysis", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-12", "sourceId": "CIT:composite-of-surmount-5-pmid-40353578-retatrutid", "drug": "n/a (class ladder)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / NuSH class", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "sema ~15% < tirz ~20-22% ~= CagriSema ~20% < reta ~24% (phase 2) / ~30% (phase 3 press); oral orforglipron ~5-8%", "finding": "EFFICACY LADDER (weight, as reported, with trial/dose/duration/population context). Semaglutide 2.4 mg ~15% (STEP-1, obesity, 68 wk); tirzepatide 15 mg ~20-22.5% (SURMOUNT-1, obesity, 72 wk); SURMOUNT-5 direct head-to-head tirz -20.2% vs sema -13.7% (72 wk); CagriSema ~20.4% (REDEFINE 1, 68 wk); retatrutide 12 mg ~24.2% phase 2 (48 wk), up to ~30% phase 3 TRIUMPH-1 (press, 80 wk); orforglipron ~7.6% (ACHIEVE-1 T2D, 40 wk).", "population": "MIXED across trials/doses/durations/populations - NOT a single comparison", "comparators": "cross-trial; placebo within each", "endpointType": "other", "notes": "EXPLICIT LADDER CAVEAT: the only true APPLES-TO-APPLES rung is SURMOUNT-5 (tirz 20.2% vs sema 13.7%, same trial/population). Every other rung-to-rung gap is CROSS-TRIAL (different durations 40-80 wk, different populations T2D vs obesity-only, different placebo responses). The numbers are recorded as REPORTED, NOT as a validated ranking. CagriSema and tirzepatide overlap. Retatrutide top rung is phase-2/press, not yet head-to-head. 'Why' (receptor count, GCGR/GIP/amylin contributions) explicitly OPEN.", "crossRef": "C-COMPARE-02, C-COMPARE-05, C-COMPARE-09", "grade": "moderate", "source": { "citation": "Composite of SURMOUNT-5 (PMID 40353578), retatrutide ph2 (PMID 37366315), REDEFINE 1 (PMID 40544433), orforglipron (PMID 40544435); STEP-1/SURMOUNT-1 referenced", "url": "https://doi.org/10.1056/NEJMoa2416394", "identifiers": "see component records", "date": "2026-06-20", "design": "phase-2 RCT", "maturity": "review", "funding": "industry - multiple, each disclosed per component: Eli Lilly / Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-13", "sourceId": "PMID38976257", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "HR >=15% weight loss 3.24 (95% CI 2.91-3.61); 12-mo weight difference -6.9% favouring tirzepatide", "finding": "REAL-WORLD comparative effectiveness (Truveta EHR, overweight/obesity). Tirzepatide associated with significantly greater on-treatment weight loss than semaglutide (both T2D-labelled formulations). Hazard of reaching thresholds: >=5% HR 1.76; >=10% HR 2.54; >=15% HR 3.24. Mean weight difference favouring tirz: -2.4% (3 mo), -4.3% (6 mo), -6.9% (12 mo). GI AE rates similar between groups.", "population": "41,222 adults with overweight/obesity (52% with T2D) on T2D-labelled tirz or sema; 18,386 after propensity-score matching; retrospective EHR cohort, May 2022-Sep 2023", "comparators": "semaglutide", "endpointType": "other", "notes": "Largest real-world tirz-vs-sema head-to-head (Truveta). Used T2D-labelled doses (Mounjaro/Ozempic), not obesity-labelled - a key caveat. Directionally concordant with SURMOUNT-5 RCT. Observational (residual confounding); recorded with its channel/maturity, not adjudicated.", "crossRef": "C-COMPARE-02, C-COMPARE-14", "grade": "low", "source": { "citation": "Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. JAMA Intern Med 2024", "url": "https://doi.org/10.1001/jamainternmed.2024.2525", "identifiers": "PMID 38976257; DOI 10.1001/jamainternmed.2024.2525", "date": "2024-09-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-14", "sourceId": "PMID41661445", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "6-mo weight -11.15% vs -8.83% (diff -2.32 pp); aOR >=15% 2.88 (2.32-3.57) favouring tirzepatide", "finding": "REAL-WORLD comparative effectiveness (US clinical practice, obesity WITHOUT diabetes). At 6 months tirzepatide -11.15% vs semaglutide -8.83% (adjusted difference -2.32 pp favouring tirz). Adjusted odds of thresholds: >=5% aOR 2.03; >=10% aOR 2.46; >=15% aOR 2.88.", "population": "2396 on-treatment adults (1003 tirz, 1393 sema) with obesity/overweight WITHOUT diabetes, retrospective EHR cohort, Dec 2023-Jun 2024, 6-month follow-up", "comparators": "semaglutide", "endpointType": "other", "notes": "Non-diabetic real-world cohort, concordant with SURMOUNT-5 and the Truveta cohort. Lilly-affiliated authorship (record the provenance). 6-month timepoint only. Observational. 'Why' OPEN.", "crossRef": "C-COMPARE-02, C-COMPARE-13", "grade": "low", "source": { "citation": "le Roux CW, Done N, Brnabic AJM, et al. J Endocrinol Invest 2026", "url": "https://doi.org/10.1007/s40618-025-02792-1", "identifiers": "PMID 41661445; DOI 10.1007/s40618-025-02792-1", "date": "2026-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COMPARE-15", "sourceId": "PMID41406444", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "increase", "magnitude": "MACE HR 0.92 (noninferior); greater HbA1c + weight reduction vs dulaglutide; kidney composite HR 0.77 Secondary: all-cause mortality HR 0.84 (95% CI 0.75-0.94), 8.6% vs 10.2% [from secondary coverage, pending NEJM full-text confirmation - non-hardened].", "finding": "DIRECT head-to-head CVOT (SURPASS-CVOT, T2D + ASCVD). Tirzepatide (up to 15 mg) was NON-INFERIOR to dulaglutide 1.5 mg for 3-point MACE (~12% vs ~13%; HR 0.92, p=0.003 noninferiority; p=0.09 superiority) over median ~4 years, while achieving GREATER HbA1c and weight reductions. Pre-specified kidney composite 23% lower with tirzepatide (HR 0.77, 95% CI 0.68-0.88).", "population": "13,299 (13,165 analysed) adults with T2D and ASCVD, double-blind active-controlled, 640 sites/30 countries, median 4.0 y; tirz up to 15 mg vs dulaglutide 1.5 mg", "comparators": "dulaglutide 1.5 mg", "endpointType": "hard-outcome", "notes": "Direct head-to-head but comparator is DULAGLUTIDE, not semaglutide. Confirms greater weight/HbA1c effect of tirz vs an established GLP-1RA AND a cardiorenal signal. Primary MACE paper PMID not separately confirmed here (cited via kidney sub-analysis PMID 42114520 and web sources) - flag for ID verification. 'Why' OPEN. [CORRECTED 2026-06-21: source was PMID 42114520 (the kidney sub-analysis); repointed to the SURPASS-CVOT primary PMID 41406444. Kidney HR 0.77 now lives in C-TIRZ-RENAL-SURPASS-01.]", "crossRef": "C-COMPARE-01, C-COMPARE-10", "grade": "high", "source": { "citation": "Nicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med 2025;393(24):2409-2420.", "url": "https://doi.org/10.1056/NEJMoa2505928", "identifiers": "PMID41406444", "date": "2025-11-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor)", "scopeLimits": "active-comparator (dulaglutide) non-inferiority design - not placebo-controlled; superiority not met (P=0.09)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COTA-HR-PH1-01", "sourceId": "PMID29926478", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "dose-dependent HR rise (acute single dose; no bpm figure in abstract)", "finding": "In a single-dose phase 1 study (36 on drug, 12 placebo), the balanced GLP-1/glucagon dual agonist cotadutide (MEDI0382) showed a dose-dependent increase in heart rate; treatment-emergent adverse events were mild/moderate (commonest vomiting, nausea, dizziness).", "population": "single-dose phase 1 study, 36 on drug / 12 placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Combination-only (GLP-1 + GCGR): the HR rise cannot be split between arms. GLP-1RAs alone also raise HR, so a co-agonist HR rise does not by itself prove a GCGR contribution; the co-agonist-minus-GLP-1RA contrast is not performed here (gap). Distinct trial from the phase-2b cotadutide HR record (C2-COTADUTIDE-HR-01, PMID33908687). Folded from T7-031 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C2-COTADUTIDE-HR-01", "grade": "low", "source": { "citation": "Ambery PD et al., Br J Clin Pharmacol 2018;84(10):2325-2335", "url": "https://doi.org/10.1111/bcp.13688", "identifiers": "PMID:29926478 DOI:10.1111/bcp.13688", "date": "2018-07-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - AstraZeneca/MedImmune (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~48); short duration", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COTA-RENAL-UACR-MODEL-01", "sourceId": "PMID40344607", "drug": "cotadutide", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "model-predicted relative change vs placebo at 26 wk with 600 ug: UACR ~-45.6%, urinary albumin ~-47.2%.", "finding": "A PK/PD model from the same phase 2b CKD/T2D study predicted ~-45.6% UACR and ~-47.2% urinary-albumin change versus placebo at 26 weeks with 600 ug cotadutide, corroborating the dose-dependent antialbuminuric effect.", "population": "Secondary PK/PD modelling analysis of the phase 2 randomised controlled trial NCT04515849 (247 participants); cotadutide 100/300/600 ug vs semaglutide 1 mg vs placebo.", "comparators": "placebo; semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "Modelling corroboration of C-COTA-RENAL-UACR-PH2B-01 (same trial programme NCT04515849). Model-predicted surrogate; combination-only dual-agonist proxy. AstraZeneca COI. Folded from thread-7 ledger entry T7-046 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-COTA-RENAL-UACR-PH2B-01", "grade": "moderate", "source": { "citation": "Yu et al., Br J Clin Pharmacol 2025;91(9):2672-2683", "url": "https://doi.org/10.1002/bcp.70093", "identifiers": "PMID:40344607 DOI:10.1002/bcp.70093", "date": "2025-09-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - AstraZeneca (cotadutide PK/PD analysis; disclosed)", "scopeLimits": "model-predicted (PK/PD) surrogate endpoint; same trial programme NCT04515849 as PMID39218393", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COTA-RENAL-UACR-PH2B-01", "sourceId": "PMID39218393", "drug": "cotadutide", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "UACR change vs placebo at wk14: -43.9% (95% CI -54.7 to -30.6) at 300 ug; -49.9% (-59.3 to -38.4) at 600 ug; effects sustained to wk26. N=248; mean eGFR 55.3; 46.8% on background SGLT2i.", "finding": "In a phase 2b trial in T2D + CKD, cotadutide (GLP-1/glucagon dual agonist) dose-dependently reduced urinary albumin-to-creatinine ratio versus placebo, reaching significance at 300 ug (-43.9%) and 600 ug (-49.9%) at week 14, sustained to week 26, on top of standard of care.", "population": "Phase 2 double-blind randomised controlled trial (NCT04515849): 248 randomised; T2D + CKD (eGFR 20 to <90, UACR >50 mg/g); cotadutide 100/300/600 ug daily vs placebo, vs open-label semaglutide 1 mg.", "comparators": "placebo; semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "DUAL-AGONIST RENAL ANCHOR (GLP-1/GCGR), previously missing from the compendium. COMBINATION-ONLY: the antialbuminuric effect cannot be split between arms and is NOT retatrutide; bridges the reta-direct renal thinness (no reta eGFR/UACR efficacy readout exists pre-TRIUMPH-Outcomes ~2029). Phase 2b surrogate (UACR). AstraZeneca COI. Folded from thread-7 ledger entry T7-045 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-COTA-RENAL-UACR-MODEL-01", "grade": "moderate", "source": { "citation": "Selvarajah V et al., Kidney Int 2024;106(6):1170-1180", "url": "https://doi.org/10.1016/j.kint.2024.08.023", "identifiers": "PMID:39218393 DOI:10.1016/j.kint.2024.08.023", "date": "2024-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - AstraZeneca (cotadutide phase 2b sponsor; disclosed)", "scopeLimits": "phase 2b surrogate (UACR) endpoint; ~47% on background SGLT2i", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-COTADUTIDE-LANDSCAPE-01", "sourceId": "NCTNCT03235050", "drug": "cotadutide", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon (GCGR) dual agonist (oxyntomodulin-analogue)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "decrease", "magnitude": "GLP-1:GCGR potency ratio approx 5:1; phase 2b (NCT03235050, 54 wk): reductions in weight, HbA1c and hepatic fat vs placebo, greater liver-fat and PRO-C3 improvement than liraglutide", "finding": "Cotadutide (MEDI0382) is a balanced GLP-1/glucagon receptor dual agonist (oxyntomodulin-like) reported to activate GLP-1 and glucagon receptors at approximately 5:1, GLP-1 activity counterbalancing glucagon-driven hepatic glucose output while glucagon adds energy expenditure and hepatic-fat-lowering. In a 54-week phase 2b study in overweight/obesity + T2D it reduced body weight, HbA1c and liver fat vs placebo and vs liraglutide; AstraZeneca reportedly deprioritised it.", "population": "Adults with overweight/obesity and T2D; phase 2a (n~65) and phase 2b 54-week study (n~834), double-blind, placebo- and liraglutide-controlled", "comparators": "placebo; liraglutide", "endpointType": "other", "notes": "Mechanism: balanced GLP-1/GCGR co-agonist, OXM-analogue. Glucagon arm framed as driving hepatic glycogenolysis/fat reduction and energy expenditure. Receptor ratio (~5:1) from review/company sources, not regulatory. Development status as reported (deprioritised), not a verdict.", "crossRef": "", "grade": "moderate", "source": { "citation": "Nahra et al., Diabetes Care 2021;44(6):1433-1442 (phase 2b); Ambery et al., Lancet 2018 (phase 2a)", "url": "https://diabetesjournals.org/care/article/44/6/1433/138721/Effects-of-Cotadutide-on-Metabolic-and-Hepatic", "identifiers": "NCT03235050", "date": "2021-06-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-CT388-LANDSCAPE-01", "sourceId": "CIT:roche-genentech-phase-2-topline-jan-2026-earlier", "drug": "CT-388 (enicepatide)", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "GIP/GLP-1 receptor dual agonist (once-weekly s.c.)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-22.5% placebo-adjusted weight at 48 wk (24 mg); >=10% in 87%, >=20% in 47.8%, >=30% in 26.1%; BMI <30 in 54% vs 13% placebo", "finding": "CT-388 (Roche/Genentech, ex-Carmot) is a once-weekly subcutaneous GLP-1/GIP dual agonist. In a phase 2 obesity trial it achieved a statistically significant placebo-adjusted weight loss of 22.5% at 48 weeks at the highest dose (24 mg), without reaching a plateau; 87% of the 24 mg group achieved >=10% and 47.8% >=20% weight loss, and 54% reached BMI <30 (vs 13% placebo).", "population": "Phase 2: 469 adults with obesity or overweight + >=1 comorbidity, dose-escalation up to 24 mg once-weekly s.c., 48 weeks, randomised double-blind placebo-controlled", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GLP-1/GIP dual agonist (same axis as tirzepatide). Phase 2 topline announced Jan 2026; full data to be presented at a medical congress; phase 3 (Enith1, Enith2) to begin. Gap-filled by parent: flagged by two clusters as core-roster but unassigned. Also being studied in combination with the amylin analogue petrelintide. Tagged press pending peer-reviewed publication.", "crossRef": "C-PETRELINTIDE-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Roche/Genentech phase 2 topline, Jan 2026; earlier phase 1b (Applied Clinical Trials)", "url": "https://www.roche.com/media/releases/med-cor-2026-01-27", "identifiers": "CT-388 (enicepatide); Roche release 2026-01-27", "date": "2026-01-27", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-DANUGLIPRON-LANDSCAPE-01", "sourceId": "CIT:pfizer-press-release-14-april-2025-stat-cnbc-bio", "drug": "danuglipron", "drugRoot": "danuglipron", "drugSlug": "danuglipron", "drugLabel": "Danuglipron", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "decrease", "magnitude": "Phase 2b (twice-daily) placebo-adjusted weight loss roughly 4-9% across doses at 32 weeks (as reported by Pfizer); programme halted before phase 3", "finding": "Oral non-peptide GLP-1RA (PF-06882961, Pfizer). Phase 2b twice-daily data showed clinically meaningful weight loss in obesity; once-daily formulation met PK objectives. Development DISCONTINUED for weight management on 14 April 2025 after a single asymptomatic participant experienced potential drug-induced liver injury that resolved on discontinuation; Pfizer stated overall liver-enzyme elevation frequency across the >1,400 participant database was in line with approved class agents.", "population": "Phase 2b: adults with obesity (with/without T2D); >1,400 participant total safety database", "comparators": "placebo", "endpointType": "other", "notes": "MECHANISM: oral non-peptide small-molecule GLP-1R agonist. DISCONTINUED Apr 2025 - single case of potential DILI (asymptomatic, resolved) plus regulator input. Pfizer's SECOND oral GLP-1 dropped for hepatic concerns (see lotiglipron). Phase-2b magnitudes are press-reported.", "crossRef": "C-LOTIGLIPRON-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Pfizer press release, 14 April 2025; STAT/CNBC/BioPharma Dive coverage", "url": "https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist", "identifiers": "PF-06882961", "date": "2025-04-14", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Pfizer (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-DULA-CARDIO-01", "sourceId": "PMID31189511", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.88 (95% CI 0.79-0.99; P=0.026); 12.0% vs 13.4% (2.4 vs 2.7/100PY); non-fatal stroke HR ~0.76. CV death and all-cause death not significantly reduced. Median 5.4 years.", "finding": "In T2D with a majority WITHOUT established CVD (primary-prevention-weighted), dulaglutide reduced MACE versus placebo, driven notably by reduced non-fatal stroke.", "population": "REWIND: N=9901; T2D, broad CV-risk (majority primary-prevention); double-blind placebo-controlled RCT; median 5.4 years (longest GLP-1 CVOT).", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS prior row. Distinct as the primary-prevention-weighted CVOT, extending class benefit to lower-baseline-risk T2D. Stroke-driven, echoing SUSTAIN-6. Dulaglutide is the active comparator in SURPASS-CVOT.", "crossRef": "C-SEMA-CARDIO-02; C-TIRZ-CARDIO-01", "grade": "high", "source": { "citation": "Gerstein HC et al. (REWIND), Lancet, 2019", "url": "https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31149-3/fulltext", "identifiers": "PMID 31189511; DOI 10.1016/S0140-6736(19)31149-3; NCT01394952 [VERIFIED 2026-06-20]", "date": "2019-06-09", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-CARDIO-RENAL-01", "sourceId": "PMID31189509", "drug": "dulaglutide (1.5 mg)", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Composite 17.1% vs 19.6%; HR 0.85 (95% CI 0.77 to 0.93; p=0.0004). New macroalbuminuria HR 0.77 (0.68-0.87); >=30% eGFR decline HR 0.89 (0.78-1.01; p=0.066); chronic RRT HR 0.75 (0.39-1.44).", "finding": "REWIND exploratory renal composite reduced with dulaglutide versus placebo (albuminuria-driven; eGFR-decline/RRT components non-significant).", "population": "REWIND: N=9,901 T2D; median 5.4 years; exploratory analysis.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Explicitly exploratory. PMID/DOI verified.", "crossRef": "C-DULA-CARDIO-01", "grade": "moderate", "source": { "citation": "Gerstein HC et al. (REWIND renal), Lancet, 2019;394:131-138", "url": "https://doi.org/10.1016/S0140-6736(19)31150-X", "identifiers": "PMID 31189509; DOI 10.1016/S0140-6736(19)31150-X", "date": "2019-06-09", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-CARDIO-RENAL-02", "sourceId": "PMID36754023", "drug": "dulaglutide (1.5 mg)", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Biomarker substudy: serum PRO-C6 lower vs glargine (wk52 -0.2% vs +8.0%; p<0.01); urine C3M higher (wk52 +20.7% vs -16.9%; p<0.05). Parent-trial eGFR/UACR headline numbers from Tuttle 2018 (not fetched).", "finding": "AWARD-7: dulaglutide slowed eGFR decline and reduced UACR versus insulin glargine at 52 weeks in T2D with moderate-to-severe CKD (parent-trial primary finding; the captured paper reports fibrosis biomarkers).", "population": "AWARD-7 subset N=330 (dulaglutide 1.5 mg vs insulin glargine); T2D + moderate-to-severe CKD; 52 weeks; post hoc biomarker analysis.", "comparators": "insulin glargine; dulaglutide 0.75 mg", "endpointType": "other", "notes": "This is a biomarker post hoc, NOT the AWARD-7 primary renal paper (Tuttle KR et al., Lancet Diabetes Endocrinol 2018 - not retrieved this pass). PMID/DOI of captured paper verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Am J Nephrol, 2023 (AWARD-7 fibrosis biomarkers)", "url": "https://doi.org/10.1159/000529374", "identifiers": "PMID 36754023; DOI 10.1159/000529374", "date": "2023-02-08", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-CARDIO-REWIND-STROKE-01", "sourceId": "PMID31924562", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "Stroke in 158/4949 (3.2%) dulaglutide vs 205/4952 (4.1%) placebo; HR 0.76 (95% CI 0.62-0.94, p=0.010). Ischaemic stroke HR 0.75 (0.59-0.94, p=0.012); haemorrhagic stroke HR 1.05 (0.55-1.99, p=0.89); disabling stroke HR 0.74 (0.56-0.99, p=0.042). Stroke severity (modified Rankin) did not differ by group.", "finding": "In a dedicated REWIND analysis, dulaglutide reduced total stroke, driven by ischaemic stroke, with no effect on haemorrhagic stroke and no change in post-stroke disability severity.", "population": "REWIND stroke analysis: N=9901 type 2 diabetes, broad CV risk; double-blind placebo-controlled randomised trial; median follow-up 5.4 years; NCT01394952.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "NET-NEW gather (WI-5). Distinct from the REWIND MACE composite (C-DULA-CARDIO-01, PMID 31189511): this is the dedicated Gerstein 2020 STROKE paper (separate PMID/source) decomposing ischaemic vs haemorrhagic vs disabling stroke. The MACE record only NOTED 'stroke-driven, non-fatal stroke HR ~0.76'; this record carries the full stroke decomposition (total 3.2% vs 4.1%, ischaemic 0.75, haemorrhagic null, disabling 0.74). An exploratory analysis of REWIND -> moderate by rule. Observation only; the 'why' open. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-CARDIO-01", "grade": "moderate", "source": { "citation": "Gerstein HC, Hart R, Colhoun HM, et al. The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol 2020;8(2):106-114.", "url": "https://doi.org/10.1016/S2213-8587(19)30423-1", "identifiers": "PMID:31924562 DOI:10.1016/S2213-8587(19)30423-1 NCT01394952", "date": "2020-01-07", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD1-01", "sourceId": "PMID24879836", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change from baseline -1.51% (LS mean)", "finding": "In AWARD-1, once-weekly dulaglutide on background metformin plus pioglitazone gave superior HbA1c reduction versus both placebo and twice-daily exenatide at 26 weeks in type 2 diabetes.", "population": "AWARD-1: phase-3, multicentre, parallel-arm randomised trial (2:2:2:1), N=976; type 2 diabetes on metformin (1500-3000 mg) + pioglitazone (30-45 mg); 52 weeks (primary endpoint 26 weeks); comparators placebo (double-blind via double-dummy) and exenatide 10 ug twice daily (OPEN-LABEL active comparator). MIXED blinding: the dulaglutide-vs-placebo comparison is double-blind, the dulaglutide-vs-exenatide superiority comparison is open-label.", "comparators": "placebo; exenatide", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Establishes dulaglutide's glycaemic head-to-head position vs exenatide (twice-daily short-acting GLP-1RA) and placebo. Phase-3 double-blind for the placebo comparison (the exenatide comparison was open-label per the trial design). Observation only; the per-receptor 'why' is left open. Industry-sponsored (Eli Lilly; dulaglutide manufacturer; several authors are Lilly employees). funding_basis is inferred-wrapper at gather time; if this record is load-bearing it must resolve to a disclosed funder with a verifiable locator before the gate graduates it. WI-5 build agent captured the substance; an independent Council interpretive review has NOT yet run.", "crossRef": "C-DULAGLUTIDE-LANDSCAPE-01", "grade": "moderate", "source": { "citation": "Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014;37(8):2159-2167.", "url": "https://doi.org/10.2337/dc13-2760", "identifiers": "PMID:24879836 DOI:10.2337/dc13-2760", "date": "2014-05-30", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD10-01", "sourceId": "PMID29483060", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c reduction at 24 weeks -1.34% vs placebo -0.54%", "finding": "In AWARD-10, adding once-weekly dulaglutide to an SGLT2 inhibitor (with or without metformin) gave superior HbA1c reduction versus placebo at 24 weeks in inadequately controlled type 2 diabetes.", "population": "AWARD-10: phase-3b, double-blind, placebo-controlled randomised trial, N=424; type 2 diabetes inadequately controlled on an SGLT2 inhibitor with or without metformin; dulaglutide 1.5/0.75 mg vs placebo; 24 weeks; NCT02597049.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Dulaglutide on top of SGLT2i - the modern combination position. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-GLYC-AWARD9-01", "grade": "high", "source": { "citation": "Ludvik B, Frias JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2018;6(5):370-381.", "url": "https://doi.org/10.1016/S2213-8587(18)30023-8", "identifiers": "PMID:29483060 DOI:10.1016/S2213-8587(18)30023-8 NCT02597049", "date": "2018-02-23", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD3-01", "sourceId": "PMID24842985", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change from baseline -0.78% (LS mean)", "finding": "In AWARD-3, dulaglutide monotherapy gave superior HbA1c reduction versus metformin monotherapy at 26 weeks in early type 2 diabetes.", "population": "AWARD-3: 52-week double-blind randomised trial, N=807; treatment-naive or low-dose-OAM type 2 diabetes (HbA1c 6.5-9.5%); subcutaneous dulaglutide 1.5/0.75 mg weekly vs metformin; primary endpoint 26 weeks.", "comparators": "metformin", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Defines dulaglutide-vs-metformin monotherapy glycaemic position. Observation only. Industry (Eli Lilly). Council interpretive review not yet run. funding_basis inferred-wrapper at gather; resolve to disclosed locator if load-bearing.", "crossRef": "C-DULA-GLYC-AWARD1-01", "grade": "high", "source": { "citation": "Umpierrez G, Tofe Povedano S, Perez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014;37(8):2168-2176.", "url": "https://doi.org/10.2337/dc13-2759", "identifiers": "PMID:24842985 DOI:10.2337/dc13-2759", "date": "2014-05-19", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD5-01", "sourceId": "PMID24762094", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "greatest Bayesian mean HbA1c change vs sitagliptin at 52 weeks -0.63%", "finding": "In AWARD-5, dulaglutide 1.5 mg added to metformin gave greater HbA1c reduction than sitagliptin over 52 weeks; the Bayesian dose-finding portion selected 1.5 mg and 0.75 mg as the doses to carry forward.", "population": "AWARD-5: adaptive, seamless, double-blind randomised dose-finding plus confirmatory trial; type 2 diabetes on metformin; randomised 3:1:1 to seven dulaglutide doses, sitagliptin 100 mg, or placebo (placebo to 26 weeks, sitagliptin to 104 weeks); Bayesian adaptive randomisation.", "comparators": "sitagliptin; placebo", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Dulaglutide-vs-sitagliptin (DPP-4i) glycaemic position plus the dose-selection rationale for the marketed 1.5/0.75 mg doses. This paper reports the dose-finding portion; the 104-week confirmatory AWARD-5 vs sitagliptin (Weinstock 2015) is a separate paper, not duplicated here. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-GLYC-AWARD1-01", "grade": "high", "source": { "citation": "Skrivanek Z, Gaydos BL, Chien JY, et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab 2014;16(8):748-756.", "url": "https://doi.org/10.1111/dom.12305", "identifiers": "PMID:24762094 DOI:10.1111/dom.12305", "date": "2014-05-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD6-01", "sourceId": "PMID25018121", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "LS-mean HbA1c reduction -1.42% (dulaglutide) vs -1.36% (liraglutide); treatment difference -0.06% (95% CI -0.19 to 0.07), p-non-inferiority<0.0001 (margin 0.4%).", "finding": "In AWARD-6, once-weekly dulaglutide 1.5 mg was non-inferior to once-daily liraglutide 1.8 mg for HbA1c reduction at 26 weeks in metformin-treated type 2 diabetes.", "population": "AWARD-6: phase-3, randomised, open-label, parallel-group non-inferiority trial, N=599 (299 dulaglutide, 300 liraglutide); metformin-treated type 2 diabetes (HbA1c 7.0-10.0%); 26 weeks; NCT01624259.", "comparators": "liraglutide", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). The key dulaglutide-vs-liraglutide head-to-head. Genuinely open-label, so graded moderate by rule even though phase-3 - recorded honestly, text not engineered to lift the grade. Observation only: HbA1c non-inferior; weight head-to-head captured separately. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-WEIGHT-AWARD6-01", "grade": "moderate", "source": { "citation": "Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014;384(9951):1349-1357.", "url": "https://doi.org/10.1016/S0140-6736(14)60976-4", "identifiers": "PMID:25018121 DOI:10.1016/S0140-6736(14)60976-4 NCT01624259", "date": "2014-07-10", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-GLYC-AWARD9-01", "sourceId": "PMID28294499", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change -1.44% (dulaglutide/glargine) vs -0.67% (placebo/glargine); difference -0.77% (95% CI -0.97 to -0.56), p<0.001. Body weight -2.41 kg difference favouring dulaglutide (p<0.001). Final glargine dose lower with dulaglutide (51 vs 65 U).", "finding": "In AWARD-9, adding once-weekly dulaglutide 1.5 mg to titrated insulin glargine gave superior HbA1c reduction versus placebo plus glargine at 28 weeks, with concurrent weight loss and a smaller required glargine dose increase.", "population": "AWARD-9: phase-3, double-blind, placebo-controlled randomised trial, N=300; type 2 diabetes inadequately controlled on titrated insulin glargine with or without metformin; dulaglutide 1.5 mg vs placebo added to glargine; 28 weeks; NCT02152371.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Dulaglutide as add-on to basal insulin - a distinct clinical position. Carries both HbA1c and weight plus an insulin-sparing observation. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-WEIGHT-AWARD9-01", "grade": "high", "source": { "citation": "Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9). Diabetes Obes Metab 2017;19(7):1024-1031.", "url": "https://doi.org/10.1111/dom.12937", "identifiers": "PMID:28294499 DOI:10.1111/dom.12937 NCT02152371", "date": "2017-04-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-HR-AWARD5-01", "sourceId": "PMID24762094", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "largest placebo-adjusted pulse-rate change +0.78 bpm", "finding": "Dulaglutide produces a small increase in pulse rate, consistent with the GLP-1 receptor agonist class, observed in the AWARD-5 dose-finding analysis.", "population": "AWARD-5: adaptive double-blind randomised dose-finding trial; type 2 diabetes on metformin; pulse rate measured as a Bayesian dose-selection criterion vs placebo at 26 weeks.", "comparators": "placebo; sitagliptin", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Opens the dulaglutide heart-rate-chronotropy cell with a per-drug record (previously inherited only via the SURPASS-CVOT comparator arm). The +0.78 bpm at 2.0 mg with a credible interval crossing zero is recorded faithfully - a small class-consistent chronotropic signal, not a large effect. Observation only; the 'why' open. Industry (Eli Lilly). Council interpretive review not yet run. funding_basis inferred-wrapper at gather; resolve to disclosed locator if load-bearing.", "crossRef": "C-DULA-GLYC-AWARD5-01", "grade": "high", "source": { "citation": "Skrivanek Z, Gaydos BL, Chien JY, et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab 2014;16(8):748-756.", "url": "https://doi.org/10.1111/dom.12305", "identifiers": "PMID:24762094 DOI:10.1111/dom.12305", "date": "2014-05-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-LIPID-LPA-01", "sourceId": "PMID38929525", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Lp(a) decreased post-treatment (p<0.05); PTX3 and MMP-9 decreased (p<0.001). CRUCIAL IN-STUDY CAVEAT: the conventional lipid panel did NOT change significantly - LDL, triglycerides, non-HDL-C and HDL-C changes were all non-significant (mean LDL and non-HDL trended slightly UP). 180-day pre/post pilot, N=34, no placebo arm; 88% on statins.", "finding": "In a small uncontrolled interventional pilot in adults with type 2 diabetes and verified atherosclerosis, dulaglutide treatment was followed by a significant reduction in lipoprotein(a) [Lp(a)] and in the plaque-instability markers pentraxin-3 and MMP-9, while the conventional lipid fractions (LDL-C, triglycerides, non-HDL-C, HDL-C) did NOT change significantly.", "population": "Uncontrolled single-arm interventional pilot (pre/post, no comparator, not randomised); N=34 adults (age 41-81, median 61) with type 2 diabetes, dyslipidaemia (88% on statins) and ultrasound-verified carotid atherosclerosis; dulaglutide 1.5-3 mg, 180 days.", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-4). Fills the previously absent Lp(a) lipoprotein in the compendium with a small single-centre class result for a GLP-1RA. Design: single-arm interventional pilot, N=34, no placebo - small N and no control are recorded scope limits. OBSERVATION only; the 'why' stays open. BOTH-POLES (rule 1.10), recorded explicitly on WI-4 audit: (a) IN THIS SAME STUDY the standard lipid panel (LDL/TG/non-HDL/HDL) was non-significant and LDL/non-HDL trended slightly upward - the paper attributes this to pre-existing statin therapy (88%) and a few outliers - so the Lp(a) signal sits beside an in-study NULL on conventional lipids; (b) Lp(a) is largely genetically determined and the broader GLP-1 class literature is mixed-to-null - the paper itself cites Ariel D et al. finding NO Lp(a) change on liraglutide in pre-diabetes, against Bechlioulis A et al. and Steven R et al. who found improvement in T2D. This small positive uncontrolled pilot does not resolve that disagreement; it is one low-grade data point within it. Academic (Medical University of Silesia, grant PCN-1-227/N/2/O); authors declare no conflicts of interest; no industry/Eli Lilly sponsor.", "crossRef": "", "grade": "low", "source": { "citation": "Hachula M, Kosowski M, Basiak M, Okopien B, Medicina (Kaunas) 2024;60(6):908", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11205508/", "identifiers": "PMID:38929525 DOI:10.3390/medicina60060908", "date": "2024-05-30", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~34)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-RENAL-AWARD7-EXPL-01", "sourceId": "PMID35373017", "drug": "dulaglutide (1.5 mg)", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Composite >=40% eGFR decline/ESKD/renal death: 5% vs 11%, HR 0.45 (95% CI 0.20-0.97; p=0.04) overall; macroalbuminuria subgroup 7% vs 22%, HR 0.25 (95% CI 0.10-0.68; p=0.006). At matched glycaemia and BP.", "finding": "AWARD-7 exploratory analysis: dulaglutide 1.5 mg reduced the composite of >=40% eGFR decline or ESKD versus insulin glargine in T2D with moderate-to-severe CKD, concentrated in the macroalbuminuria subgroup; benefit at MATCHED glycaemia and BP argues for a glycaemia-independent renal effect.", "population": "AWARD-7 prespecified exploratory secondary analysis of a randomised controlled trial: dulaglutide 0.75/1.5 mg weekly vs daily insulin glargine; T2D + moderate-to-severe CKD (stage 3-4); 1 year; active comparator at matched glycaemia/BP.", "comparators": "insulin glargine; dulaglutide 0.75 mg", "endpointType": "hard-outcome", "notes": "NET-NEW source/observation: distinct from C-DULA-CARDIO-RENAL-02 (PMID 36754023, AWARD-7 fibrosis-BIOMARKER substudy, which only RESTATED the parent finding); this is the AWARD-7 exploratory clinical-event analysis (Kidney360 2020) carrying the composite HR 0.45 / macroalbuminuria HR 0.25 directly. Exploratory (parent trial Tuttle 2018). Eli Lilly COI. Folded from thread-7 ledger entry T7-010 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-DULA-CARDIO-RENAL-02", "grade": "moderate", "source": { "citation": "Tuttle KR et al. (AWARD-7 exploratory), Kidney360 2020;2(2):254-262", "url": "https://doi.org/10.34067/KID.0005852020", "identifiers": "PMID:35373017 DOI:10.34067/KID.0005852020", "date": "2020-12-22", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company (AWARD-7 sponsor; disclosed)", "scopeLimits": "exploratory analysis (parent trial Tuttle 2018); active comparator insulin glargine at matched glycaemia/BP", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-RENAL-AWARD7-PARENT-01", "sourceId": "PMID29910024", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "mixed", "magnitude": "HbA1c non-inferior to glargine at 26 weeks (difference -0.05% for 1.5 mg). At 52 weeks eGFR (CKD-EPI cystatin C) was higher with dulaglutide 1.5 mg (34.0 mL/min/1.73m2, p=0.005 vs glargine) and 0.75 mg (33.8, p=0.009) than glargine (31.3). UACR reduction not significantly different from glargine. ESKD in 8/192 (4%) dulaglutide 1.5 mg, 14/190 (7%) 0.75 mg, 16/194 (8%) glargine.", "finding": "AWARD-7 parent trial: in type 2 diabetes with moderate-to-severe CKD, dulaglutide gave HbA1c control non-inferior to insulin glargine with a slower decline in eGFR over 52 weeks.", "population": "AWARD-7: phase-3, multicentre, open-label, randomised trial, N=577; type 2 diabetes plus moderate-to-severe CKD (stages 3-4) on ACEi/ARB; dulaglutide 1.5/0.75 mg vs daily insulin glargine, both with insulin lispro; 52 weeks; NCT01621178.", "comparators": "insulin glargine", "endpointType": "hard-outcome", "notes": "NET-NEW gather (WI-5). The AWARD-7 PARENT renal/eGFR result (Tuttle 2018 Lancet Diabetes Endocrinol), DISTINCT from the two existing AWARD-7 records: C-DULA-RENAL-AWARD7-EXPL-01 (PMID 35373017, Kidney360 clinical-event composite HR 0.45) and C-DULA-CARDIO-RENAL-02 (PMID 36754023, fibrosis-biomarker work). This record carries the parent-trial eGFR (34.0/33.8 vs 31.3 mL/min/1.73m2) and ESKD counts. Open-label -> moderate by rule. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-RENAL-AWARD7-EXPL-01", "grade": "moderate", "source": { "citation": "Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018;6(8):605-617.", "url": "https://doi.org/10.1016/S2213-8587(18)30104-9", "identifiers": "PMID:29910024 DOI:10.1016/S2213-8587(18)30104-9 NCT01621178", "date": "2018-06-14", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-SAFETY-REWIND-COGN-01", "sourceId": "PMID32562683", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Cognitive outcome (MoCA or DSST score >=1.5 SD below baseline country mean): 4.05 vs 4.35 per 100 patient-years. PRESPECIFIED PRIMARY (unadjusted) HR 0.93 (95% CI 0.85-1.02, p=0.11) - NULL. Only a POST-HOC analysis adjusted for individual standardised baseline scores reached significance: HR 0.86 (0.79-0.95, p=0.0018).", "finding": "In a REWIND exploratory substudy, dulaglutide did NOT significantly reduce incident substantive cognitive impairment on the prespecified primary (unadjusted) analysis; significance appeared only in a post-hoc baseline-score-adjusted analysis.", "population": "REWIND cognition substudy: N=8828 with baseline plus follow-up MoCA/DSST (of 9901); type 2 diabetes; double-blind placebo-controlled randomised trial; median 5.4 years; NCT01394952.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "NET-NEW gather (WI-5). The REWIND COGNITION substudy. BOTH-POLES recorded honestly (rule 1.10): the prespecified primary cognitive outcome was NULL (HR 0.93, p=0.11); only the baseline-adjusted analysis was significant (HR 0.86). The finding states the null first and the adjusted-positive second, so it is not presented as an unqualified cognitive benefit. An exploratory substudy of REWIND -> moderate by rule; not the cell-best in safety-other (cell carried by a high record). Observation only. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-CARDIO-01", "grade": "moderate", "source": { "citation": "Cukierman-Yaffe T, Gerstein HC, Colhoun HM, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol 2020;19(7):582-590.", "url": "https://doi.org/10.1016/S1474-4422(20)30173-3", "identifiers": "PMID:32562683 DOI:10.1016/S1474-4422(20)30173-3 NCT01394952", "date": "2020-06-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-TOLGI-AWARD10-01", "sourceId": "PMID29483060", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "AWARD-10 (vs placebo): nausea 15% (1.5 mg) vs 5% (0.75 mg) vs 4% (placebo); diarrhoea 6%/10%/3%; vomiting 4%/3%/1%. AWARD-6 (vs liraglutide): nausea 20% vs 18%, diarrhoea 12% vs 12%, vomiting 7% vs 8%; discontinuation for adverse events 6% in each group. Severe hypoglycaemia rare/absent on dulaglutide backgrounds without insulin.", "finding": "Across the AWARD programme, dulaglutide's most common adverse events are gastrointestinal (nausea, diarrhoea, vomiting), dose-related and mostly mild-to-moderate and transient, with low study-drug discontinuation.", "population": "AWARD programme phase-3 double-blind randomised trials: AWARD-10 (N=424, vs placebo, on SGLT2i) and the open-label AWARD-6 (N=599, vs liraglutide, on metformin); GI adverse-event incidence and discontinuation.", "comparators": "placebo; liraglutide", "endpointType": "other", "notes": "NET-NEW gather (WI-5). Opens the dulaglutide tolerability-gi cell with a per-drug GI/discontinuation record (dulaglutide GI was previously inherited only via the SURPASS-CVOT comparator arm). AWARD-10 (placebo-controlled) and AWARD-6 (vs liraglutide) GI percentages confirmed from abstracts; AWARD-6 discontinuation 6%/6% confirmed. Observation only; the dose-relation of nausea (15% at 1.5 mg vs 5% at 0.75 mg in AWARD-10) is recorded as an observation. Industry (Eli Lilly). Council interpretive review not yet run.", "crossRef": "C-DULA-GLYC-AWARD6-01", "grade": "high", "source": { "citation": "Ludvik B, Frias JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2018;6(5):370-381.", "url": "https://doi.org/10.1016/S2213-8587(18)30023-8", "identifiers": "PMID:29483060 DOI:10.1016/S2213-8587(18)30023-8 NCT02597049", "date": "2018-02-23", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-TOLGI-DISCONT-AWARD6-01", "sourceId": "PMID25018121", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "no-change", "magnitude": "Discontinuation due to adverse events: 18 of 299 (6%) with dulaglutide vs 18 of 300 (6%) with liraglutide over 26 weeks; hypoglycaemia rate 0.34 vs 0.52 events/patient/year, no severe hypoglycaemia.", "finding": "In the AWARD-6 head-to-head, study or study-drug discontinuation because of adverse events was the same for once-weekly dulaglutide and once-daily liraglutide.", "population": "AWARD-6: phase-3 open-label non-inferiority randomised trial, N=599; metformin-treated type 2 diabetes; dulaglutide 1.5 mg weekly vs liraglutide 1.8 mg daily; 26 weeks.", "comparators": "liraglutide", "endpointType": "other", "notes": "NET-NEW gather (WI-5). Discrete discontinuation-rate observation (a WI-5 target): a dulaglutide-vs-liraglutide equality at 6%/6%. Open-label -> moderate by rule. Observation only. Council interpretive review not yet run.", "crossRef": "C-DULA-TOLGI-AWARD10-01", "grade": "moderate", "source": { "citation": "Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014;384(9951):1349-1357.", "url": "https://doi.org/10.1016/S0140-6736(14)60976-4", "identifiers": "PMID:25018121 DOI:10.1016/S0140-6736(14)60976-4 NCT01624259", "date": "2014-07-10", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-WEIGHT-AWARD1-01", "sourceId": "PMID24879836", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "mixed", "magnitude": "Weight is a secondary endpoint; on the metformin+pioglitazone (weight-gaining) background, dulaglutide 1.5 mg gave near-neutral weight change and 0.75 mg a modest gain. The abstract reports the comparison directionally and does not give a single placebo-adjusted kg for weight.", "finding": "In AWARD-1 (type 2 diabetes on metformin plus pioglitazone), dulaglutide produced modest weight change against a weight-gaining background regimen, with the 1.5 mg dose giving near-neutral weight and 0.75 mg a small gain.", "population": "AWARD-1: phase-3 parallel-arm randomised trial, N=976; type 2 diabetes on metformin + pioglitazone; 52 weeks; comparators placebo (double-blind) and exenatide (OPEN-LABEL active comparator).", "comparators": "placebo; exenatide", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Opens the dulaglutide weight-loss cell. IN-RECORD CAVEAT: the pioglitazone background is itself weight-gaining, so AWARD-1 understates dulaglutide's intrinsic weight effect; AWARD-3 (metformin background) and AWARD-6 (vs liraglutide) are cleaner weight reads, recorded separately. Observation only. Magnitude is directional from the abstract (no single placebo-adjusted kg stated there); flagged magnitude-from-abstract, full-text kg to be confirmed. Council interpretive review not yet run.", "crossRef": "C-DULA-WEIGHT-AWARD3-01", "grade": "moderate", "source": { "citation": "Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 2014;37(8):2159-2167.", "url": "https://doi.org/10.2337/dc13-2760", "identifiers": "PMID:24879836 DOI:10.2337/dc13-2760", "date": "2014-05-30", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-WEIGHT-AWARD3-01", "sourceId": "PMID24842985", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Decrease in weight was similar with dulaglutide 1.5 mg and metformin, and smaller with dulaglutide 0.75 mg (the abstract reports the direction/comparison; no single placebo-adjusted kg figure is given there). Weight is a secondary endpoint.", "finding": "In AWARD-3, weight change with dulaglutide on a metformin-comparator monotherapy background was similar to metformin for the 1.5 mg dose and smaller (less loss) for 0.75 mg.", "population": "AWARD-3: 52-week double-blind randomised trial, N=807; early type 2 diabetes; dulaglutide 1.5/0.75 mg vs metformin monotherapy.", "comparators": "metformin", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Cleaner weight read than AWARD-1 (no pioglitazone) but comparator is metformin (weight-neutral/loss). Observation only; magnitude directional-from-abstract, full-text kg to be confirmed. Council interpretive review not yet run.", "crossRef": "C-DULA-WEIGHT-AWARD1-01", "grade": "high", "source": { "citation": "Umpierrez G, Tofe Povedano S, Perez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 2014;37(8):2168-2176.", "url": "https://doi.org/10.2337/dc13-2759", "identifiers": "PMID:24842985 DOI:10.2337/dc13-2759", "date": "2014-05-19", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-WEIGHT-AWARD6-01", "sourceId": "PMID25018121", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Both arms lost weight over 26 weeks with a similar tolerability and efficacy profile alongside HbA1c non-inferiority; liraglutide numerically slightly greater weight loss. Weight was a secondary endpoint; the abstract does not give the placebo-adjusted kg.", "finding": "In AWARD-6, once-weekly dulaglutide 1.5 mg and once-daily liraglutide 1.8 mg produced broadly similar weight reduction over 26 weeks, with liraglutide numerically slightly greater.", "population": "AWARD-6: phase-3 open-label non-inferiority trial, N=599; metformin-treated type 2 diabetes; dulaglutide 1.5 mg weekly vs liraglutide 1.8 mg daily; 26 weeks.", "comparators": "liraglutide", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Open-label -> moderate by rule. Weight magnitude directional-from-abstract; the widely-cited full-text figures (dulaglutide ~ -2.9 kg vs liraglutide ~ -3.6 kg) are NOT pinned from the abstract and are deliberately not stated as exact, to avoid fabrication - full-text kg to be confirmed. Observation only. Council interpretive review not yet run.", "crossRef": "C-DULA-GLYC-AWARD6-01", "grade": "moderate", "source": { "citation": "Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014;384(9951):1349-1357.", "url": "https://doi.org/10.1016/S0140-6736(14)60976-4", "identifiers": "PMID:25018121 DOI:10.1016/S0140-6736(14)60976-4 NCT01624259", "date": "2014-07-10", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULA-WEIGHT-AWARD9-01", "sourceId": "PMID28294499", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Body weight decreased with dulaglutide/glargine and increased with placebo/glargine; LS-mean between-group difference -2.41 kg (SE 0.39), p<0.001, at 28 weeks.", "finding": "In AWARD-9, dulaglutide added to titrated insulin glargine produced weight loss whereas placebo plus glargine produced weight gain.", "population": "AWARD-9: phase-3 double-blind placebo-controlled randomised trial, N=300; type 2 diabetes on titrated glargine; dulaglutide 1.5 mg vs placebo; 28 weeks.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-5). Weight benefit even on a weight-gaining insulin background; placebo-adjusted -2.41 kg confirmed exact from the abstract. Observation only. Council interpretive review not yet run.", "crossRef": "C-DULA-GLYC-AWARD9-01", "grade": "high", "source": { "citation": "Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9). Diabetes Obes Metab 2017;19(7):1024-1031.", "url": "https://doi.org/10.1111/dom.12937", "identifiers": "PMID:28294499 DOI:10.1111/dom.12937 NCT02152371", "date": "2017-04-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-DULAGLUTIDE-LANDSCAPE-01", "sourceId": "DOI10.2337/DC20-1473", "drug": "dulaglutide", "drugRoot": "dulaglutide", "drugSlug": "dulaglutide", "drugLabel": "Dulaglutide", "drugClass": "GLP-1 receptor monoagonist (GLP-1 analogue fused to modified IgG4 Fc, once-weekly s.c.)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c approx -1.9% at 36 weeks", "finding": "Once-weekly dulaglutide at 4.5 mg gave superior HbA1c reduction (approx -1.9%) and weight change (-4.7 kg) vs 1.5 mg (-1.5%, -3.1 kg) at 36 weeks in metformin-treated T2D.", "population": "AWARD-11: T2D on metformin, randomised to dulaglutide 1.5/3.0/4.5 mg, 52 weeks (primary at 36 weeks)", "comparators": "dulaglutide 1.5 mg; dulaglutide 3.0 mg", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GLP-1(7-37) analogue linked to modified human IgG4 Fc (~5 day half-life, once-weekly). Marketed as Trulicity (T2D); approved US/EU. CV benefit in REWIND. No dedicated obesity (non-T2D) indication; weight is secondary. AWARD-11 identifiers are the established ones, reconfirm flag noted.", "crossRef": "", "grade": "high", "source": { "citation": "Frias JP et al. (AWARD-11), Diabetes Care 2021;44:765", "url": "https://doi.org/10.2337/dc20-1473", "identifiers": "DOI 10.2337/dc20-1473 [VERIFIED 2026-06-20]", "date": "", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-ECNO-GLY-PH2-01", "sourceId": "PMID39333121", "drug": "ecnoglutide", "drugRoot": "ecnoglutide", "drugSlug": "ecnoglutide", "drugLabel": "Ecnoglutide", "drugClass": "GLP-1 receptor agonist (cAMP-biased)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Phase-2 (China, n=145, 20 wk): HbA1c -1.81/-1.90/-2.39% (0.4/0.8/1.2 mg) vs -0.55% placebo (p<0.0001); >=5% weight loss 33.3% vs 3.0% at 1.2 mg.", "finding": "The cAMP-biased GLP-1 agonist ecnoglutide lowered HbA1c by up to ~2.4% in phase-2 type-2 diabetes.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "efficacy", "notes": "Phase-2; China-only; injectable. The ecnoglutide phase-3 OBESITY result (PMID 40555243) is already in the corpus (C2-ECNO-WL-01).", "crossRef": "", "grade": "moderate", "source": { "citation": "Ecnoglutide in type 2 diabetes, phase-2, Nat Commun 2024", "url": "https://doi.org/10.1038/s41467-024-52353-y", "identifiers": "DOI:10.1038/s41467-024-52353-y", "date": "2024-09-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "Sciwind Biosciences", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ECNOGLUTIDE-LANDSCAPE-01", "sourceId": "DOI10.1038/S41467-024-52353-Y", "drug": "ecnoglutide", "drugRoot": "ecnoglutide", "drugSlug": "ecnoglutide", "drugLabel": "Ecnoglutide", "drugClass": "injectable cAMP-biased GLP-1 receptor agonist (peptide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "decrease", "magnitude": "Phase 2 T2D: HbA1c -1.81/-1.90/-2.39% vs -0.55% placebo, 20 wk; >=5% weight loss 33.3% (1.2 mg) vs 3.0% placebo", "finding": "CLARIFICATION RECORD: ecnoglutide (XW003, Sciwind Biosciences) is NOT an oral small-molecule GLP-1RA. It is an injectable long-acting modified GLP-1(7-37) PEPTIDE (Ala8->Val8 plus C18 fatty-acid conjugation at Lys30), once-weekly s.c., and a cAMP signalling-BIASED GLP-1R agonist. Phase 2 (T2D, N=145, China, 20 wk): HbA1c -1.81/-1.90/-2.39% (0.4/0.8/1.2 mg) vs -0.55% placebo; 33.3% of 1.2 mg achieved >=5% weight loss vs 3.0% placebo. Phase 3 obesity and T2D (EECOH/EECOH-1) reported.", "population": "Phase 2 T2D: 145 adults, China, once-weekly s.c., 20 wk, placebo-controlled; phase 3 obesity and T2D (EECOH/EECOH-1)", "comparators": "placebo", "endpointType": "other", "notes": "MECHANISM CLARIFICATION: peptide, injectable (once-weekly s.c.), cAMP-biased GLP-1R agonist - NOT an oral small molecule. Roster listed it under oral small-molecule GLP-1 but identity does not match; recorded here with corrected classification. cAMP bias hypothesised to reduce receptor internalisation and enhance insulin secretion.", "crossRef": "", "grade": "moderate", "source": { "citation": "Zhang et al., Nat Commun 2024;15:8408 (phase 2 T2D); Lancet Diabetes Endocrinol 2025 (phase 3 obesity)", "url": "https://www.nature.com/articles/s41467-024-52353-y", "identifiers": "XW003; Nat Commun DOI 10.1038/s41467-024-52353-y; Lancet DOI 10.1016/S2213-8587(25)00141-X", "date": "2024-09-27", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Hangzhou Sciwind Biosciences (sponsor of record; disclosed)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-EFINOPEGDUTIDE-LANDSCAPE-01", "sourceId": "NCTNCT04944992", "drug": "efinopegdutide", "drugRoot": "efinopegdutide", "drugSlug": "efinopegdutide", "drugLabel": "Efinopegdutide", "drugClass": "GLP-1/glucagon (GCGR) dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "weight loss LS mean 8.5% vs semaglutide 7.1%", "finding": "Efinopegdutide (MK-6024; formerly HM12525A / JNJ-64565111; Merck, licensed from Hanmi) is a GLP-1/glucagon co-agonist developed primarily for MASLD/MASH. In a phase 2a active-comparator open-label study in NAFLD, efinopegdutide 10 mg weekly produced a significantly greater relative liver-fat reduction at 24 weeks than semaglutide 1 mg weekly; weight loss was 8.5% (efinopegdutide) vs 7.1% (semaglutide), with higher GI adverse-event incidence.", "population": "Adults with NAFLD; phase 2a randomised active-comparator open-label, efinopegdutide 10 mg vs semaglutide 1 mg weekly, 24 wk (NCT04944992)", "comparators": "semaglutide", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GLP-1/GCGR co-agonist; glucagon arm framed as driving hepatic-fat clearance, giving a head-to-head liver-fat advantage over pure GLP-1RA. Phase 2b precirrhotic NASH (NCT05877547) and compensated-cirrhosis studies ongoing. DOI not captured; cite via J Hepatol 2023 + NCT.", "crossRef": "", "grade": "moderate", "source": { "citation": "Romero-Gomez et al., phase IIa efinopegdutide in NAFLD, J Hepatol 2023 (EASL 2023)", "url": "https://www.journal-of-hepatology.eu/article/S0168-8278(23)00342-2/fulltext", "identifiers": "NCT04944992", "date": "2023-08-01", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Merck Sharp & Dohme LLC (efinopegdutide licensed from Hanmi)", "scopeLimits": "no outcome data yet (ongoing); open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EFOCIPEGTRUTIDE-LANDSCAPE-01", "sourceId": "DOI10.1016/J.CCT.2023.107176", "drug": "efocipegtrutide", "drugRoot": "efocipegtrutide", "drugSlug": "efocipegtrutide", "drugLabel": "Efocipegtrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Phase 1b/2a: significant liver-fat reduction vs placebo after 12 weeks plus body-weight reduction (specific percentages not pinned to a peer-reviewed primary in this pass)", "finding": "Efocipegtrutide (HM15211, Hanmi) is a long-acting GLP-1/GIP/glucagon triple co-agonist developed primarily for MASH/NASH rather than obesity. In a phase 1b/2a study it significantly reduced liver fat and body weight in obese subjects with NAFLD; a phase 2 biopsy-confirmed NASH trial (HM-TRIA-201) followed.", "population": "Phase 1b/2a multicentre randomised placebo-controlled in obese subjects with NAFLD. Phase 2 HM-TRIA-201: adaptive randomised double-blind 52-week study, N=217 biopsy-confirmed NASH.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "CONFIRMED GLP-1/GIP/glucagon triple, lead indication MASH/NASH not obesity. Headline is liver-fat; weight loss secondary. Primary phase 2 efficacy not captured from peer-reviewed journal this pass; HM-TRIA-201 NCT flagged as to-confirm (NOT asserted as verified).", "crossRef": "C-HM15275-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Abdelmalek MF et al. HM-TRIA-201: phase 2 study of HM15211 (efocipegtrutide) in biopsy-confirmed NASH - study design and rationale. Contemp Clin Trials 2023;130:107176.", "url": "https://doi.org/10.1016/j.cct.2023.107176", "identifiers": "PMID 37028504; DOI 10.1016/j.cct.2023.107176", "date": "2023-04-05", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Hanmi (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (design/protocol paper); small sample (N~217)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EFOCIPEGTRUTIDE-MASH-STATUS", "sourceId": "PMID37028504", "drug": "efocipegtrutide", "drugRoot": "efocipegtrutide", "drugSlug": "efocipegtrutide", "drugLabel": "Efocipegtrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "No published human MASH histology RESULTS as of 2026-06. The phase-2 biopsy-MASH trial HM-TRIA-201 is published only as a study-DESIGN/protocol paper (planned N=217, adaptive, primary = resolution of steatohepatitis without worsening fibrosis at 52 wk); results not reported. Earlier phase-1b/2a in obese NAFLD reduced liver fat and weight (no histology).", "finding": "Efocipegtrutide (HM15211; Hanmi, GLP-1/GIP/glucagon TRIPLE) is the closest published triple-agonist comparator to retatrutide for MASH, but its phase-2 histology trial (HM-TRIA-201) exists only as a PROTOCOL paper - no histologic outcome results published. The triple's MASH-resolution endpoint remains UNREAD in humans.", "population": "HM-TRIA-201 (protocol): planned N=217, biopsy NASH/MASH, adaptive RCT, 52 wk; primary = resolution without worsening fibrosis. Results pending.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "STATUS row (honest gap-flag). MOST RETA-RELEVANT mechanistically (also a GLP-1/GIP/glucagon TRIPLE), which makes the absence of results notable: even the OTHER triple has no read-out MASH histology trial, so there is currently NO published triple-agonist histologic MASH evidence to anchor expectations for retatrutide. Reta itself has NO dedicated MASH histology trial (only the phase-2a MRI-PDFF substudy). Sponsor Hanmi.", "crossRef": "C-EFOCIPEGTRUTIDE-LANDSCAPE-01; C2-RETATRUTIDE-MASH-01", "grade": "very-low", "source": { "citation": "Abdelmalek MF et al. Phase 2 52-week study of HM15211 in biopsy-confirmed NASH - design (HM-TRIA-201). Contemp Clin Trials 2023;130:107176.", "url": "https://doi.org/10.1016/j.cct.2023.107176", "identifiers": "PMID37028504", "date": "2023-04-05", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Hanmi (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing); small sample (N~217)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EFPE-CARDIO-01", "sourceId": "PMID34215025", "drug": "efpeglenatide", "drugRoot": "efpeglenatide", "drugSlug": "efpeglenatide", "drugLabel": "Efpeglenatide", "drugClass": "GLP-1 receptor agonist (exendin-4-based)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.73 (95% CI 0.58-0.92; P=0.007). Expanded CV composite HR 0.79. Kidney composite HR 0.68 (0.57-0.79). Median 1.8 years.", "finding": "In T2D with CVD or kidney disease plus another risk factor, efpeglenatide reduced MACE versus placebo, with a dose-dependent trend, and reduced a kidney composite. An exendin-4-based agent showing hard CV benefit.", "population": "AMPLITUDE-O: N=4076; T2D with CVD or kidney disease; double-blind placebo-controlled RCT; median 1.8 years.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "ADDED. Key because efpeglenatide is exendin-4-BASED yet showed clear CV benefit (HR 0.73), countering the idea that exendin-based agents are inert on MACE; it is the trial folded into the Sattar 2021 class meta-analysis. High background SGLT2i use enabled interaction analyses.", "crossRef": "C-CLASS-CARDIO-01; C-EXEN-CARDIO-01", "grade": "moderate", "source": { "citation": "Gerstein HC et al., N Engl J Med, 2021", "url": "https://doi.org/10.1056/NEJMoa2108269", "identifiers": "PMID34215025", "date": "2021-06-28", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Sanofi (efpeglenatide, AMPLITUDE-O; disclosed)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EFPE-RENAL-AMPLITUDE-01", "sourceId": "PMID34215025", "drug": "efpeglenatide", "drugRoot": "efpeglenatide", "drugSlug": "efpeglenatide", "drugLabel": "Efpeglenatide", "drugClass": "GLP-1 receptor agonist (exendin-based)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Composite renal outcome (decreased kidney function or new macroalbuminuria): 353/2717 (13.0%) efpeglenatide vs 250/1359 (18.4%) placebo; HR 0.68 (95% CI 0.57-0.79; P<0.001).", "finding": "AMPLITUDE-O: in T2D with cardiovascular disease or kidney disease plus a risk factor, efpeglenatide reduced a composite renal outcome (decreased kidney function or new macroalbuminuria) versus placebo (HR 0.68), a prespecified secondary alongside the MACE primary.", "population": "AMPLITUDE-O (NCT03496298): 4076 randomised (2717 efpeglenatide 4/6 mg, 1359 placebo); T2D + CVD or CKD (eGFR 25.0-59.9) + a risk factor; median follow-up 1.81 years; double-blind RCT; SGLT2i-stratified.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "NEW-GATHER (identifier already in corpus as MACE-only finding C-EFPE-CARDIO-01; the RENAL composite was missing). Top-tier CVOT renal secondary. Net-new OBSERVATION on an EXISTING source (PMID 34215025, Gerstein NEJM 2021, DOI 10.1056/NEJMoa2108269); inherits the source's grade. Albuminuria-inclusive composite (not a hard kidney-failure-only endpoint). AMPLITUDE-O renal composite HR 0.68 (95% CI 0.57-0.79; P<0.001), 13.0% vs 18.4%, independently re-confirmed via PubMed get_article_metadata 2026-06-24. Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-EFPE-CARDIO-01", "grade": "moderate", "source": { "citation": "Gerstein HC et al., N Engl J Med, 2021", "url": "https://doi.org/10.1056/NEJMoa2108269", "identifiers": "PMID34215025", "date": "2021-06-28", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Sanofi (efpeglenatide, AMPLITUDE-O; disclosed)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-ELECOGLIPRON-LANDSCAPE-01", "sourceId": "NCTNCT06579092", "drug": "elecoglipron", "drugRoot": "elecoglipron", "drugSlug": "elecoglipron", "drugLabel": "Elecoglipron", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Phase 1/1b: clinically meaningful weight reduction and glycaemic improvement reported by sponsor (percentages not quantified in topline); phase 2b ongoing", "finding": "Oral non-peptide GLP-1RA (ECC5004/AZD5004; INN elecoglipron), discovered by Eccogene, licensed to AstraZeneca. US phase 1 reported clinically meaningful weight reductions regardless of T2D status plus glycaemic improvements in T2D. Eccogene reported positive topline phase 1b (China, Feb 2026). Advanced to phase 2b: VISTA (obesity), SOLSTICE (T2D).", "population": "Phase 1 (US) and phase 1b (China) in adults with obesity/overweight +/- T2D; phase 2b VISTA/SOLSTICE ongoing", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "MECHANISM: oral non-peptide small-molecule GLP-1R agonist, once daily. ECC5004 = AZD5004 = elecoglipron (INN). DISTINCT from aleniglipron (GSBR-1290) - the roster's 'ECC5004 = aleniglipron' was a conflation; both mapped separately. VISTA/SOLSTICE NCTs from press, verify against ClinicalTrials.gov before primary citation.", "crossRef": "", "grade": "very-low", "source": { "citation": "Eccogene/AstraZeneca press (license Nov 2023; phase 1b topline Feb 2026)", "url": "https://www.businesswire.com/news/home/20260210405505/en/", "identifiers": "ECC5004 / AZD5004; NCT06579092 (VISTA); NCT06579105 (SOLSTICE)", "date": "2026-02-10", "design": "regulatory document / agency review", "maturity": "press", "funding": "industry (company press release on own pipeline)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-ENOBOSARM-BODYCOMP-01", "sourceId": "NCTNCT06282458", "drug": "enobosarm + semaglutide", "drugRoot": "enobosarm", "drugSlug": "enobosarm", "drugLabel": "Enobosarm", "drugClass": "selective androgen receptor modulator (SARM); muscle-preserving combo with GLP-1RA", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Company topline (press): 71% reduction in lean-mass loss vs placebo at 16 wk (P=0.002, pooled doses); lean = 9.4% of weight lost (enobosarm) vs 32% (placebo); 27% more fat-mass reduction; physical-function signal (46.2% relative reduction in patients with >=10% stair-climb-power decline, 6 mg).", "finding": "Veru phase-2b QUALITY trial (NCT06282458): enobosarm added to semaglutide in older adults (>=60 y) reported large reductions in lean-mass loss and a physical-function signal versus placebo+semaglutide. This is muscle PRESERVATION (anti-catabolic). NON-GRADUATING: the figures are a company press topline only, with no peer-reviewed publication.", "population": "QUALITY phase-2b dose-finding RCT, N=168, double-blind placebo-controlled, 16 weeks, adults >=60 y on semaglutide; enobosarm 3/6 mg vs placebo.", "comparators": "placebo + semaglutide", "endpointType": "imaging/physiological surrogate", "notes": "NON-GRADUATING press claim (channel/maturity = press -> very-low) per the press rule; recorded for provenance until a PMID/DOI appears. Registry confirmed NCT06282458 (Veru, Completed, primary = total lean mass at 112 days). A follow-on phase-2b PLATEAU (NCT07446998, recruiting, weight + function endpoints at 68 wk) is a registry promissory note, folded here. COI (Council): the favourable lean-preservation topline is MANUFACTURER-issued (Veru), with no independent or peer-reviewed verification and a selective-disclosure risk. The stair-climb-power figure is a press responder-threshold (>=10% decline), NOT a continuous strength endpoint, and does NOT close the function gap (C-CLASS-BODYCOMP-08). Enobosarm+semaglutide - UNTESTED on retatrutide.", "crossRef": "C-MUSCLE-PRESERVATION-MECH-01; C-APITEGROMAB-BODYCOMP-01", "grade": "very-low", "source": { "citation": "Veru Inc., Phase-2b QUALITY topline press release, 27 Jan 2025; NCT06282458", "url": "https://clinicaltrials.gov/study/NCT06282458", "identifiers": "NCT06282458", "date": "2025-01-27", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~168)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-EXEN-CARDIO-01", "sourceId": "PMID28910237", "drug": "exenatide (once-weekly)", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist (exendin-4-based)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "MACE HR 0.91 (95% CI 0.83-1.00; P<0.001 non-inferiority; P=0.06 superiority NOT met); 11.4% vs 12.2% (3.7 vs 4.0/100PY). All-cause death HR 0.86 (nominal). Median 3.2 years.", "finding": "In T2D (most with prior CVD), once-weekly exenatide was non-inferior to placebo for MACE; superiority was not met (HR favoured exenatide, CI crossed 1).", "population": "EXSCEL: N=14,752; T2D, ~73% with prior CVD; double-blind placebo-controlled pragmatic RCT; median 3.2 years.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "ADDED (not in prior rows). Largest GLP-1 CVOT; non-inferior with a near-miss on superiority (P=0.06). Sits between the neutral (ELIXA) and superior (LEADER/SUSTAIN-6/REWIND) trials. Exendin-4-based, yet the class meta found no heterogeneity by structural homology.", "crossRef": "C-LIXI-CARDIO-01; C-CLASS-CARDIO-01", "grade": "high", "source": { "citation": "Holman RR et al., N Engl J Med, 2017", "url": "https://doi.org/10.1056/NEJMoa1612917", "identifiers": "PMID28910237", "date": "2017-09-14", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Amylin Pharmaceuticals (AstraZeneca subsidiary)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EXENATIDE-CNS-01", "sourceId": "PMID36066977", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "mixed", "magnitude": "Primary (reduction in heavy drinking days): NOT significant vs placebo. Secondary: significant attenuation of ventral-striatal/septal alcohol-cue fMRI reactivity; lower dopamine-transporter availability. Exploratory obese subgroup (BMI>30): reduced heavy drinking days + total intake.", "finding": "ADDICTION (alcohol) - the counter-pole RCT: in treatment-seeking AUD patients, once-weekly exenatide added to CBT did NOT significantly reduce heavy drinking days (primary endpoint NEGATIVE), but attenuated fMRI alcohol-cue reactivity in the ventral striatum and lowered dopamine-transporter availability, with an exploratory benefit in the obese subgroup. The cleaner test of real-world drinking, and it failed its primary.", "population": "Klausen AUD RCT (NCT03232112): N=127 treatment-seeking AUD; double-blind placebo-controlled; exenatide 2 mg weekly + CBT, 26 weeks; Denmark.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "The important counterweight to the EHR enthusiasm: a randomised test of real drinking FAILED its primary endpoint. Yet it provides the strongest HUMAN reward-circuit data (reduced alcohol-cue striatal reactivity + lower DAT). Obese-subgroup benefit hints BMI moderates response (echoed elsewhere). A confirmatory trial (NCT05895643) and a PEth-biomarker secondary (delayed effect in obese only) followed. BOTH POLES.", "crossRef": "C-SEMAGLUTIDE-CNS-01", "grade": "low", "source": { "citation": "Klausen MK, Jensen ME, Moller M et al., JCI Insight, 2022", "url": "https://doi.org/10.1172/jci.insight.159863", "identifiers": "PMID36066977", "date": "2022-10-10", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EXENATIDE-CNS-02", "sourceId": "PMID33831213", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Biochemically-confirmed 7-day point-prevalence abstinence 46.3% (exenatide) vs 26.8% (placebo); risk ratio 1.70 (95% credible interval 0.96-3.27; Bayesian posterior probability 96.5%); post-cessation weight 5.6 lb lower; reduced craving/withdrawal.", "finding": "ADDICTION (tobacco) - the smoking RCT: extended-release exenatide added to nicotine patch improved biochemically-confirmed smoking abstinence vs patch alone at 6 weeks and reduced post-cessation weight gain, in prediabetic/overweight smokers.", "population": "Yammine pilot RCT: N=84 prediabetic/overweight smokers; double-blind; exenatide 2 mg weekly vs placebo, both with nicotine patch; 6 weeks; CO-confirmed.", "comparators": "placebo (with nicotine patch in both arms)", "endpointType": "other", "notes": "The only randomised smoking-cessation efficacy trial here with a biochemically-confirmed endpoint. LOW: explicitly pilot, small N=84, 6 weeks, credible interval touches 1; significance is Bayesian. Metabolically-enriched sample. Needs confirmation. VALIDATOR: confirm PMID 33831213.", "crossRef": "C-SEMAGLUTIDE-CNS-03", "grade": "high", "source": { "citation": "Yammine L, Green CE, Kosten TR et al., Nicotine Tob Res, 2021", "url": "https://doi.org/10.1093/ntr/ntab066", "identifiers": "PMID33831213", "date": "2021-08-29", "design": "double-blind RCT", "maturity": "human-primary", "funding": "academic / NIH - UTHealth Center for Clinical and Translational Sciences (NIH CTSA) + PARTNERS Research Awards; no industry sponsor (prior 'AstraZeneca' inference was WRONG)", "scopeLimits": "small sample (N~84)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EXENATIDE-CNS-03", "sourceId": "PMID28781108", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "MDS-UPDRS part 3 (off-medication) at 60 weeks: adjusted mean difference -3.5 points (95% CI -6.7 to -0.3; P=0.0318) favouring exenatide, sustained beyond a 12-week washout.", "finding": "NEURODEGENERATION (Parkinson's) - the positive phase-2: in a single-centre phase-2 trial in moderate Parkinson's, exenatide improved off-medication motor scores vs placebo at 60 weeks; the authors could not distinguish disease modification from a long-lasting symptomatic effect. The result that drove a decade of GLP-1-in-PD optimism.", "population": "Athauda phase-2 (NCT01971242): N=62 moderate idiopathic PD; single-centre double-blind RCT; exenatide 2 mg weekly, 48 weeks + 12-week washout.", "comparators": "placebo", "endpointType": "other", "notes": "POSITIVE POLE - read ALONGSIDE its own phase-3 failure (C-EXENATIDE-CNS-04). Small N=62, single-centre, disease-modification-vs-symptomatic unresolved. Michael J Fox Foundation funded. IDENTIFIER NOTE: the correct PMID is 28781108 (a commonly-miscited 28811472 is an unrelated anatomy paper). VALIDATOR: confirm 28781108.", "crossRef": "C-EXENATIDE-CNS-04", "grade": "moderate", "source": { "citation": "Athauda D, Maclagan K, Skene SS et al., Lancet, 2017", "url": "https://doi.org/10.1016/S0140-6736(17)31585-4", "identifiers": "PMID28781108", "date": "2017-08-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic / philanthropic - Michael J Fox Foundation for Parkinson's Research (not AstraZeneca)", "scopeLimits": "single-centre/referral-enriched; small sample (N~62)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EXENATIDE-CNS-04", "sourceId": "PMID39919773", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "no-change", "magnitude": "Primary MDS-UPDRS part III (off-medication) at 96 weeks: +5.7 (SD 11.2) exenatide vs +4.5 (SD 11.4) placebo; adjusted coefficient 0.92 (95% CI -1.56 to 3.39; P=0.47) - NO difference (point estimate slightly favoured placebo).", "finding": "NEURODEGENERATION (Parkinson's) - THE LOAD-BEARING NEGATIVE: the definitive multicentre phase-3 trial found that once-weekly exenatide did NOT slow Parkinson's progression. The authors concluded there is no evidence to support exenatide as disease-modifying. This OVERTURNS the positive phase-2.", "population": "Vijiaratnam/Foltynie phase-3 (NCT04232969): N=194 PD; six UK hospitals; double-blind RCT; extended-release exenatide 2 mg weekly, 96 weeks.", "comparators": "placebo", "endpointType": "other", "notes": "DO NOT BURY. This pivotal phase-3 (high robustness) is the single most important counterweight to GLP-1-in-PD optimism. NIHR + Cure Parkinson's funded (investigator-led, non-industry). The senior authors (Foltynie, Athauda) ran the positive phase-2 too - a self-correcting replication failure, not a competing-group artefact. VALIDATOR: confirm PMID 39919773 + P=0.47 null.", "crossRef": "C-EXENATIDE-CNS-03", "grade": "moderate", "source": { "citation": "Vijiaratnam N, Girges C, Auld G et al., Lancet, 2025", "url": "https://doi.org/10.1016/S0140-6736(24)02808-3", "identifiers": "PMID39919773", "date": "2025-02-04", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic-NIHR + charity-Cure Parkinson's (NOT AstraZeneca)", "scopeLimits": "small sample (N~194)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-EXENATIDE-LANDSCAPE-01", "sourceId": "DOI10.1016/S0140-6736(08)61206-4", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor monoagonist (exendin-4 analogue; twice-daily IR and once-weekly ER formulations)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c -1.9% (ER) vs -1.5% (IR); weight approx -3.6 kg both arms at 30 weeks", "finding": "Exenatide ER 2 mg once weekly reduced HbA1c by approx -1.9% vs -1.5% for exenatide IR 10 mcg twice daily at 30 weeks; weight loss approx -3.6 kg with either formulation.", "population": "DURATION-1: 295 patients with T2D on background therapy, exenatide ER 2 mg weekly vs IR 10 mcg twice daily, 30-week controlled phase, open-label non-inferiority", "comparators": "exenatide IR (twice daily)", "endpointType": "surrogate/biomarker", "notes": "Mechanism: synthetic exendin-4 (Gila monster venom), GLP-1 receptor agonist resistant to DPP-4. IR = Byetta (twice-daily), ER = Bydureon/Bydureon BCise (once-weekly depot). CV neutral in EXSCEL. PMID 20215461 corresponds to a 52-week DURATION-1 report; 30-week numbers anchored to Lancet 2008 primary - discrepancy noted.", "crossRef": "", "grade": "moderate", "source": { "citation": "Drucker DJ et al., Lancet 2008 (DURATION-1)", "url": "https://pubmed.ncbi.nlm.nih.gov/20215461/", "identifiers": "DOI 10.1016/S0140-6736(08)61206-4; NCT00308139", "date": "2008-10-04", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Amylin Pharmaceuticals / Eli Lilly (disclosed)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GCGRDUAL-CARDIO-01", "sourceId": "PMID42209267", "drug": "GLP-1/glucagon dual agonists (cotadutide, survodutide, mazdutide, pemvidutide, efinopegdutide)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon (GCGR) dual agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No outcome data exists.", "finding": "ABSENCE OF EVIDENCE: as of the 2026-06-21 (non-exhaustive) sweep, no powered hard-endpoint CV outcome trial has REPORTED for any GLP-1/glucagon dual agonist; the class sits in the phase-2/early-phase-3 era with weight, glycaemic, hepatic (MASH) and CV-risk-factor readouts only. This absence is NOT reassurance: the glucagon arm's CV-risk hypothesis has never been tested at hard-endpoint level in any agent, so the net effect is UNMEASURED, not measured-and-null. It is an evidence GAP, not a demonstration of CV neutrality or harm, and does not exclude ongoing/unreported trials.", "population": "Class-level absence statement (cotadutide, survodutide, mazdutide, pemvidutide, efinopegdutide); efficacy/surrogate data only; no dedicated CVOT reported.", "comparators": "", "endpointType": "hard-outcome", "notes": "The absence is the finding. PMID 42209267 (De Fano review) RESOLVED on validation but is GIP-centric: it supports the class CV-outcome gap by analogy, NOT by per-agent enumeration, so the class-level absence rests on the 2026-06-21 PubMed search sweep (non-exhaustive). Matters because the glucagon (GCGR) arm carries an open CV-risk tension (C-RETA-CARDIO-02) that only a powered outcome trial could resolve.", "crossRef": "C-RETA-CARDIO-02; C-RETA-CARDIO-01", "grade": "moderate", "source": { "citation": "Absence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial record returned; review context, De Fano M et al., Diabetes Obes Metab, 2026", "url": "https://doi.org/10.1111/dom.70888", "identifiers": "PMID42209267", "date": "2026-01-01", "design": "phase-2 RCT", "maturity": "review", "funding": "academic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)", "scopeLimits": "animal data; human relevance uncertain; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-GIP-AXIS-PARADOX-01", "sourceId": "PMID35658024", "drug": "GIP-axis (tirzepatide vs maridebart cafraglutide)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP-axis comparator observation", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "mixed", "magnitude": "GIP agonism (tirzepatide) -> up to ~22.5% weight loss; GIP antagonism (MariTide) -> up to ~20% weight loss; both atop GLP-1 activity", "finding": "RECORDED OBSERVATION (why explicitly open): Two clinically active obesity agents act in OPPOSITE directions on the GIP receptor yet both produce substantial weight loss atop GLP-1 activity. Tirzepatide AGONISES GIP (plus GLP-1) and delivers ~22.5% weight loss (SURMOUNT-1); MariTide ANTAGONISES GIP (plus GLP-1 agonism) and delivers ~20% weight loss (phase 2). Separately, the selective GIP agonist LY3537021 reduces weight with GIP agonism alone. These findings stand side by side; the mechanism is not adjudicated.", "population": "Cross-trial juxtaposition: SURMOUNT-1 (tirzepatide, N=2539, 72 wk) vs MariTide phase 2 (N=592, 52 wk); not head-to-head", "comparators": "placebo", "endpointType": "other", "notes": "OBSERVATION record, not a verdict. The 'why' (GIPR desensitisation/downregulation under sustained agonism mimicking antagonism; differing tissue effects; dosing/exposure) is left OPEN. Cross-trial only - different populations/durations/designs.", "crossRef": "C-TIRZEPATIDE-LANDSCAPE-01; C-MARITIDE-LANDSCAPE-01", "grade": "high", "source": { "citation": "Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY3537021 phase 1 (2025)", "url": "https://pubmed.ncbi.nlm.nih.gov/35658024/", "identifiers": "PMID 35658024; NCT05669599; PMID 41391569", "date": "2022-06-04", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (SURMOUNT-1; disclosed)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GIP-RENAL-GAP-01", "sourceId": "PMID42209267", "drug": "GIP (native; physiology)", "drugRoot": "GIP (native infusion / GIP(3-30) antagonist)", "drugSlug": "gip-native-infusion-gip-3-30-antagonist", "drugLabel": "GIP (native Infusion / GIP(3-30) Antagonist)", "drugClass": "GIP receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "n/a", "magnitude": "no isolating human renal GIP data (gap record)", "finding": "No published study has measured a direct renal effect (natriuresis, sodium handling, GFR, renal blood flow) of selective/isolating GIP-receptor agonism, GIP infusion, or GIPR antagonism in humans; renal GIP-receptor expression is sparse and the independent renal contribution of the GIP arm is unestablished. Honest gap record.", "population": "Narrative review (GIP in cardiovascular and kidney disease) attesting the absence/controversy; carries no positive attribution.", "comparators": "", "endpointType": "other", "notes": "EXPLICIT PERMANENT-GAP FLAG (renal). The one selective GIP agonist trial (LY3537021) measured no renal endpoint; no human GIP renal-handling study exists. Do NOT backfill the tirz-minus-dulaglutide renal differential (C-TIRZ-CARDIO-RENAL-02) as a GIP effect (weight/glycaemia confound). Review tier (1.8). Shares existing source PMID 42209267 (already in corpus for two cv-outcomes gap findings). Folded from thread-7 ledger entry T7-016 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-TIRZ-CARDIO-RENAL-02", "grade": "moderate", "source": { "citation": "Absence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial record returned; review context, De Fano M et al., Diabetes Obes Metab, 2026", "url": "https://doi.org/10.1111/dom.70888", "identifiers": "PMID42209267", "date": "2026-01-01", "design": "phase-2 RCT", "maturity": "review", "funding": "academic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)", "scopeLimits": "animal data; human relevance uncertain; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GIPNAT-HR-01", "sourceId": "PMID25564476", "drug": "GIP (native; isoglycaemic clamp infusion)", "drugRoot": "GIP (native; isoglycaemic clamp infusion)", "drugSlug": "gip-native-isoglycaemic-clamp-infusion", "drugLabel": "GIP (native; Isoglycaemic Clamp Infusion)", "drugClass": "GIP (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "no-change", "magnitude": "HR/BP/FMD no change; only femoral blood flow rose during hyperglycaemia", "finding": "Under a two-stage somatostatin (pancreatic) clamp in healthy young men (n=10), native GIP infusion produced NO change in heart rate, blood pressure or flow-mediated dilation; the sole haemodynamic change was increased femoral-artery blood flow during hyperglycaemia. The cleanest isolating human GIP haemodynamic dataset - a measured HR null under acute infusion.", "population": "healthy young men, n=10, two-stage pancreatic (somatostatin) clamp, GIP infusion 1.5 pmol/kg/min", "comparators": "control; GLP-1", "endpointType": "surrogate/biomarker", "notes": "Isolating human GIP HR dataset: MEASURED-NULL for HR/BP under acute somatostatin-clamp GIP infusion (the GIP null pole). Acute only; chronic selective agonism unmeasured; young lean healthy men = context-narrow. DISCREPANCY (1.10) vs the review-level transient-HR signal (C-GIPNAT-HR-02): a weak transient acute GIP chronotropic signal cannot be excluded - both poles recorded, neither crowned. Folded from T7-012 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "", "grade": "low", "source": { "citation": "Karstoft K et al., Am J Physiol Endocrinol Metab 2015;308(5):E426-33", "url": "https://doi.org/10.1152/ajpendo.00520.2014", "identifiers": "PMID:25564476 DOI:10.1152/ajpendo.00520.2014", "date": "2015-03-01", "design": "unspecified", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~10); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GIPNAT-HR-02", "sourceId": "PMID38615716", "drug": "GIP (native infusion / GIP(3-30) antagonist)", "drugRoot": "GIP (native infusion / GIP(3-30) antagonist)", "drugSlug": "gip-native-infusion-gip-3-30-antagonist", "drugLabel": "GIP (native Infusion / GIP(3-30) Antagonist)", "drugClass": "GIP (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "moderate, transient HR increase (unquantified at review level)", "finding": "A systematic review of native GIP(1-42) administration in humans (67 studies, 30 min to 6 days) found that, among the 15% of studies reporting safety events, the most frequent was a moderate and transient increase in heart rate; no correlation between achieved GIP concentration and reported events.", "population": "systematic review of 67 human native-GIP(1-42) administration studies", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Review-tier (cannot outweigh primary); underlying studies are isolating (native human GIP infusion). DISCREPANCY (1.10) vs the Karstoft clamp null (C-GIPNAT-HR-01): a weak transient acute GIP chronotropic signal cannot be excluded. Both poles recorded. Folded from T7-013 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-GIPNAT-HR-01", "grade": "low", "source": { "citation": "Helsted MM et al., Peptides 2024;177:171214", "url": "https://doi.org/10.1016/j.peptides.2024.171214", "identifiers": "PMID:38615716 DOI:10.1016/j.peptides.2024.171214", "date": "2024-07-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "conference/abstract-level; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GIPNAT-RENAL-NACL-NULL-01", "sourceId": "PMID32770661", "drug": "GIP (native; physiology)", "drugRoot": "GIP (native infusion / GIP(3-30) antagonist)", "drugSlug": "gip-native-infusion-gip-3-30-antagonist", "drugLabel": "GIP (native Infusion / GIP(3-30) Antagonist)", "drugClass": "GIP receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "no-change", "magnitude": "GIP postprandial response unchanged by added NaCl (whereas postprandial GLP-1 was selectively amplified).", "finding": "An oral sodium-load study in 10 lean healthy men found that adding 6 g NaCl to an oral glucose load selectively amplified postprandial plasma GLP-1 but did NOT change the postprandial GIP response; the proposed acute feed-forward natriuretic gut-kidney signal was attributed to GLP-1, with GIP showing no sodium-sensitivity.", "population": "10 lean healthy male participants; crossover (75 g glucose + 6 g NaCl vs glucose alone).", "comparators": "glucose alone (no added NaCl)", "endpointType": "surrogate/biomarker", "notes": "GIP RENAL NULL: isolates the acute gut-kidney natriuretic axis AWAY from GIP and TO GLP-1. Indirect (studies endogenous GIP secretion vs a sodium stimulus, not a GIPR renal action), but the closest human renal-relevant GIP datum and it points AWAY from a GIP natriuretic role; small N=10. Folded from thread-7 ledger entry T7-015 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-GIP-RENAL-GAP-01", "grade": "low", "source": { "citation": "Asmar A et al., Physiol Rep 2020;8(15):e14519", "url": "https://doi.org/10.14814/phy2.14519", "identifiers": "PMID:32770661 DOI:10.14814/phy2.14519", "date": "2020-08-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~10) lean healthy men; mechanistic crossover; indirect (GIP secretion vs sodium stimulus, not a GIPR renal action)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLP1CLASS-CARDIO-HR-01", "sourceId": "DOI10.1161/HYPERTENSIONAHA.114.03062", "drug": "liraglutide / dulaglutide / exenatide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonists", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "Liraglutide ~+3 bpm (LEADER); dulaglutide 1.5 mg +3 to +4 bpm (24h HR); class range ~2-4 bpm.", "finding": "Established GLP-1RAs raise resting/24-hour heart rate modestly (class effect, sinoatrial-node mediated).", "population": "T2D CVOTs/ABPM studies (LEADER; dulaglutide ABPM/REWIND).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Composite class record; per-agent bpm from secondary/review sources, identifiers not all PubMed-verified this pass. Cross-refs the LIVE HFrEF HR/safety caution.", "crossRef": "C-LIRA-CARDIO-HF-02", "grade": "low", "source": { "citation": "Ferdinand KC et al. (dulaglutide ABPM/HR), Hypertension, 2014;64:731-737; LEADER 2016", "url": "https://doi.org/10.1161/HYPERTENSIONAHA.114.03062", "identifiers": "DOI 10.1161/HYPERTENSIONAHA.114.03062", "date": "2014-10-01", "design": "narrative review", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLP1CLASS-EE-01", "sourceId": "PMID41782395", "drug": "class (GLP-1RA mono + combination)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GLP-1RA and incretin combinations", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "mixed", "magnitude": "Monotherapy: no EE effect beyond weight loss. +glucagon: varied (RQ n=3, RMR n=1, sleep MR n=1). +GIP: decreased RQ, increased fat utilisation (n=1)", "finding": "Scoping review of human EE studies (23 studies): acute or chronic GLP-1RA MONOtherapy does not appear to impact energy expenditure independent of weight loss. Combination with glucagon produced varied impacts on EE components (RQ, RMR, sleep metabolic rate); combination with GIP decreased RQ and increased fat utilisation. Eight studies (34.8%) concluded non-significant EE effects; 11 (47.8%) were inconclusive due to statistical analyses. Most assessed RMR; only 4 used 24-h whole-room calorimetry; none used doubly labelled water.", "population": "Scoping review, humans, inception to Oct 2025; 23 studies (10 monotherapy: 4 exenatide, 4 liraglutide, 1 semaglutide, 1 beinaglutide; 13 combination: 11 dual, 2 triple agonists)", "comparators": "placebo; across-study heterogeneity", "endpointType": "imaging/physiological surrogate", "notes": "Class-level landmark for the 'whole-body-EE-null' pole in humans. Note the differential signal: +GIP lowers RQ/raises fat oxidation (matches the tirzepatide fat-oxidation finding, C-TIRZEPATIDE-EE-03), while +glucagon affects EE components variably. Co-author Heymsfield (Pennington). Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-03; C-RETATRUTIDE-EE-01", "grade": "low", "source": { "citation": "Vieira FT, Deng Z, Muller MJ, et al. Effects of GLP-1 Receptor Agonists (Mono and Combination Therapy) on Energy Expenditure: A Scoping Review. Obes Rev. 2026;e70116", "url": "https://doi.org/10.1111/obr.70116", "identifiers": "PMID 41782395; DOI 10.1111/obr.70116", "date": "2026-03-04", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLP1NAT-HR-01", "sourceId": "PMID24467746", "drug": "GLP-1 (native; physiology)", "drugRoot": "GLP-1 (native; physiology)", "drugSlug": "glp-1-native-physiology", "drugLabel": "GLP-1 (native; Physiology)", "drugClass": "GLP-1 receptor (native/physiology)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "n/a", "magnitude": "n/a (receptor localisation)", "finding": "The GLP-1 receptor localises to myocytes of the human (and monkey) sinoatrial node by validated-monoclonal-antibody immunohistochemistry (and to renal/lung arterial smooth muscle); it is NOT found in working cardiomyocytes - giving an anatomical DIRECT substrate for the GLP-1 heart-rate effect at the sinoatrial node.", "population": "human and monkey cardiac tissue; validated monoclonal-antibody immunohistochemistry localisation study", "comparators": "n/a", "endpointType": "surrogate/biomarker", "notes": "Receptor-isolating (single-receptor antibody). DIRECT cardiac substrate is the SAN, not working myocardium (so a direct inotropic effect is not anatomically supported). Sponsor-authored (Novo Nordisk antibody) - COI noted. Folded from T7-001 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "", "grade": "low", "source": { "citation": "Pyke C et al., Endocrinology 2014;155(4):1280-90", "url": "https://doi.org/10.1210/en.2013-1934", "identifiers": "PMID:24467746 DOI:10.1210/en.2013-1934", "date": "2014-04-01", "design": "unspecified", "maturity": "human-primary", "funding": "industry - Novo Nordisk (validated monoclonal antibody; sponsor-authored)", "scopeLimits": "single-centre/referral-enriched; sponsor-authored COI (Novo Nordisk antibody)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLP1NAT-RENAL-NHE3-01", "sourceId": "PMID24791975", "drug": "GLP-1 (native; physiology)", "drugRoot": "GLP-1 (native; physiology)", "drugSlug": "glp-1-native-physiology", "drugLabel": "GLP-1 (native; Physiology)", "drugClass": "GLP-1 receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "natriuresis increased (mechanism review; no single human effect size)", "finding": "GLP-1 increases natriuresis principally by inhibiting the sodium-hydrogen exchanger isoform 3 (NHE3) in the renal proximal tubule, a candidate mechanism for the antihypertensive effect of GLP-1 receptor agonists; GLP-1 regulation of GFR is more complex and may involve atrial natriuretic peptide and the renin-angiotensin system.", "population": "Review-tier mechanism synthesis of GLP-1 renal actions (human-relevant physiology).", "comparators": "", "endpointType": "other", "notes": "REVIEW maturity (Constitution 1.8) - cannot outweigh primary; cannot alone carry a load-bearing attribution. Renal GLP-1R localises to ARTERIAL smooth muscle not tubular epithelium (cf. Pyke 2014, C-GLP1NAT-HR-01), so the direct-tubular-NHE3 route is a CANDIDATE not a settled fact. Folded from thread-7 ledger entry T7-011 (per-receptor status: verified at REVIEW grade, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-GLP1NAT-HR-01", "grade": "low", "source": { "citation": "Skov J, Rev Endocr Metab Disord 2014;15(3):197-207", "url": "https://doi.org/10.1007/s11154-014-9287-7", "identifiers": "PMID:24791975 DOI:10.1007/s11154-014-9287-7", "date": "2014-09-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "mechanism review; cannot outweigh primary; renal GLP-1R localises to arterial smooth muscle not tubular epithelium (direct-tubular NHE3 route is candidate not settled)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-HR-01", "sourceId": "PMID5420074", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "positive chronotropy + inotropy; cardiac output +42% in acute MI (acute bolus)", "finding": "An intravenous glucagon bolus (2 or 5 mg) in 29 patients produced immediate positive inotropy, raised cardiac output and positive chronotropy, peaking within ~10 min and dissipating within ~30 min; in acute myocardial infarction glucagon raised cardiac output by 42%. The classic human positive-chronotropy/inotropy dataset.", "population": "29 patients, single intravenous glucagon bolus 2-5 mg", "comparators": "n/a", "endpointType": "surrogate/biomarker", "notes": "ACUTE supraphysiological mg-bolus pharmacology, GCGR-isolating; cannot be carried to chronic weekly-agonism strain. DISCREPANCY (1.10): directly contradicted by the human-tissue null (C-GLUCNAT-HR-04), which finds no effect and no cardiac GCGR. Carry both poles. Folded from T7-020 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "", "grade": "low", "source": { "citation": "Murtagh JG et al., Br Heart J 1970;32(3):307", "url": "https://doi.org/10.1136/hrt.32.3.307", "identifiers": "PMID:5420074 DOI:10.1136/hrt.32.3.307", "date": "1970-05-01", "design": "unspecified", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~29); short duration", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-HR-02", "sourceId": "PMID2159595", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "L-type Ca2+ current (ICa) enhancement (mechanism, frog/rat myocytes)", "finding": "Glucagon's positive inotropic/chronotropic cardiac effect is mediated by adenylyl-cyclase activation and inhibition of low-Km cAMP phosphodiesterase, raising cAMP and enhancing the cardiac L-type Ca2+ current (ICa); the effect resembles a beta-adrenergic agent but is NOT blocked by propranolol.", "population": "frog and rat ventricular myocytes", "comparators": "propranolol", "endpointType": "surrogate/biomarker", "notes": "Rodent/amphibian mechanism (frog + rat ventricular myocytes). The canonical cAMP/PKA/ICa GCGR cardiostimulatory route; propranolol-insensitivity underpins clinical glucagon use in beta-blocker overdose. Human translation contested (C-GLUCNAT-HR-04). Folded from T7-021 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-GLUCNAT-HR-01", "grade": "very-low", "source": { "citation": "Mery PF et al., Nature 1990;345(6271):158-61", "url": "https://doi.org/10.1038/345158a0", "identifiers": "PMID:2159595 DOI:10.1038/345158a0", "date": "1990-05-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-HR-03", "sourceId": "PMID41516006", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "positive chronotropy (HCN/sinus-node mediated); NEGATIVE inotropy in mouse atria/LV", "finding": "In isolated adult-mouse cardiac preparations, glucagon (0.1-100 nM) exerted concentration-dependent POSITIVE CHRONOTROPY in spontaneously beating right atria - reversed by GCGR antagonists and attenuated by the HCN-blocker ivabradine, but not by propranolol or the PDE4 inhibitor rolipram - while DECREASING force of contraction; GCGR mRNA was highest in right atrium.", "population": "isolated adult-mouse cardiac preparations (spontaneously beating right atria; ventricle)", "comparators": "propranolol; ivabradine; rolipram; SC203972; desglucagon", "endpointType": "surrogate/biomarker", "notes": "Rodent, GCGR-isolating (antagonist-reversible). HR rise localises to the sinoatrial node via HCN (funny-current) channels. SPECIES DISCREPANCY on inotropy (1.10): human/rat report positive inotropy, adult-mouse atria/LV show negative inotropy - both poles flagged. Folded from T7-022 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-GLUCNAT-HR-01", "grade": "very-low", "source": { "citation": "Neumann J et al., Int J Mol Sci 2025;27(1):126 (e-pub 2025-12-22)", "url": "https://doi.org/10.3390/ijms27010126", "identifiers": "PMID:41516006 DOI:10.3390/ijms27010126", "date": "2025-12-22", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-HR-04", "sourceId": "PMID37254135", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon (native infusion)", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "no-change", "magnitude": "no detectable inotropy/chronotropy in human myocardium; GCGR undetected", "finding": "In isolated failing and non-failing human heart tissue (atria, ventricles, sinoatrial nodes), glucagon exerted NO inotropic or chronotropic effect (with or without the PDE inhibitor IBMX) and glucagon receptors were NOT detected in the human samples; a non-human positive control confirmed assay validity. The key human-primary contested-null pole.", "population": "isolated failing and non-failing human heart tissue (RA/LA/RV/LV/sinoatrial node); positive control confirmed assay validity", "comparators": "IBMX; positive control", "endpointType": "surrogate/biomarker", "notes": "Human-primary, GCGR-isolating, and the KEY DISCREPANCY POLE (1.10): directly contradicts the Murtagh positive-inotropy/chronotropy pole (C-GLUCNAT-HR-01). Same-tier human/animal conflict on whether human cardiac GCGR is functional - carried as an open question, NOT resolved here. Caveat: ex-vivo failing/non-failing explanted tissue (receptor down-regulation or assay sensitivity cannot be excluded). NOTE (WI-1 Council, OQ-WI1-01): whether this human null implies retatrutide's clinical HR rise is non-cardiac-GCGR is LEFT OPEN - a mechanism verdict is out of scope for this descriptive layer. Folded from T7-023 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-GLUCNAT-HR-01", "grade": "low", "source": { "citation": "Aranda-Domene R et al. (Hernandez-Cascales), Cardiovasc Diabetol 2023;22(1):128", "url": "https://doi.org/10.1186/s12933-023-01859-8", "identifiers": "PMID:37254135 DOI:10.1186/s12933-023-01859-8", "date": "2023-05-01", "design": "unspecified", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "ex-vivo failing-heart tissue (down-regulation possible)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-RENAL-COAGONIST-LOGIC-01", "sourceId": "PMID6318231", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "glucagon RPF/GFR up (dose-dependent); GLP-1 GFR/RPF flat at baseline (contrast pole)", "finding": "Acute glucagon infusion raises renal plasma flow, GFR and natriuresis at the isolated GCGR level, whereas pure GLP-1R agonism is natriuretic but does not change GFR/RPF at healthy baseline; the co-agonist-minus-GLP-1 logic therefore attributes any GFR/RPF rise on a co-agonist toward the GCGR arm, with both arms independently natriuretic suggesting additive natriuresis.", "population": "Review-tier (glucagon side, Farah 1983); GLP-1 contrast poles are human-primary (Skov JCEM 2013 PMID 23463656; Asmar AJP-Endo 2015 PMID 25670826) cited as contrast only.", "comparators": "", "endpointType": "other", "notes": "REVIEW maturity on the GCGR side (1.8); SECONDARY-CORROBORATED upstream. The co-agonist-minus-GLP-1 LOGIC for renal haemodynamics. GLP-1 contrast poles recorded as CONTRAST only, NOT GCGR attributions. Natriuresis attribution rests on Skov, not Asmar. Keep WEAK; never anchor a high cell. Folded from thread-7 ledger entry T7-033 (per-receptor status: secondary-corroborated, Session D). Independently audited 2026-06-24 (WI-2 audit agent): graduated as SECONDARY-CORROBORATED upstream (Farah 1983 review primary-unreached; direction corroborated by PMID 6141338); see validation_evidence.", "crossRef": "C-GLUCNAT-RENAL-RPF-GFR-01", "grade": "low", "source": { "citation": "Farah AE, Pharmacol Rev 1983;35(3):181-217 (Glucagon and the circulation)", "url": "https://pubmed.ncbi.nlm.nih.gov/6318231/", "identifiers": "PMID:6318231 (no DOI)", "date": "1983-09-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "1983 review; primaries uncited at this locator; species-mixed (dog/rat micropuncture for the direct-tubular mechanism); 'large doses' qualifier limits transport to therapeutic exposures", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-RENAL-FASTNATRIURESIS-01", "sourceId": "PMID6318231", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "natriuresis (fasting-glucagon-linked; qualitative)", "finding": "Starvation (fasting) natriuresis has been linked to raised circulating glucagon, the likely mechanism being that glucagon increases renal excretion of organic acids by inhibiting their tubular reabsorption.", "population": "Review-tier synthesis; the fasting-natriuresis/glucagon link is correlational.", "comparators": "", "endpointType": "other", "notes": "REVIEW maturity (1.8); SECONDARY-CORROBORATED upstream (Farah 1983 review). Weakest record of the renal GCGR cluster - correlational association, not a controlled infusion result. Cross-thread link to the glucagon amino-acid/fasting axis. Keep WEAK; never anchor a high cell. Folded from thread-7 ledger entry T7-028 (per-receptor status: secondary-corroborated, Session D). Independently audited 2026-06-24 (WI-2 audit agent): graduated as SECONDARY-CORROBORATED upstream (Farah 1983 review primary-unreached; direction corroborated by PMID 6141338); see validation_evidence.", "crossRef": "C-GLUCNAT-RENAL-RPF-GFR-01", "grade": "low", "source": { "citation": "Farah AE, Pharmacol Rev 1983;35(3):181-217 (Glucagon and the circulation)", "url": "https://pubmed.ncbi.nlm.nih.gov/6318231/", "identifiers": "PMID:6318231 (no DOI)", "date": "1983-09-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "1983 review; primaries uncited at this locator; species-mixed (dog/rat micropuncture for the direct-tubular mechanism); 'large doses' qualifier limits transport to therapeutic exposures", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-RENAL-GLOMHYPER-01", "sourceId": "PMID6318231", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "glomerular hypertrophy + hyperfiltration (chronic-hyperglucagonaemia-associated)", "finding": "Glucagon increased RNA concentration in glomerular tissue (a cAMP-independent effect), related to glomerular enlargement and basement-membrane thickening seen in poorly controlled insulin-dependent diabetes (low insulin, high glucagon); the increased glomerular filtration of poorly controlled diabetes has been linked to the same hyperglucagonaemia.", "population": "Review-tier synthesis; chronic-hyperglucagonaemia/diabetes association data.", "comparators": "", "endpointType": "other", "notes": "REVIEW maturity (1.8); SECONDARY-CORROBORATED upstream - chronic-hyperglucagonaemia glomerular-hypertrophy/hyperfiltration direction corroborated by Alvestrand & Bergstrom 1984 (PMID 6141338). TENSION FLAG (1.10): glucagon acutely natriuretic/renoprotective-looking (C-GLUCNAT-RENAL-RPF-GFR-01) yet chronically associated with maladaptive glomerular hyperfiltration/hypertrophy - opposite-direction renal readouts on different time-frames; the chronic GCGR-isolated renal-safety question is OPEN. Keep WEAK; never anchor a high cell. Folded from thread-7 ledger entry T7-029 (per-receptor status: secondary-corroborated, Session D). Independently audited 2026-06-24 (WI-2 audit agent): graduated as SECONDARY-CORROBORATED upstream (Farah 1983 review primary-unreached; direction corroborated by PMID 6141338); see validation_evidence.", "crossRef": "C-GLUCNAT-RENAL-RPF-GFR-01", "grade": "low", "source": { "citation": "Farah AE, Pharmacol Rev 1983;35(3):181-217 (Glucagon and the circulation)", "url": "https://pubmed.ncbi.nlm.nih.gov/6318231/", "identifiers": "PMID:6318231 (no DOI)", "date": "1983-09-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "1983 review; primaries uncited at this locator; species-mixed (dog/rat micropuncture for the direct-tubular mechanism); 'large doses' qualifier limits transport to therapeutic exposures", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-RENAL-HIGHPROTEIN-01", "sourceId": "PMID19812175", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "GFR +13% (141 vs 125 mL/min; p<0.001); filtration fraction up (28% vs 23%); BUN, uric acid, plasma glucagon, natriuresis and urinary albumin/urea up; renal plasma flow and renal vascular resistance unchanged.", "finding": "In 24 healthy young men, a 7-day high-protein versus normal-protein diet raised glomerular filtration rate by ~13% and filtration fraction, with concurrent rises in plasma GLUCAGON, natriuresis, urinary albumin and urea; renal plasma flow and renal vascular resistance were unchanged.", "population": "24 healthy young men; 7-day high-protein (2.4 g/kg/d) vs normal-protein (1.2 g/kg/d) crossover.", "comparators": "normal-protein diet", "endpointType": "other", "notes": "COMBINATION-ONLY / NOT GCGR-isolating: protein loading raises glucagon AND amino acids together, so the GFR/natriuresis rise is confounded (amino-acid hyperfiltration is itself a recognised mechanism). Supportive context that the glucagon-rise / hyperfiltration / natriuresis cluster co-occurs in humans; cannot carry a per-receptor renal attribution alone. Folded from thread-7 ledger entry T7-030 (per-receptor status: verified, Session D). Independently compendium substance-audited 2026-06-24 (WI-2 audit agent, distinct from the wi2-fold collector); see validation_evidence.", "crossRef": "C-GLUCNAT-RENAL-RPF-GFR-01", "grade": "low", "source": { "citation": "Frank H et al., Am J Clin Nutr 2009;90(6):1509-16", "url": "https://doi.org/10.3945/ajcn.2009.27601", "identifiers": "PMID:19812175 DOI:10.3945/ajcn.2009.27601", "date": "2009-12-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~24); crossover mechanistic study; combination-only (protein co-raises glucagon and amino acids)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-GLUCNAT-RENAL-RPF-GFR-01", "sourceId": "PMID6318231", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon receptor (native/physiology)", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "increase", "magnitude": "increased renal plasma flow, glomerular filtration and electrolyte excretion (dose-dependent); unilateral intra-arterial natriuresis without GFR change = direct tubular action", "finding": "At relatively large doses glucagon increased renal plasma flow, glomerular filtration and electrolyte excretion; intra-renal-arterial injection raised electrolyte excretion on the injected side with minimal/no GFR change, indicating a DIRECT renal tubular natriuretic action probably mediated via tubular cAMP and prostaglandin formation in the ascending limb and collecting ducts.", "population": "Review-tier synthesis of glucagon renal physiology (mixed-species mechanism; gross RPF/GFR/excretion rise the human-relevant datum).", "comparators": "", "endpointType": "other", "notes": "REVIEW maturity (1.8); SECONDARY-CORROBORATED upstream - Farah 1983 is a review not a retrievable primary, direction corroborated by the peer-reviewed primary Alvestrand & Bergstrom, Lancet 1984 (PMID 6141338, glucagon-infusion glomerular hyperfiltration). Keep WEAK (low grade); never anchor a high cell; flag the unreached primary at every load-bearing use. Renal GCGR is the 2nd-highest-abundance GCGR tissue. Folded from thread-7 ledger entry T7-027 (per-receptor status: secondary-corroborated, Session D). Independently audited 2026-06-24 (WI-2 audit agent): graduated as SECONDARY-CORROBORATED upstream (Farah 1983 review primary-unreached; direction corroborated by PMID 6141338); see validation_evidence.", "crossRef": "", "grade": "low", "source": { "citation": "Farah AE, Pharmacol Rev 1983;35(3):181-217 (Glucagon and the circulation)", "url": "https://pubmed.ncbi.nlm.nih.gov/6318231/", "identifiers": "PMID:6318231 (no DOI)", "date": "1983-09-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "1983 review; primaries uncited at this locator; species-mixed (dog/rat micropuncture for the direct-tubular mechanism); 'large doses' qualifier limits transport to therapeutic exposures", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-HM15275-LANDSCAPE-01", "sourceId": "CIT:hanmi-pharmaceutical-ada-2025-poster-774-p-and-o", "drug": "HM15275", "drugRoot": "HM15275", "drugSlug": "hm15275", "drugLabel": "HM15275", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Phase 1: ~5% mean body-weight loss after 4 weeks (up to ~10% in an individual case). Sponsor states a target/potential of >25% total body-weight loss (preclinical/positioning claim, NOT a phase 1 result). Preclinical 6-week: greater body-weight/fat-mass reduction than comparators with no lean-mass difference.", "finding": "HM15275 (Hanmi) is a once-weekly long-acting GLP-1/GIP/glucagon triple agonist engineered for obesity, designed to optimise receptor-activity balance to deliver weight loss while minimising lean-mass loss. Phase 1 reported favourable safety and early weight loss; FDA-cleared for phase 2, which is under way.", "population": "Phase 1: adults, ~4-week early readout, safety/PK/PD. Phase 2 initiated H2 2025. Preclinical efficacy in rodent obesity models.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Distinct molecule from sponsor's MASH-focused efocipegtrutide. The >25% figure is a sponsor positioning/preclinical claim, NOT a clinical result. No verified ClinicalTrials.gov identifier located (Hanmi/Korean trials may sit in non-CT.gov registries); flagged, NOT fabricated.", "crossRef": "C-EFOCIPEGTRUTIDE-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Hanmi Pharmaceutical, ADA 2025 poster 774-P and ObesityWeek 2025 / company press", "url": "https://www.hanmi.co.kr/science-pdf/HM15275/2025_ADA_Poster_HM15275_774-P.pdf", "identifiers": "Hanmi ADA 2025 abstract 774-P (conference); no verified NCT pinned", "date": "2025-06-01", "design": "preclinical (rodent)", "maturity": "conference-abstract", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-INCRETIN-MASH-F4-GAP", "sourceId": "CIT:derived-from-essence-and-maestro-nash-inclusion-", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1 / dual / triple incretin agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "No published positive registrational trial of any incretin in compensated MASH CIRRHOSIS (F4). The pivotal trials EXCLUDE F4: ESSENCE F2/F3 only; MAESTRO-NASH F1B-F3. No incretin has shown benefit on hard cirrhosis outcomes (decompensation, portal hypertension, HCC, transplant, mortality) in established cirrhosis.", "finding": "COMPENSATED-CIRRHOSIS (MASH F4) FRONTIER - EVIDENCE GAP. The landmark registrational MASH programmes systematically EXCLUDE established cirrhosis (ESSENCE F2/F3; MAESTRO-NASH F1B-F3). As of this gather no incretin (GLP-1 mono, GLP-1/glucagon dual, or triple) has a published trial showing histological OR clinical benefit in compensated MASH cirrhosis or portal hypertension. This row FLAGS the gap, it does not assert a finding.", "population": "n/a - characterises absence of F4 evidence; ESSENCE (F2/F3) and MAESTRO-NASH (F1B-F3) cited as the exclusion evidence.", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Honest GAP capture. The entire registrational MASH surrogate base sits at F1B-F3; the F4/cirrhosis stage - where hard outcomes actually accrue - is essentially untested for incretins. NEUTRAL on whether incretins would help cirrhotics; JUDGEMENTAL that the evidence does not exist. Reta relevance: a key open frontier; if reta's larger metabolic effect translated to cirrhosis-stage benefit it would be class-leading, but there is NO incretin F4 evidence to anchor that. Non-graduating until a published F4 result exists.", "crossRef": "C2-SEMAGLUTIDE-MASH-01; C-RESMETIROM-MASH-MAESTRO-CONTEXT; C-CLASS-MASH-SURROGATE-GAP", "grade": "low", "source": { "citation": "Derived from ESSENCE and MAESTRO-NASH inclusion criteria, both of which exclude F4 cirrhosis; no dedicated incretin compensated-cirrhosis MASH outcomes publication identified.", "url": "", "identifiers": "CIT:incretin-mash-f4-cirrhosis-gap-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-CARDIO-01", "sourceId": "PMID27295427", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.87 (95% CI 0.78-0.97; P<0.001 non-inferiority, P=0.01 superiority); 13.0% vs 14.9%. CV death HR 0.78 (0.66-0.93); all-cause death HR 0.85 (0.74-0.97). Median 3.8 years.", "finding": "In T2D at high CV risk, liraglutide reduced MACE versus placebo; unlike SUSTAIN-6, CV death and all-cause death were also significantly reduced.", "population": "LEADER: N=9340; T2D high CV risk; double-blind placebo-controlled RCT; median 3.8 years.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS prior row. Mortality reduction (CV and all-cause) distinguishes LEADER from SUSTAIN-6 within the same sponsor's portfolio; recorded as observation, the why left open.", "crossRef": "C-SEMA-CARDIO-02", "grade": "high", "source": { "citation": "Marso SP et al. (LEADER), NEJM, 2016", "url": "https://doi.org/10.1056/NEJMoa1603827", "identifiers": "PMID 27295427; DOI 10.1056/NEJMoa1603827; NCT01179048", "date": "2016-06-13", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk + academic-NIH (co-funded)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-CARDIO-HF-01", "sourceId": "PMID27483064", "drug": "liraglutide (1.8 mg/day)", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "no-change", "magnitude": "Primary global rank P=0.31. Deaths 12% vs 11%, HR 1.10 (95% CI 0.57-2.14). HF rehospitalisations 41% vs 34%, HR 1.30 (0.89-1.88).", "finding": "FIGHT: in patients recently hospitalised for acute HFrEF, liraglutide did NOT improve post-hospitalisation clinical stability (null), with numerically more deaths and rehospitalisations.", "population": "N=300, established HFrEF (median LVEF 25%), recently hospitalised, 59% T2D; 180 days; phase 2 RCT vs placebo.", "comparators": "placebo", "endpointType": "other", "notes": "CAUTION pole: null primary; numerically worse death/rehospitalisation on liraglutide (non-significant). PMID/DOI verified.", "crossRef": "C-LIRA-CARDIO-HF-02", "grade": "moderate", "source": { "citation": "Margulies KB et al. (FIGHT), JAMA, 2016;316:500-508", "url": "https://doi.org/10.1001/jama.2016.10260", "identifiers": "PMID 27483064; DOI 10.1001/jama.2016.10260; NCT01800968", "date": "2016-08-02", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic-NHLBI (study drug supplied by Novo Nordisk)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-CARDIO-HF-02", "sourceId": "PMID27790809", "drug": "liraglutide (1.8 mg/day)", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "mixed", "magnitude": "LVEF change diff -0.8% (95% CI -2.1 to 0.5; P=0.24). Heart rate +7 bpm (95% CI 5 to 9; P<0.0001). Serious cardiac events 10% vs 3% (P=0.04).", "finding": "LIVE: in stable chronic HFrEF on optimal therapy, liraglutide did NOT change LV systolic function but raised heart rate and was associated with more serious cardiac adverse events (safety caution).", "population": "N=241, LVEF <=45% (mean ~34%), clinically stable, with/without diabetes; 24 weeks; investigator-initiated RCT vs placebo.", "comparators": "placebo", "endpointType": "other", "notes": "KEY CAUTION pole: HR rise + excess serious cardiac events in HFrEF. Cross-refs the class chronotropy records. PMID/DOI verified.", "crossRef": "", "grade": "high", "source": { "citation": "Jorsal A et al. (LIVE), Eur J Heart Fail, 2017;19:69-77", "url": "https://doi.org/10.1002/ejhf.657", "identifiers": "PMID 27790809; DOI 10.1002/ejhf.657", "date": "2016-10-28", "design": "double-blind RCT", "maturity": "human-primary", "funding": "investigator-initiated (academic; not manufacturer-run)", "scopeLimits": "small sample (N~241)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-CARDIO-RENAL-01", "sourceId": "PMID28854085", "drug": "liraglutide (up to 1.8 mg/day)", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Renal composite HR 0.78 (95% CI 0.67 to 0.92; p=0.003); new macroalbuminuria HR 0.74 (0.60-0.91; p=0.004); hard endpoint (creatinine doubling/ESRD) less pronounced.", "finding": "LEADER prespecified secondary renal composite reduced with liraglutide versus placebo (driven by new macroalbuminuria).", "population": "LEADER: N=9,340 T2D, high CV risk; median 3.84 years; RCT.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Benefit mainly albuminuria-driven. PMID/DOI verified.", "crossRef": "C-LIRA-CARDIO-01", "grade": "moderate", "source": { "citation": "Mann JFE et al. (LEADER renal), NEJM, 2017;377:839-848", "url": "https://doi.org/10.1056/NEJMoa1616011", "identifiers": "PMID 28854085; DOI 10.1056/NEJMoa1616011", "date": "2017-08-31", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk + academic-NIH (co-funded)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-HF-NP-01", "sourceId": "PMID32627271", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "decrease", "magnitude": "NT-proBNP -25% / MR-proANP -27% in T2D subgroup only; null in non-T2D", "finding": "In a LIVE substudy (231 HFrEF patients), liraglutide reduced natriuretic peptides only in the type-2-diabetes subgroup (NT-proBNP -25%, MR-proANP -27% vs placebo) with no change in non-diabetic patients (significant T2D interaction), indicating any neurohormonal benefit in HFrEF was confined to the diabetic subset.", "population": "LIVE substudy, 231 chronic HFrEF patients (LVEF <=45%), with and without T2D, 24 wk; NCT01472640", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "GLP-1R class. Nuances (does not overturn) the HFrEF caution: a neurohormonal benefit existed but only in the T2D subgroup. Surrogate (natriuretic peptides); substudy; the parent LIVE trial still showed net HR rise + more serious cardiac events. Distinct substudy PMID from the LIVE primary (C-LIRA-CARDIO-HF-02). Folded from T12-GLP1R-10 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-LIRA-CARDIO-HF-02", "grade": "moderate", "source": { "citation": "Nielsen R et al., Diabetes Obes Metab 2020;22(11):2141-2150 (LIVE natriuretic-peptide substudy)", "url": "https://doi.org/10.1111/dom.14135", "identifiers": "PMID:32627271 DOI:10.1111/dom.14135 NCT01472640", "date": "2020-11-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "investigator-initiated (academic; not manufacturer-run)", "scopeLimits": "surrogate/exploratory endpoint; small sample (N~231)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-HF-PET-01", "sourceId": "PMID28770459", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "no-change", "magnitude": "myocardial glucose uptake / blood flow / flow reserve all unchanged (NS)", "finding": "In a LIVE PET sub-study (36 non-diabetic HFrEF patients), liraglutide did NOT change myocardial glucose uptake, myocardial blood flow or myocardial flow reserve versus placebo despite lowering weight and HbA1c - so the increased cardiac-event signal with liraglutide in chronic HF does not appear to be mediated by changes in myocardial perfusion or substrate uptake.", "population": "LIVE PET substudy, 36 non-diabetic HFrEF patients (LVEF <=45%); NCT01472640", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "GLP-1R class. Mechanistic NEGATIVE: the HFrEF adverse signal is NOT explained by a myocardial perfusion/glucose-uptake change, leaving the chronotropic/HR mechanism as the leading remaining candidate by exclusion. Small (n=36); surrogate imaging. Distinct substudy PMID from the LIVE primary. Folded from T12-GLP1R-11 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-LIRA-CARDIO-HF-02", "grade": "moderate", "source": { "citation": "Nielsen R et al., J Nucl Cardiol 2019;26(2):585-597 (LIVE PET substudy)", "url": "https://doi.org/10.1007/s12350-017-1000-2", "identifiers": "PMID:28770459 DOI:10.1007/s12350-017-1000-2 NCT01472640", "date": "2019-04-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "investigator-initiated (academic; not manufacturer-run)", "scopeLimits": "surrogate/exploratory endpoint; small sample (N~36)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-HF-SR-01", "sourceId": "PMID32867644", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "no-change", "magnitude": "FIGHT primary P=0.31 (per source); LIVE LVEF NS; adverse-leaning", "finding": "A systematic review of the two isolating GLP-1RA HFrEF RCTs (FIGHT and LIVE, combined n=541, 24-week liraglutide) found no benefit and an adverse-leaning signal - no between-group difference in FIGHT's global rank/deaths/HF rehospitalisation and no LVEF change in LIVE - concluding liraglutide use in HFrEF was associated with increased risk of HF-related outcomes.", "population": "systematic review of FIGHT + LIVE (two GLP-1RA HFrEF RCTs), combined n=541", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Review-tier corroborator of the HFrEF caution; carries the LIVE corroboration. UPSTREAM STATUS secondary-corroborated (the FIGHT/LIVE primaries govern by maturity) - kept at a weaker, NON-graduating status here and deliberately NOT used to anchor any cell (the FIGHT/LIVE primaries carry the liraglutide HF cell at high). Corroborator named: Hamad F et al. 2021. Folded from T12-NET-08 (per-receptor secondary-corroborated); compendium independent substance-check completed 2026-06-26 (see validation_evidence).", "crossRef": "C-LIRA-CARDIO-HF-01", "grade": "low", "source": { "citation": "Hamad F et al., Curr Diabetes Rev 2021;17(3):280-292 (systematic review FIGHT+LIVE)", "url": "https://doi.org/10.2174/1573399816999200821164129", "identifiers": "PMID:32867644 DOI:10.2174/1573399816999200821164129", "date": "2021-01-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-HR-SAN-01", "sourceId": "PMID34256040", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "dose-dependent firing-rate rise (isolated heart/myocyte; no single % carried)", "finding": "Liraglutide raised sinoatrial firing rate by a DIRECT action on the node in isolated (denervated) rabbit Langendorff hearts and murine SAN myocytes: the effect survived beta-blockade (propranolol) but was abolished by funny-current (I_f) blockade with ivabradine, isolating an I_f-mediated direct-SAN component independent of autonomic reflexes.", "population": "isolated denervated rabbit Langendorff hearts and isolated murine sinoatrial-node myocytes", "comparators": "propranolol; ivabradine", "endpointType": "surrogate/biomarker", "notes": "Receptor-isolating (pure GLP-1RA), DIRECT-on-SAN pole; mechanism = I_f/funny current. Rodent/rabbit -> human translation caveat. Does not exclude an additional central/autonomic component in vivo. Folded from T7-002 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-GLP1NAT-HR-01", "grade": "very-low", "source": { "citation": "Jons C et al., Life Sci 2021;282:119815", "url": "https://doi.org/10.1016/j.lfs.2021.119815", "identifiers": "PMID:34256040 DOI:10.1016/j.lfs.2021.119815", "date": "2021-10-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-IRON-01", "sourceId": "PMID39045670", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Liraglutide lowered serum AND hepatic iron via a HEPCIDIN-INDEPENDENT mechanism (Hamp not differentially expressed) in an HFE-knockout haemochromatosis mouse model.", "finding": "In an HFE-knockout haemochromatosis mouse model, liraglutide lowered both serum and hepatic iron through a hepcidin-independent mechanism (Hamp not differentially expressed), arguing for a genuine iron-handling effect rather than only an acute-phase change.", "population": "HFE-knockout (HFE-KO) haemochromatosis mice; hepatic and serum iron, Hamp/hepcidin expression measured. Murine model; no human read-across.", "comparators": "vehicle-treated HFE-KO mice", "endpointType": "safety-event/signal", "notes": "Murine HFE-KO model, NOT human; Novo Nordisk co-authors. Rodent evidence; human relevance uncertain; no human read-across.", "crossRef": "", "grade": "very-low", "source": { "citation": "Bozadjieva-Kramer N et al. Liraglutide lowers iron in HFE-knockout mice independent of hepcidin. Endocrinology 2024;165(9):bqae090.", "url": "https://doi.org/10.1210/endocr/bqae090", "identifiers": "PMID 39045670 / DOI 10.1210/endocr/bqae090 / PMC11311705", "date": 2024, "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-MICROBIOME-01", "sourceId": "DOI10.1038/srep33251", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "Liraglutide reproducibly shifts rodent gut-microbiota composition (Firmicutes/Bacteroidetes balance; enrichment of lean-associated taxa). In Wang 2016 HFD mice a ridge regression statistically SEPARATED the liraglutide effect on microbiota (drug beta ~0.389 / -0.508, p~1e-5) from the reduced-food-intake effect (food-intake beta -0.182, p=0.043), i.e. the drug effect is statistically separable from caloric restriction in at least this one study; corroborated in rats (Zhao 2018, B/F ratio).", "finding": "In high-fat-diet rodents, liraglutide reproducibly changes gut-microbiota composition, and in one study the drug's effect on the microbiota was statistically separable (by ridge regression) from the effect of reduced food intake - but this is a compositional shift only, with no test of whether the shift causes any metabolic benefit.", "population": "High-fat-diet C57BL/6 mice (Wang 2016 Sci Rep, liraglutide vs saxagliptin/control; 16S rRNA), corroborated by Wistar and Goto-Kakizaki rats (Zhao 2018 Front Endocrinol; 16S).", "comparators": "saxagliptin; saline/control", "endpointType": "mechanistic/physiological", "notes": "RODENT, 16S compositional only, very-low. 'direction: no-change' = this is a COMPOSITIONAL-SHIFT/mechanism finding, not a weight/glycaemic efficacy direction. The ridge-regression separability is a genuine but single-study signal; the dominant confounder across the corpus is drug-induced reduced food intake (see C-CLASS-MICROBIOME-NOCAUSE-01). NO causal weight-loss mediation tested.", "crossRef": "C-CLASS-MICROBIOME-NOCAUSE-01", "grade": "very-low", "source": { "citation": "Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the relationship with body weight: compared evaluation of liraglutide and saxagliptin treatment. Sci Rep 2016;6:33251.", "url": "https://doi.org/10.1038/srep33251", "identifiers": "DOI:10.1038/srep33251", "date": "2016-09", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; 16S compositional only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-MICROBIOME-FMT-01", "sourceId": "PMID33723651", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "The single strongest causal result is ONE mouse study (Charpentier/Burcelin 2021, antibiotic + germ-free FMT): antibiotics abolished liraglutide's effects on GLUCOSE-INDUCED INSULIN SECRETION and the intestinal immune system (Th1 down, Treg up), and germ-free mice colonised with liraglutide-shifted microbiota reproduced the improved glucose-induced insulin secretion - a genuine transfer-of-phenotype. BUT this is for INSULIN SECRETION / INTESTINAL IMMUNITY, NOT WEIGHT LOSS; it is LIRAGLUTIDE-SPECIFIC (Exendin-4 did NOT reproduce the signature); it is ANIMAL-ONLY with NO human equivalent.", "finding": "The one study that does show causation (a germ-free/antibiotic faecal-transplant experiment in mice) transferred an improvement in INSULIN SECRETION and gut immunity - not weight loss - was specific to liraglutide (exendin-4 did not reproduce it), and has no human equivalent; it does not show the microbiome mediates GLP-1-RA weight loss.", "population": "Germ-free + antibiotic-treated diet-induced-dysmetabolic mice; faecal microbiota transfer from liraglutide-treated vs control mice; Exendin-4 as a non-reproducing comparator (Charpentier/Burcelin 2021 Acta Diabetol).", "comparators": "vehicle; Exendin-4; germ-free recipients of control microbiota", "endpointType": "mechanistic/physiological", "notes": "RODENT FMT, very-low. R2 scope guard: the scope limit (insulin secretion/immunity NOT weight loss; liraglutide-specific; animal-only; no human equivalent) is in the FINDING TEXT, not just here. Strongest causal datum in the cluster and the easiest to mis-summarise as 'microbiome causes the weight loss' - it does not.", "crossRef": "C-CLASS-MICROBIOME-NOCAUSE-01", "grade": "very-low", "source": { "citation": "Charpentier J, Briand F, Lelouvier B, et al. (Burcelin R, senior). Liraglutide targets the gut microbiota and the intestinal immune system to regulate insulin secretion. Acta Diabetol 2021;58(7):881-897.", "url": "https://doi.org/10.1007/s00592-020-01657-8", "identifiers": "DOI:10.1007/s00592-020-01657-8", "date": "2021-03", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent (INSERM/I2MC Toulouse; Burcelin lab)", "scopeLimits": "animal data; human relevance uncertain; 16S compositional only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-REG-COUNTERREG-01", "sourceId": "CIT:victoza-nda-022341-clinpharm-ocr", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "no-change", "magnitude": "glucagon counter-regulatory response preserved (glucagon rose ~1.5-fold with falling glucose in both arms); counter-regulation not impaired", "finding": "FDA Victoza Clinical Pharmacology review: in a stepwise hypoglycaemic clamp, a single liraglutide dose did NOT impair the glucagon counter-regulatory response (glucagon rose ~1.5-fold with falling glucose in both arms). This is the GLP-1-monoagonist baseline for the retatrutide GCGR-arm hypoglycaemia-counter-regulation question: pure GLP-1 does not impair counter-regulation; whether chronic GCGR agonism plus incretin insulin secretion does is retatrutide-specific and open.", "population": "Stepwise hypoglycaemic clamp, single-dose liraglutide vs comparator (FDA Victoza NDA 022341 ClinPharm/OCP review, counter-regulation section, Fig 10)", "comparators": "placebo/comparator arm", "endpointType": "physiological-surrogate", "notes": "Promoted from sweep SW-REG-07 (2026-06-21). Baseline for the chronic-GCGR-agonism counter-regulation open question (retatrutide-specific; the relevant clamp NCT06982846 completed, unposted). Moderate, sponsor-derived single-dose substudy.", "crossRef": "", "grade": "moderate", "source": { "citation": "FDA Victoza NDA 022341 Clinical Pharmacology (OCP) Review (scanned/OCR)", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000ClinPharmR.pdf", "identifiers": "FDA NDA 022341 Clinical Pharmacology/OCP Review", "date": "2010-01-25", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "industry - Novo Nordisk (applicant/manufacturer; FDA Clinical Pharmacology/OCP review of Novo's NDA 022341 submission)", "scopeLimits": "scanned/OCR source; single-dose hypoglycaemic-clamp substudy", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-SAFETY-GI06", "sourceId": "DOI10.1056/NEJMOA1411892", "drug": "liraglutide (3.0 mg)", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Nausea 39.3% vs 13.8%; diarrhoea 20.9% vs 9.9%; constipation 19.4% vs 8.5%; vomiting 15.7% vs 3.6%; AE discontinuation ~9.9% vs ~3.8%", "finding": "GI AEs more frequent than placebo, largely mild-to-moderate, transient, in escalation; AE-related discontinuation higher than placebo.", "population": "SCALE Obesity and Prediabetes: 3731 adults BMI>=30 (or >=27+comorbidity); liraglutide 3.0 mg daily vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "Per-symptom rates via secondary reporting; DOI confirmed, PMID not confirmed this pass.", "crossRef": "C-SEMA-SAFETY-GI01", "grade": "high", "source": { "citation": "Pi-Sunyer X et al., N Engl J Med 2015 (SCALE)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1411892", "identifiers": "PMID 26132939; DOI 10.1056/NEJMoa1411892; NCT00422058", "date": "2015-07-02", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (disclosed in publication)", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-SAFETY-MTC08", "sourceId": "PMID21209033", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Geometric-mean calcitonin <=1.0 ng/L at 2 yr (below upper normal); very low proportions exceeding 20 ng/L in all groups", "finding": "Rodent C-cell tumour/calcitonin signal does not translate: human sequential calcitonin screening over up to 2 yr in >5000 liraglutide/control subjects showed no consistent dose/time-dependent rise and no between-group difference.", "population": ">5000 subjects with T2D or non-diabetic obesity; calcitonin at 3-month intervals up to 2 yr", "comparators": "control therapy", "endpointType": "safety-event/signal", "notes": "Human NULL pole against the rodent C-cell signal that underpins the boxed warning.", "crossRef": "C-SEMA-SAFETY-MTC09; C-TIRZ-SAFETY-MTC10", "grade": "high", "source": { "citation": "Hegedus L et al., J Clin Endocrinol Metab 2011", "url": "https://doi.org/10.1210/jc.2010-2318", "identifiers": "PMID:21209033 / DOI:10.1210/jc.2010-2318", "date": "2011-01-05", "design": "regulatory document / agency review", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-T1D-01", "sourceId": "PMID27506222", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "HbA1c estimated treatment difference vs placebo -0.20% at week 26", "finding": "In the two pivotal double-blind RCTs, liraglutide added to insulin in type-1 diabetes produced a small, dose-dependent placebo-adjusted HbA1c reduction (about -0.2% at the top dose over 52 weeks), significant only at the higher doses - a modest glycaemic benefit.", "population": "Liraglutide pivotal double-blind T1D RCTs (Mathieu et al., ADJUNCT ONE, 52wk, n=1,398, 3:1, NCT01836523; corroborated by Ahren et al., ADJUNCT TWO, 26wk, n=835, NCT02098395).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "Modest magnitude; HbA1c benefit waned over 52wk (peak at wk26, see C-CLASS-T1D-PEAK-01). This is the efficacy pole that must be read SIDE-BY-SIDE with the HIGH-graded disease-specific harm (C-LIRA-T1D-SAFETY-01/02).", "crossRef": "C-LIRA-T1D-SAFETY-02", "grade": "high", "source": { "citation": "Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016;39(10):1702-1710.", "url": "https://doi.org/10.2337/dc16-0691", "identifiers": "DOI:10.2337/dc16-0691", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT01836523)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-T1D-02", "sourceId": "PMID27506222", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "weight loss estimated treatment difference vs placebo -4.9 kg", "finding": "Liraglutide added to insulin in type-1 diabetes produced significant weight loss at every dose (about -5kg at the top dose) and a modest reduction in total insulin requirement - the metabolic benefits beyond glycaemia.", "population": "Liraglutide pivotal double-blind T1D RCTs (Mathieu ADJUNCT ONE, NCT01836523; Ahren ADJUNCT TWO, NCT02098395).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "Weight/insulin benefits are the most consistent efficacy signal (all doses), unlike the dose-gated HbA1c effect. Still off-label and still attended by the disease-specific harm signals.", "crossRef": "C-LIRA-T1D-01", "grade": "high", "source": { "citation": "Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016;39(10):1702-1710.", "url": "https://doi.org/10.2337/dc16-0691", "identifiers": "DOI:10.2337/dc16-0691", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT01836523)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-T1D-CONCLUSION-01", "sourceId": "PMID27506222", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Trialists' verdict (both pivotal RCTs, verbatim sense): despite reductions in HbA1c, insulin dose and body weight, the increased symptomatic hypoglycaemia and hyperglycaemia-with-ketosis 'limit clinical use' of liraglutide as an insulin adjunct in type-1 diabetes.", "finding": "The pivotal-trial investigators themselves concluded that, despite the metabolic benefits, the increased hypoglycaemia and hyperglycaemia-with-ketosis limit the clinical use of liraglutide as an insulin adjunct in T1D - the honest net verdict.", "population": "Liraglutide pivotal double-blind T1D RCTs (Mathieu ADJUNCT ONE; Ahren ADJUNCT TWO) - authors' own conclusions.", "comparators": "placebo (insulin background)", "endpointType": "other", "notes": "This is the trialists' OWN net judgement (high-grade framing): modest efficacy is outweighed by the disease-specific harm for routine use. Ties the efficacy pole (C-LIRA-T1D-01/02) to the harm pole (C-LIRA-T1D-SAFETY-01/02) and the off-label status (C-CLASS-T1D-OFFLABEL-01).", "crossRef": "C-LIRA-T1D-SAFETY-02", "grade": "high", "source": { "citation": "Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016;39(10):1702-1710.", "url": "https://doi.org/10.2337/dc16-0691", "identifiers": "DOI:10.2337/dc16-0691", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT01836523)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-T1D-SAFETY-01", "sourceId": "PMID27493132", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "symptomatic hypoglycaemia 21.3 vs 16.6 events/patient/year (P=0.03)", "finding": "Liraglutide added to insulin significantly increased the rate of symptomatic hypoglycaemia in type-1 diabetes - a disease-specific harm that accompanies the modest efficacy.", "population": "Liraglutide pivotal double-blind T1D RCTs (Ahren ADJUNCT TWO, 26wk, NCT02098395; corroborated by Mathieu ADJUNCT ONE, NCT01836523).", "comparators": "placebo (insulin background)", "endpointType": "safety-event/signal", "notes": "SYMPTOMATIC (not severe) hypoglycaemia. Note the pooled metas found severe hypoglycaemia NOT increased (Rebelos: similar; Tan: severe-hypo OR 0.86; Kateel: RR 0.74 Low certainty) - the harm is in symptomatic events, the reassurance is only for SEVERE events. Read with C-LIRA-T1D-SAFETY-02.", "crossRef": "C-LIRA-T1D-SAFETY-02", "grade": "high", "source": { "citation": "Ahren B, Hirsch IB, Pieber TR, et al. Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial. Diabetes Care 2016;39(10):1693-1701.", "url": "https://doi.org/10.2337/dc16-0690", "identifiers": "DOI:10.2337/dc16-0690", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT02098395)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRA-T1D-SAFETY-02", "sourceId": "PMID27506222", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "hyperglycaemia-with-ketosis event rate ratio 2.22 (95% CI 1.13,4.34)", "finding": "Both pivotal trials showed a dose-dependent increase in hyperglycaemia-with-ketosis at the highest liraglutide dose (event rate roughly doubled) - the real, disease-specific DKA-adjacent safety signal that, with the hypoglycaemia, limits clinical use.", "population": "Liraglutide pivotal double-blind T1D RCTs (Mathieu ADJUNCT ONE, NCT01836523; Ahren ADJUNCT TWO, NCT02098395).", "comparators": "placebo (insulin background)", "endpointType": "safety-event/signal", "notes": "LOAD-BEARING HARM: dose-dependent (1.8mg only), disease-specific, biologically plausible (ketosis on a background of insulin deficiency). This is the individual-trial signal that the pooled-DKA-null (C-CLASS-T1D-SAFETY-03) does NOT overturn - see that finding's cross-ref. With C-LIRA-T1D-SAFETY-01 this is the trialists' stated reason for limiting clinical use.", "crossRef": "C-CLASS-T1D-SAFETY-03", "grade": "high", "source": { "citation": "Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. Diabetes Care 2016;39(10):1702-1710.", "url": "https://doi.org/10.2337/dc16-0691", "identifiers": "DOI:10.2337/dc16-0691", "date": "2016-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor; NCT01836523)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-BODYCOMP-01", "sourceId": "PMID34358471", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "VAT change -12.49% (liraglutide) vs -1.63% (placebo); estimated treatment difference -10.86% (95% CI -6.97 to -14.75, p<0.0001).", "finding": "Phase 4 MRI RCT (high-CV-risk overweight/obesity, no diabetes): liraglutide 3.0 mg significantly lowered visceral adipose tissue over 40 weeks vs placebo (primary endpoint VAT% by MRI).", "population": "n=185 randomised (liraglutide 92, placebo 93); 128 analysed; 92% female, 37% Black; mean BMI 37.7; 40 weeks + 500 kcal-deficit diet; RCT (NCT03038620)", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Dedicated visceral-fat MRI RCT. Systematic-review context: liraglutide VAT reductions 12.49-23% across trials.", "crossRef": "C-LIRAGLUTIDE-BODYCOMP-02", "grade": "high", "source": { "citation": "Neeland IJ et al., Lancet Diabetes Endocrinol, 2021", "url": "https://doi.org/10.1016/S2213-8587(21)00179-0", "identifiers": "PMID 34358471; DOI 10.1016/S2213-8587(21)00179-0; NCT03038620", "date": "2021-08-03", "design": "double-blind RCT", "maturity": "human-primary", "funding": "academic-led (University of Texas Southwestern) with Novo Nordisk collaborator", "scopeLimits": "small sample (N~185)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-BODYCOMP-02", "sourceId": "PMID38561962", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Thigh-muscle fat mean %change -2.87% (liraglutide) vs +0.05% (placebo); adjusted treatment difference -0.24% (95% CI -0.41 to -0.06, p=0.009). Adverse muscle composition 11.0%->8.2% (liraglutide), no change placebo.", "finding": "Pre-specified MRI secondary analysis: liraglutide 3.0 mg reduced thigh-muscle fat (myosteatosis) and adverse muscle composition vs placebo - a muscle-QUALITY improvement distinct from muscle quantity.", "population": "n=128 with follow-up MRI (liraglutide 73, placebo 55); 92.2% women, 36.7% Black; median 36 wk; same trial as NCT03038620", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Directly addresses the myosteatosis / muscle-quality question: liraglutide improved (reduced) intramuscular fat. Supports the 'muscle quality improves even if quantity falls' pole. Cross-ref C-LIRAGLUTIDE-BODYCOMP-01 (same RCT).", "crossRef": "C-LIRAGLUTIDE-BODYCOMP-01", "grade": "moderate", "source": { "citation": "Pandey A et al., J Cachexia Sarcopenia Muscle, 2024", "url": "https://doi.org/10.1002/jcsm.13445", "identifiers": "PMID 38561962; DOI 10.1002/jcsm.13445", "date": "2024-04-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "small sample (N~128)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-CNS-01", "sourceId": "PMID41326666", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "mixed", "magnitude": "Primary (cerebral glucose metabolism, FDG-PET): difference -0.17 (95% CI -0.39 to 0.06), P=0.14 (NOT met). Secondary ADAS-Executive: 0.15 (0.03 to 0.28), unadjusted P=0.01 (favours liraglutide). ADCS-ADL and CDR-SoB: null.", "finding": "NEURODEGENERATION (Alzheimer's): the ELAD phase-2b trial of liraglutide in mild-moderate Alzheimer's MISSED its primary endpoint (cerebral glucose metabolism), with a surviving positive SECONDARY cognitive signal (ADAS-Executive) on an unadjusted p-value among several null secondaries. A missed-primary trial with a hypothesis-generating cognitive secondary, not a clean positive.", "population": "ELAD (NCT01843075): N=204 mild-moderate AD, non-diabetic; multicentre double-blind RCT; daily s.c. liraglutide vs placebo, 52 weeks.", "comparators": "placebo", "endpointType": "other", "notes": "BOTH POLES. Often cited as 'slowed decline', but the published PRIMARY (glucose metabolism) was NULL; the positive is a secondary on an unadjusted p (multiplicity risk). Phase-2 -> moderate. Consistent in direction with the EVOKE biomarker-but-not-clinical pattern. VALIDATOR: confirm PMID 41326666 + that the primary was not met.", "crossRef": "C-SEMAGLUTIDE-CNS-04", "grade": "moderate", "source": { "citation": "Edison P, Femminella GD, Ritchie C et al., Nat Med, 2025 (ELAD)", "url": "https://doi.org/10.1038/s41591-025-04106-7", "identifiers": "PMID41326666", "date": "2025-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic / non-commercial (ELAD; Imperial College / MRC + charities; disclosed)", "scopeLimits": "small sample (N~204)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-LANDSCAPE-01", "sourceId": "PMID26132939", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor monoagonist (peptide, once-daily s.c.)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "body weight -8.0% vs placebo -2.6%", "finding": "Once-daily subcutaneous liraglutide 3.0 mg produced a mean weight loss of -8.0% (-8.4 kg) vs -2.6% (-2.8 kg) placebo at week 56; 63.2% achieved >=5% weight loss vs 27.1% placebo.", "population": "SCALE Obesity and Prediabetes: 3731 adults without T2D, BMI >=30 (or >=27 with comorbidity), 56 weeks, randomised 2:1 double-blind vs placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: acylated GLP-1 receptor agonist, ~13 h half-life (once-daily). Marketed as Saxenda (obesity, 3.0 mg) and Victoza (T2D, up to 1.8 mg); approved US/EU. CV benefit in LEADER. Also studied in children 6 to <12 y.", "crossRef": "", "grade": "high", "source": { "citation": "Pi-Sunyer X et al., NEJM 2015 (SCALE Obesity and Prediabetes)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1411892", "identifiers": "PMID 26132939; DOI 10.1056/NEJMoa1411892; NCT01272219", "date": "2015-07-02", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-MAINT-01", "sourceId": "PMID23812094", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "decrease", "magnitude": "-6.2% further loss vs placebo -0.2% (difference -6.1%, P<0.0001)", "finding": "SCALE Maintenance: adults who first lost >=5% on a low-calorie-diet run-in were randomised to liraglutide 3.0 mg or placebo to test MAINTENANCE of diet-induced loss. Liraglutide held and added to the loss while placebo did not. SCOPE CAVEAT: this tests maintenance-vs-placebo on a background of diet-induced loss, NOT withdrawal of established drug responders, so it is mechanistically maintenance-vs-placebo, not active-drug-discontinuation regain.", "population": "SCALE Maintenance (NCT00781937): N=422; obese/overweight adults without diabetes who lost >=5% on a low-calorie diet; double-blind RCT, 56 weeks.", "comparators": "placebo", "endpointType": "other", "notes": "The closest liraglutide analogue to STEP-4, but indirect: its placebo arm is diet-maintenance (near-flat -0.2%) on continued lifestyle support, NOT drug discontinuation, so it is not directly comparable to the +6.9/+14.0% regain seen when established sema/tirz responders switch to placebo. Direction tagged 'decrease' (continued loss on active drug). Graded moderate. VALIDATOR: confirm PMID 23812094 + the design (maintenance-of-diet-loss, not drug withdrawal).", "crossRef": "C-SEMAGLUTIDE-MAINT-01", "grade": "moderate", "source": { "citation": "Wadden TA, Hollander P, Klein S et al., Int J Obes (Lond), 2013 (SCALE Maintenance)", "url": "https://doi.org/10.1038/ijo.2013.120", "identifiers": "PMID23812094", "date": "2013-07-01", "design": "randomised-withdrawal RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-MASH-LEAN-PH2", "sourceId": "PMID26608256", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Resolution of definite NASH without worsening fibrosis at 48 wk: 9/23 (39%) liraglutide vs 2/22 (9%) placebo; RR 4.3 (95% CI 1.0-17.7; P=0.019). Fibrosis PROGRESSION (a worsening endpoint): 9% vs 36%; RR 0.2 (95% CI 0.1-1.0; P=0.04).", "finding": "LEAN was the historical GLP-1-mono proof-of-concept for histological NASH resolution: liraglutide 1.8 mg/day increased resolution of definite NASH without worsening fibrosis vs placebo and reduced the proportion with fibrosis PROGRESSION. Small (n=52 randomised, ~45 biopsied), single-group (A'Hern) design. The fibrosis result is LESS PROGRESSION, distinct from active >=1-stage IMPROVEMENT. Resolution is a SURROGATE; no hard liver-outcome data.", "population": "LEAN (NCT01237119), phase 2 double-blind RCT, 4 UK centres. n=52 (26/26); biopsy NASH; 48 wk; analysed among ~45 end-of-treatment biopsies. A'Hern single-group design.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Historical GLP-1-mono MASH-resolution proof-of-concept that motivated the semaglutide programme. DISCIPLINE: LEAN's fibrosis result is reduced PROGRESSION, NOT >=1-stage IMPROVEMENT - do not conflate with the ESSENCE/resmetirom fibrosis-improvement endpoint. Wide CIs (resolution RR CI 1.0-17.7). Part Novo-funded. Reta relevance: shows even a modest-potency GLP-1-mono moves MASH histology, framing the dose-response question a triple extends.", "crossRef": "C2-SEMAGLUTIDE-MASH-01; C2-SEMAGLUTIDE-MASH-02", "grade": "moderate", "source": { "citation": "Armstrong MJ, Gaunt P et al. (LEAN). Lancet 2016;387:679-690.", "url": "https://doi.org/10.1016/S0140-6736(15)00803-X", "identifiers": "PMID26608256", "date": "2016-02-13", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic / non-commercial (LEAN; investigator-initiated NIHR/Wellcome; disclosed)", "scopeLimits": "few events/wide CI; small sample (N~52)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIRAGLUTIDE-OSA-SCALE", "sourceId": "PMID27005405", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "decrease", "magnitude": "AHI change -12.2 events/hr (treatment difference -6.1 events/hr, P=0.0150)", "finding": "SCALE Sleep Apnea was the historical GLP-1 mono-agonist OSA RCT and proof-of-concept that an incretin lowers AHI: liraglutide 3.0 mg, adjunct to diet/exercise, reduced AHI more than placebo at 32 weeks in obese non-diabetic adults with moderate-to-severe OSA unwilling/unable to use CPAP. The effect is modest and parallels modest (~4% placebo-subtracted) weight loss.", "population": "SCALE Sleep Apnea (NCT01557166); N=359 (liraglutide 180, placebo 179); obese (mean BMI 39.1) non-diabetic, baseline mean AHI 49.2 events/hr, 67% severe; CPAP-refusing; 32-wk double-blind RCT, both arms on a 500 kcal/day deficit + exercise.", "comparators": "placebo", "endpointType": "other", "notes": "AHI IS A SURROGATE; no hard OSA/CV outcomes assessed. Modest AHI reduction parallels modest weight loss - consistent with weight-mediation (the weight-loss-AHI link rests on a non-prespecified association, not a primary endpoint). Novo-sponsored (flag). Reta relevance: reta's far larger weight loss would, IF weight-mediated, predict substantially larger AHI reduction than liraglutide - expectation, not data.", "crossRef": "C-CLASS-OSA-MECHANISM; C-CLASS-OSA-SURROGATE", "grade": "high", "source": { "citation": "Blackman A, Foster GD, Zammit G et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe OSA: SCALE Sleep Apnea. Int J Obes (Lond) 2016;40(8):1310-9.", "url": "https://doi.org/10.1038/ijo.2016.52", "identifiers": "PMID27005405", "date": "2016-03-23", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "post-hoc (not prespecified); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIXI-CARDIO-01", "sourceId": "DOI10.1056/NEJMOA1509225", "drug": "lixisenatide", "drugRoot": "lixisenatide", "drugSlug": "lixisenatide", "drugLabel": "Lixisenatide", "drugClass": "GLP-1 receptor agonist (exendin-4-based)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "Primary composite (CV death, MI, stroke, hospitalisation for unstable angina) HR 1.02 (95% CI 0.89-1.17; P<0.001 non-inferiority; P=0.81 superiority); 13.4% vs 13.2%. No reduction in HF hospitalisation or death.", "finding": "In T2D after a recent acute coronary syndrome, lixisenatide was non-inferior but NOT superior to placebo for the CV composite: a fully NEUTRAL CV outcome.", "population": "ELIXA: N=6068; T2D with ACS within 180 days; double-blind placebo-controlled RCT; median 25 months.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "BOTH-POLES NEUTRAL anchor: a flat GLP-1 CVOT (HR ~1.02), first of the class, in a post-ACS population. DEEPENS prior row. Recorded as reported, not averaged into the positive trials.", "crossRef": "C-EXEN-CARDIO-01; C-CLASS-CARDIO-01", "grade": "high", "source": { "citation": "Pfeffer MA et al. (ELIXA), NEJM, 2015", "url": "https://doi.org/10.1056/NEJMoa1509225", "identifiers": "PMID 26630143; DOI 10.1056/NEJMoa1509225; NCT01147250 [VERIFIED 2026-06-20]", "date": "2015-09-03", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Sanofi (disclosed in publication)", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIXISENATIDE-CNS-01", "sourceId": "PMID38598572", "drug": "lixisenatide", "drugRoot": "lixisenatide", "drugSlug": "lixisenatide", "drugLabel": "Lixisenatide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "MDS-UPDRS part III (on-medication) at 12 months: -0.04 (lixisenatide) vs +3.04 (placebo); difference 3.08 points (95% CI 0.86-5.30; P=0.007). Attenuated after a 2-month washout. GI burden: nausea 46%, vomiting 13%.", "finding": "NEURODEGENERATION (Parkinson's) - the middle pole: in the LIXIPARK phase-2 trial in early Parkinson's, lixisenatide produced less motor-disability progression than placebo at 12 months (~3-point MDS-UPDRS difference), but the effect attenuated after washout and came with substantial GI side effects.", "population": "LIXIPARK (NCT03439943): N=156 early PD (<3 years); double-blind RCT; daily s.c. lixisenatide, 12 months + 2-month washout.", "comparators": "placebo", "endpointType": "other", "notes": "Between the positive exenatide ph2 and the negative exenatide ph3. Modest absolute difference (~3 points, clinical relevance uncertain); attenuation after washout leaves symptomatic-vs-disease-modifying open; high GI burden. French Ministry of Health funded (non-industry). Phase-2 -> moderate. IDENTIFIER NOTE: correct PMID 38598572 (a commonly-miscited 38587247 is an olezarsen paper). VALIDATOR: confirm 38598572.", "crossRef": "C-EXENATIDE-CNS-03", "grade": "moderate", "source": { "citation": "Meissner WG, Remy P, Giordana C et al., N Engl J Med, 2024 (LIXIPARK)", "url": "https://doi.org/10.1056/NEJMoa2312323", "identifiers": "PMID38598572", "date": "2024-04-04", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic / non-commercial (LIXIPARK; French PHRC government programme; disclosed)", "scopeLimits": "small sample (N~156)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LIXISENATIDE-LANDSCAPE-01", "sourceId": "PMID26630143", "drug": "lixisenatide", "drugRoot": "lixisenatide", "drugSlug": "lixisenatide", "drugLabel": "Lixisenatide", "drugClass": "GLP-1 receptor monoagonist (exendin-4-based, short-acting, once-daily s.c.)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c approx -0.5% to -0.9% (GetGoal); MACE hazard ratio approximately 1.02 (neutral) in ELIXA; modest weight effect", "finding": "In the GetGoal phase 3 programme lixisenatide reduced HbA1c by approx 0.5-0.9%; in the ELIXA cardiovascular outcomes trial it was MACE-neutral vs placebo in T2D after acute coronary syndrome.", "population": "GetGoal: ~5000 T2D across settings. ELIXA: 6068 T2D within 70 days of ACS, lixisenatide vs placebo, median ~2.1 years", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Mechanism: exendin-4-derived short-acting GLP-1 receptor agonist with pronounced gastric-emptying delay (strong postprandial lowering). Marketed Adlyxin (US)/Lyxumia (EU); also fixed-ratio with insulin glargine (Soliqua/Suliqua). First GLP-1 RA CV outcomes trial; CV-safe, no benefit. Later largely withdrawn commercially in some markets.", "crossRef": "", "grade": "high", "source": { "citation": "Pfeffer MA et al., NEJM 2015 (ELIXA)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa1509225", "identifiers": "PMID 26630143; DOI 10.1056/NEJMoa1509225; NCT01147250", "date": "2015-12-03", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Sanofi", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-LOTIGLIPRON-LANDSCAPE-01", "sourceId": "DOI10.1111/DOM.15643", "drug": "lotiglipron", "drugRoot": "lotiglipron", "drugSlug": "lotiglipron", "drugLabel": "Lotiglipron", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Transaminase elevation 6.0-6.6% (lotiglipron) vs 1.6% (placebo), obesity cohort; programme halted at phase 1/early phase 2", "finding": "Oral non-peptide GLP-1RA (PF-07081532, Pfizer/Sosei Heptares). Two phase 1 MAD studies in T2D and obesity reported PK/PD signals. Development DISCONTINUED June 2023 on elevated transaminases in phase 1 DDI studies and ongoing phase 2 (transaminase elevation 6.0-6.6% on lotiglipron vs 1.6% placebo, obesity cohort); no liver symptoms/failure. Pfizer noted such elevations had not been seen with danuglipron at that time.", "population": "Two phase 1 randomised placebo-controlled MAD studies in T2D and obesity; plus ongoing phase 2", "comparators": "placebo", "endpointType": "other", "notes": "MECHANISM: oral non-peptide small-molecule GLP-1R agonist, once daily. DISCONTINUED June 2023 - elevated transaminases. First of two Pfizer oral GLP-1 hepatic-signal discontinuations. Records the recurring hepatic-safety theme in the oral small-molecule GLP-1 landscape as an observation.", "crossRef": "C-DANUGLIPRON-LANDSCAPE-01", "grade": "low", "source": { "citation": "Buckeridge et al., Diabetes Obes Metab 2024 (phase 1); Pfizer update June 2023", "url": "https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15643", "identifiers": "PF-07081532; DOI 10.1111/dom.15643", "date": "2023-06-26", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-LY3463251-LANDSCAPE-01", "sourceId": "PMID36630958", "drug": "LY3463251", "drugRoot": "LY3463251", "drugSlug": "ly3463251", "drugLabel": "LY3463251", "drugClass": "long-acting GDF15 receptor (GFRAL/RET) agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "decrease", "magnitude": "significant reductions in food intake and appetite scores; body-weight reduction modest (below GLP-1-class magnitudes)", "finding": "Proof-of-mechanism: in overweight/obese participants, 12-week multiple-ascending-dose LY3463251 significantly reduced food intake and appetite scores independent of nausea/emesis, but produced only modest body-weight reduction. The GDF15 axis suppresses appetite without the expected weight magnitude, a challenge for clinical weight-loss use.", "population": "Phase 1 multiple-ascending-dose, 12 weeks, healthy and overweight/obese participants, placebo-controlled", "comparators": "placebo", "endpointType": "other", "notes": "Mechanism: agonist at GFRAL/RET (the GDF15 receptor complex restricted to area postrema/NTS), suppressing appetite via a non-incretin brainstem pathway. Eli Lilly. Co-occurs in incretin comparisons as the canonical GDF15/GFRAL mechanism and a contrast case (appetite suppression without proportional weight loss).", "crossRef": "", "grade": "low", "source": { "citation": "Benichou et al., Cell Metab 2023 (LY3463251 discovery and clinical proof of mechanism)", "url": "https://pubmed.ncbi.nlm.nih.gov/36630958/", "identifiers": "PMID 36630958", "date": "2023-01-10", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-MARITIDE-LANDSCAPE-01", "sourceId": "NCTNCT05669599", "drug": "maridebart cafraglutide", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIP-receptor antagonist + GLP-1 receptor agonist (peptide-antibody bispecific conjugate)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight (52 wk, treatment-policy estimand): -12.3% to -16.2% (obesity, no T2D) vs -2.5% placebo; -8.4% to -12.3% (T2D) vs -1.7% placebo. HbA1c: -1.2 to -1.6 pts (T2D)", "finding": "Maridebart cafraglutide (MariTide; formerly AMG 133) is a peptide-antibody conjugate that ANTAGONISES the GIP receptor while AGONISING the GLP-1 receptor; half-life ~21 days. In phase 2 (NEJM 2025), mean weight change at 52 weeks was -12.3% to -16.2% in obesity without T2D (vs -2.5% placebo) and -8.4% to -12.3% in T2D (vs -1.7% placebo) on the treatment-policy (ITT) estimand, with weight loss not plateaued by 52 weeks. HbA1c fell 1.2 to 1.6 percentage points in the T2D cohort.", "population": "Phase 2 (NCT05669599): N=592. Cohort A obesity no T2D (n=465); Cohort B obesity with T2D (n=127). Monthly fixed doses 140/280/420 mg + 8-week 420 mg arm vs placebo; 52 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GIP-receptor ANTAGONISM conjugated to a GLP-1 agonist. Preclinical/ph1 background PMC10896721. Tagged press/conference (ADA 2025) - peer-reviewed phase 2 should supersede. NCT05669599 confirmed.", "crossRef": "C-GIP-AXIS-PARADOX-01", "grade": "very-low", "source": { "citation": "Amgen, Phase 2 MariTide presented at ADA 85th Scientific Sessions 2025; earlier topline Nov 2024", "url": "https://investors.amgen.com/news-releases/news-release-details/results-amgens-phase-2-obesity-study-monthly-maritide-presented", "identifiers": "NCT05669599", "date": "2025-06-20", "design": "observational cohort", "maturity": "conference-abstract", "funding": "industry (company press release on own pipeline)", "scopeLimits": "conference/abstract-level", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-MASH-NATURAL-HISTORY-REGULATORY", "sourceId": "CIT:fda-accelerated-approval-framework-for-mash-subp", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "n/a (regulatory / natural-history context)", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "Context: MASH fibrosis STAGE is the dominant predictor of liver-related outcomes, risk rising steeply at F3-F4. The accepted surrogate endpoints are validated as 'reasonably likely to predict' clinical benefit (accelerated-approval standard), NOT as proven clinical-outcome surrogates.", "finding": "NATURAL-HISTORY / REGULATORY CONTEXT: MASH fibrosis stage predicts liver-related clinical outcomes (decompensation, HCC, liver death), risk rising steeply at advanced stages - which is why histological fibrosis improvement was adopted as an endpoint. CRUCIAL DISTINCTION: the accepted surrogates (MASH resolution; >=1-stage fibrosis improvement) are validated as 'REASONABLY LIKELY to predict' benefit (the statutory basis for FDA accelerated approval), NOT as PROVEN clinical-outcome surrogates. Confirmatory hard-outcome trials are required to convert reasonably-likely to proven, and for the incretin class those readouts have not yet reported.", "population": "n/a - regulatory/natural-history framing applicable to the whole MASH field.", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Anchors the surrogate-gap story in the regulatory standard: accelerated approval rests on an endpoint REASONABLY LIKELY to predict benefit, explicitly weaker than a validated clinical-outcome surrogate. This is why C-CLASS-MASH-SURROGATE-GAP grades hard liver outcomes as UNPROVEN even where surrogate endpoints are met. Synthesis/context row (CIT id; no single citable source; fabrication barred).", "crossRef": "C-CLASS-MASH-SURROGATE-GAP; C-RETATRUTIDE-MASH-TRIAL-GAP", "grade": "low", "source": { "citation": "FDA accelerated-approval framework for MASH (subpart H; histological surrogate 'reasonably likely to predict clinical benefit') and MASH natural-history literature linking fibrosis stage to outcomes. Composite regulatory framing, no single PMID.", "url": "", "identifiers": "CIT:mash-natural-history-regulatory-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-MAZDUTIDE-BODYCOMP-01", "sourceId": "CIT:innovent-eli-lilly-glory-1-and-glory-2-phase-3-m", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Weight -14.8% (6 mg, 48 wk, GLORY-1); -20.08% (9 mg, Week 60, GLORY-2). Waist circumference reduced; liver-fat content reduced (exact DXA fat/lean partition not reported in located sources).", "finding": "GLORY-1/GLORY-2 phase 3 (Chinese adults with obesity): mazdutide met key secondary endpoints including reduced waist circumference and liver-fat content; dual GCG/GLP-1 mechanism described as potentially yielding more favourable fat-vs-muscle partition, but no quantified DXA fat/lean split located.", "population": "GLORY-1 (n=610) and GLORY-2 phase 3 RCTs in Chinese adults with obesity; 48-60 weeks", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "GAP: quantified DXA fat/lean partition for mazdutide not found in this sweep; waist circumference and liver fat are the available body-composition-adjacent readouts. Flagged for follow-up against the published GLORY papers.", "crossRef": "", "grade": "very-low", "source": { "citation": "Innovent / Eli Lilly, GLORY-1 and GLORY-2 phase 3 (mazdutide)", "url": "https://www.prnewswire.com/news-releases/mazdutide-9-mg-achieves-up-to-20-1-weight-loss-in-chinese-adults-with-obesity-glory-2-study-meets-primary-and-all-key-secondary-endpoints-302620471.html", "identifiers": "GLORY-1; GLORY-2 (company press)", "date": 2025, "design": "phase-2 RCT (pipeline)", "maturity": "press", "funding": "industry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-MAZDUTIDE-GLORY1-WL-01", "sourceId": "PMID40421736", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -14.01% (95% CI -15.36 to -12.66) vs placebo +0.30%", "finding": "In the registrational Chinese phase-3, the GLP-1/glucagon dual agonist mazdutide produced 11-14% weight loss with low (~1%) discontinuation.", "population": "GLORY-1 (NCT05607680): 610 Chinese adults with obesity or overweight (BMI >=28, or 24-<28 plus a weight-related condition), mazdutide 4/6 mg vs placebo 1:1:1; 48-week phase-3 randomised double-blind placebo-controlled RCT.", "comparators": "", "endpointType": "efficacy", "notes": "China-only population (BMI thresholds 28 / 24+comorbidity differ from Western cut-offs) - GENERALISABILITY caveat; placebo-controlled, not head-to-head.", "crossRef": "", "grade": "moderate", "source": { "citation": "Mazdutide in Chinese adults with obesity (GLORY-1), NEJM 2025", "url": "https://doi.org/10.1056/NEJMoa2411528", "identifiers": "DOI:10.1056/NEJMoa2411528", "date": "2025-05-29", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "Innovent Biologics", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-MAZDUTIDE-LANDSCAPE-01", "sourceId": "NCTNCT05607680", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon (GCGR) dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "GLORY-1 48-wk: -11.00% (4 mg), -14.01% (6 mg) vs +0.30% placebo (wk32 primary -10.09% / -12.55% vs +0.45%); >=15% weight loss 49.5% (6 mg) vs 2.0%; phase 2 9 mg ~20% at ~48 wk", "finding": "Mazdutide (IBI362 / LY3305677; Innovent, licensed from Lilly) is a GLP-1/glucagon dual agonist (mammalian oxyntomodulin analogue) developed largely in Chinese populations. In phase 3 GLORY-1 (overweight/obesity, no T2D), mean weight change at 48 weeks was -11.00% (4 mg) and -14.01% (6 mg) vs +0.30% placebo (primary endpoint week 32: -10.09% / -12.55% vs +0.45% placebo); 49.5% of the 6 mg group achieved >=15% weight loss vs 2.0% placebo. Phase 2 with a 9 mg dose showed ~20% weight loss at ~48 weeks.", "population": "GLORY-1: 610 Chinese adults overweight (BMI>=24 + comorbidity) or obesity (BMI>=28), once-weekly s.c. 4/6 mg vs placebo, 48 wk; phase 2 (n~248) doses to 9 mg", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GLP-1/GCGR dual (OXM analogue); glucagon arm linked to added energy expenditure and hepatic-fat reduction. GLORY-1 6 mg in NEJM 2025; 9 mg from phase 2. DREAMS-3 head-to-head vs semaglutide ongoing. Approved in China for weight management (2025, as reported). GLORY-1 NCT and NEJM DOI to re-verify.", "crossRef": "", "grade": "very-low", "source": { "citation": "Ji et al., GLORY-1 phase 3, NEJM 2025 (Innovent); ADA 2024; Nat Commun 2023 phase 2", "url": "https://www.prnewswire.com/news-releases/phase-3-clinical-study-of-mazdutide-in-chinese-adults-with-overweight-or-obesity-glory-1-published-in-the-new-england-journal-of-medicine-nejm-302464859.html", "identifiers": "NCT05607680", "date": "2025-06-01", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-MAZDUTIDE-MASH-STATUS", "sourceId": "PMID41901218", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "No published human MASH histology-endpoint or controlled MRI-PDFF MASLD outcome trial as of 2026-06. Human liver signal is secondary/exploratory within obesity/T2D phase-2 programmes. Preclinical (rodent MASLD): reduced hepatic steatosis, liver-injury markers, inflammation; rodent MRI head-to-head reduced hepatic PDFF more than semaglutide.", "finding": "Mazdutide (IBI362; Innovent/Lilly, GLP-1/glucagon dual) has NO published dedicated human MASH histology trial. Human liver benefit is so far described within obesity/T2D programmes; the histology evidence is rodent. A dedicated clinical MASLD/MASH programme is referenced in reviews but not yet published.", "population": "Preclinical: high-fat-diet mouse MASLD + FFA hepatocytes (PMID 41901218; rodent MRI PMID 40828048). Human MASH histology trial: not yet published.", "comparators": "semaglutide (preclinical comparator)", "endpointType": "surrogate/biomarker", "notes": "STATUS row (honest gap-flag), rodent only - do NOT transfer rodent steatosis/fibrosis to humans. Glucagon-fibrosis hypothesis: the rodent MRI head-to-head is consistent with the glucagon arm aiding liver-FAT clearance, but rodent-only and on STEATOSIS not fibrosis. Reta relevance: shared glucagon arm; reta is the triple. No read-across.", "crossRef": "C2-MULTI-MASH-02; C-MULTI-MASH-GLUCAGON-FIBROSIS", "grade": "very-low", "source": { "citation": "Gan L, Duan L, Zheng X. Mazdutide ameliorates MASLD (rodent). Pharmaceuticals 2026;19(3):371.", "url": "https://doi.org/10.3390/ph19030371", "identifiers": "PMID41901218", "date": "2026-02-26", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-MONLUNABANT-CNS-01", "sourceId": "PMID41038215", "drug": "monlunabant", "drugRoot": "monlunabant", "drugSlug": "monlunabant", "drugLabel": "Monlunabant", "drugClass": "peripherally-restricted CB1 receptor inverse agonist (non-incretin; obesity landscape contrast)", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "mixed", "magnitude": "Phase-2a (16 wk, N=242): AE-driven withdrawals dose-dependent 13% (10 mg) -> 42% (50 mg), 0 placebo; psychiatric disorders among most common AEs (anxiety, irritability, sleep disorder); weight loss -6.4 to -8.0 kg (efficacy only modestly dose-dependent while AEs strongly dose-dependent).", "finding": "CB1 CONTRAST (non-incretin landscape context): monlunabant, a CB1 inverse agonist designed to be peripherally restricted, showed dose-dependent NEUROPSYCHIATRIC adverse events in its phase-2a obesity trial, against the rimonabant precedent (CB1-antagonist depression/suicidality led to withdrawal). A preclinical study found monlunabant suppresses appetite via CENTRAL CB1 receptors, suggesting it is not fully peripherally confined and may carry rimonabant-like psychiatric risk. Decision-relevant CNS-safety contrast: CB1-antagonism carries a mechanism-specific neuropsychiatric liability the incretins do not appear to share.", "population": "Monlunabant phase-2a (NCT05891834): N=242 obesity + metabolic syndrome, 16 weeks, Canada; + a male-mouse central-mechanism study.", "comparators": "placebo", "endpointType": "other", "notes": "NEUTRAL contrast row (NON-incretin, included as landscape context). Cautionary pole: dose-dependent neuropsychiatric AEs/withdrawals + rimonabant precedent + preclinical central action. Mitigating pole: no deaths, mostly mild-moderate, authors propose 10 mg may retain efficacy with fewer AEs. The contrast is the point: CB1-antagonism's mechanism-specific psychiatric liability versus the broadly-reassuring incretin suicidality reviews (C-CLASS-CNS-05). Resolves the existing C-MONLUNABANT-LANDSCAPE-01 (DOI-only) to PMID 41038215. COI: Inversago/Novo Nordisk-sponsored phase-2a (abstract-only - confirm AE figures on full text). FRAMING (Council Red-team): this contrast establishes only that neuropsychiatric AE liability is MECHANISM-SPECIFIC (CB1); it is NOT positive evidence that incretins are psychiatrically safe - incretin reassurance rests on its OWN data (C-CLASS-CNS-05), not on the comparison.", "crossRef": "C-MONLUNABANT-LANDSCAPE-01; C-CLASS-CNS-05", "grade": "moderate", "source": { "citation": "Knop FK et al., Lancet Diabetes Endocrinol, 2025 (monlunabant phase-2a, PMID 41038215); central-mechanism preclinical PMID 39969070", "url": "https://doi.org/10.1016/S2213-8587(25)00216-5", "identifiers": "PMID41038215", "date": "2025-09-29", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk (Inversago Pharma)", "scopeLimits": "conference/abstract-level; small sample (N~242)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-MONLUNABANT-LANDSCAPE-01", "sourceId": "DOI10.1016/S2213-8587(25)00216-5", "drug": "monlunabant (INV-202)", "drugRoot": "monlunabant", "drugSlug": "monlunabant", "drugLabel": "Monlunabant", "drugClass": "oral small-molecule peripheral CB1 (cannabinoid receptor 1) inverse agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-7.1 kg (10 mg) vs -0.7 kg placebo at 16 wk; AE-driven withdrawals 13/27/42% at 10/20/50 mg vs 0% placebo", "finding": "In adults with obesity and metabolic syndrome, once-daily oral monlunabant 10 mg gave 7.1 kg weight loss vs 0.7 kg placebo at 16 weeks. Higher doses (20, 50 mg) showed dose-dependent withdrawals driven by neuropsychiatric/GI adverse events.", "population": "Phase 2a, N=243, 16 wk, randomised double-blind placebo-controlled dose-ranging (10/20/50 mg), 25 centres Canada; adults obesity + metabolic syndrome", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: peripherally-restricted CB1 inverse agonist (endocannabinoid axis), designed to avoid the CNS neuropsychiatric liability that withdrew rimonabant; mild-moderate neuropsychiatric events still reported. Novo (from Inversago). Distinct non-incretin mechanism co-occurring in obesity-pipeline comparisons.", "crossRef": "", "grade": "moderate", "source": { "citation": "Knop et al., Lancet Diabetes Endocrinol 2025; Novo Nordisk press 2024-09-20", "url": "https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00216-5/abstract", "identifiers": "NCT05891834; DOI 10.1016/S2213-8587(25)00216-5", "date": "2025-08-01", "design": "randomised-withdrawal RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (disclosed; amycretin)", "scopeLimits": "small sample (N~243)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-MULTI-MASH-GLUCAGON-FIBROSIS", "sourceId": "CIT:cross-agent-observation-from-pmid-38847460-survo", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1/glucagon + GIP/GLP-1 + triple co-agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "mixed", "magnitude": "Fibrosis >=1-stage improvement vs placebo across published phase-2 MASH biopsy trials: survodutide (GLP-1/glucagon) 34-36% vs 22% (secondary, modest); pemvidutide (GLP-1/glucagon) 33-36% vs 28%, NON-SIGNIFICANT (p=0.59/0.27, 24 wk); tirzepatide (GIP/GLP-1, NO glucagon) 51-55% vs 30% (wide CIs); semaglutide phase-2b (GLP-1-mono) fibrosis NOT significant; ESSENCE (sema ph3) later positive. No head-to-head isolates the glucagon contribution.", "finding": "BALANCED OBSERVATION on the glucagon-anti-fibrosis hypothesis. POLE FOR: the mechanistic rationale (hepatic GCGR action on lipid oxidation/stellate biology) plus survodutide's strong MASH-improvement result and rodent dual>mono liver-fat data. POLE AGAINST: on the FIBROSIS endpoint specifically the human evidence does NOT show glucagon-containing duals out-performing GIP/GLP-1 or GLP-1-mono - pemvidutide (a glucagon dual) MISSED fibrosis at 24 wk, tirzepatide (NO glucagon) posted the numerically highest fibrosis rates, and GLP-1-mono semaglutide showed its own fibrosis signal in ESSENCE. Cross-trial comparison is confounded by fibrosis stage, duration, endpoint definitions and weight loss.", "population": "Cross-agent synthesis of published phase-2 MASH histology trials (survodutide, SYNERGY-NASH, IMPACT, semaglutide ph2b/ESSENCE).", "comparators": "placebo; semaglutide; tirzepatide; survodutide; pemvidutide", "endpointType": "surrogate/biomarker", "notes": "NEUTRAL on science, judgemental on evidence. VERDICT: the evidence is TOO HETEROGENEOUS to conclude that glucagon-containing co-agonists deliver a stronger FIBROSIS-improvement signal than GLP-1-mono. The cleanest test available (pemvidutide's glucagon dual MISSING fibrosis at 24 wk while tirzepatide without glucagon posted the highest fibrosis numbers) actively cuts against a simple glucagon=anti-fibrotic story at the fibrosis endpoint. KEY CONFOUND: all these agents drive large weight loss (itself MASH-improving), so no trial separates a DIRECT hepatic glucagon effect from a weight-mediated one. Glucagon's apparent edge (where it exists) is clearer on liver-FAT/disease-activity than on FIBROSIS. Reta relevance: reta is the most potent triple but has NO MASH histology trial - this pattern must NOT be read as a prediction of observed reta fibrosis outcomes.", "crossRef": "C2-SURVODUTIDE-MASH-01; C2-TIRZEPATIDE-MASH-01; C2-PEMVIDUTIDE-MASH-01; C2-SEMAGLUTIDE-MASH-02; C2-MULTI-MASH-02", "grade": "low", "source": { "citation": "Cross-agent observation from PMID 38847460 (survodutide), 38856224 (tirzepatide), 41237796 (pemvidutide IMPACT), 40305708 (ESSENCE); synthesis, not a single source.", "url": "", "identifiers": "CIT:glucagon-fibrosis-hypothesis-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "analyst cross-agent synthesis (no study funding; not a sponsored output)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-MUSCLE-PRESERVATION-MECH-01", "sourceId": "PMID41178728", "drug": "muscle-preserving co-therapy class (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "activin/myostatin-ActRII blockers + SARMs as adjuncts to GLP-1-class weight loss", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "n/a (narrative review); cited GLP-1RA lean-mass loss ranges ~15% to 40-60% of weight lost across studies.", "finding": "Mechanistic / landscape anchor: incretin weight loss is accompanied by fat-free-mass loss (heterogeneously ~15% to 40-60% of weight lost), motivating adjuncts that preserve or add lean mass. The myostatin/activin-ActRII axis is a negative regulator of muscle growth; blocking it (at the receptor, bimagrumab; at ligands, trevogrumab/anti-GDF8, garetosmab/anti-activin A, apitegromab/anti-latent-myostatin) repartitions loss toward fat and can add lean mass. SARMs (enobosarm) anabolise via androgen-receptor selectivity. Bimagrumab and enobosarm have the most human data; most agents remain early-phase with limited long-term safety.", "population": "Narrative reviews of preclinical + phase-2/3 human studies of lean-mass-preserving pharmacotherapy during GLP-1RA / dual-agonist weight loss.", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "NEW. Mechanism/landscape anchor for the muscle-preservation cluster. Records the open question of how much GLP-1RA lean loss is harmful vs adaptive without adjudicating it. Narrative review (low). SPECIES (Council Species/Translation seat): the myostatin/activin-ActRII 'negative regulator of muscle growth' framing is established PRECLINICALLY (rodent knockout/antibody + livestock genetic data); a HUMAN anabolic/preservation effect is demonstrated only for bimagrumab and enobosarm, with trevogrumab/garetosmab/apitegromab still reading out. No muscle-preservation adjunct has been tested WITH retatrutide.", "crossRef": "C-BIMAGRUMAB-LANDSCAPE-01; C-TREVOGRUMAB-LANDSCAPE-01; C-ENOBOSARM-BODYCOMP-01; C-APITEGROMAB-BODYCOMP-01", "grade": "low", "source": { "citation": "Aimelet V & Holst JJ, Diabetes Obes Metab, 2025", "url": "https://doi.org/10.1111/dom.70229", "identifiers": "PMID41178728", "date": "2025-11-03", "design": "narrative review", "maturity": "review", "funding": "academic (Aimelet & Holst, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; no external funding statement; author COIs disclosed)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-ORF-MAINT-SAFETY-GI13", "sourceId": "PMID42120723", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Qualitative; per-symptom rates not in abstract", "finding": "In a weight-maintenance setting (after injectable tirzepatide or semaglutide), most common AEs with orforglipron were GI, mostly mild-to-moderate.", "population": "ATTAIN-MAINTAIN: 376 adults (205 prior tirzepatide; 171 prior semaglutide); 52 weeks; phase 3b RCT, orforglipron daily vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "PMID confirmed. Maintenance-phase tolerability after switching from injectables.", "crossRef": "C-ORF-SAFETY-GI05", "grade": "high", "source": { "citation": "Aronne LJ et al., Nat Med 2026 (ATTAIN-MAINTAIN)", "url": "https://doi.org/10.1038/s41591-026-04386-7", "identifiers": "PMID:42120723 / DOI:10.1038/s41591-026-04386-7 / NCT06584916", "date": "2026-05-13", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORF-SAFETY-DC16", "sourceId": "DOI10.1056/NEJMOA2511774", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "AE discontinuation ATTAIN-1 (no diabetes): 5.3%/7.9%/10.3% (6/12/36 mg) vs 2.7%. ATTAIN-2 (T2D): 7.3%/10.3%/10.9% vs 4.6%. Nausea up to 36.4%, vomiting up to 23.1%", "finding": "AE-related discontinuation rose with orforglipron dose; GI events the commonest AEs, mostly mild-to-moderate, in escalation.", "population": "ATTAIN-1 (obesity, no diabetes) and ATTAIN-2 (obesity + T2D) phase 3 trials", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ATTAIN-2 numbers via Medscape/HCPLive press pending indexing; ATTAIN-1 NEJM DOI confirmed.", "crossRef": "C-ORF-SAFETY-GI05; C-CAGRISEMA-SAFETY-DC17", "grade": "high", "source": { "citation": "Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2511774", "identifiers": "DOI:10.1056/NEJMoa2511774 (ATTAIN-1); NCT05872464", "date": "2025-09-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORF-SAFETY-GI05", "sourceId": "DOI10.1056/NEJMOA2511774", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "ATTAIN-1: nausea 28.9%/35.9%/33.7% (6/12/36 mg) vs 10.4%; vomiting 13.0%/21.4%/24.0% vs 3.5%; constipation 21.7%/29.8%/25.4% vs 9.3%; diarrhoea 21.0%/22.8%/23.1% vs 9.6%; AE discontinuation 5.3%/7.9%/10.3% vs 2.7%", "finding": "GI AEs most common, mostly mild-to-moderate, concentrated in escalation; per-symptom rates and AE-related discontinuation dose-related.", "population": "ATTAIN-1: adults with obesity (no diabetes); phase 3 RCT, orforglipron 6/12/36 mg vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "Per-symptom rates via Lilly press/secondary reporting; NEJM DOI + NCT confirmed, PMID not confirmed this pass.", "crossRef": "C-ORF-SAFETY-DC16; C-ORF-MAINT-SAFETY-GI13", "grade": "high", "source": { "citation": "Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2511774", "identifiers": "DOI:10.1056/NEJMoa2511774 (ATTAIN-1); NCT05872464", "date": "2025-09-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORF-SAFETY-GI09", "sourceId": "PMID41398455", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Qualitative: GI events dominant, dose-escalation-mitigated", "finding": "Review-channel: safety profile consistent with GLP-1 class, dominated by manageable GI events mitigated by slow escalation; small mild-pancreatitis signal noted (logged as class context).", "population": "ACHIEVE-3 (T2D) and ATTAIN-2 (obesity+T2D) programme; phase 3", "comparators": "oral semaglutide; placebo", "endpointType": "other", "notes": "Per-symptom GI rates not quantified here (see C-ORF-SAFETY-GI05).", "crossRef": "C-ORF-SAFETY-GI05", "grade": "low", "source": { "citation": "Pillai AA et al., Cardiol Rev 2025 (orforglipron review)", "url": "https://doi.org/10.1097/CRD.0000000000001139", "identifiers": "PMID:41398455 / DOI:10.1097/CRD.0000000000001139", "date": "2025-12-16", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORFOR-CARDIO-BP-01", "sourceId": "PMID40481478", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral non-peptide GLP-1RA", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "Significant placebo-adjusted SBP decreases; 12 mg similar to 24/36/45 mg. Exact mmHg not in abstract.", "finding": "Orforglipron produced significant placebo-adjusted BP decreases in phase 2 T2D and obesity; plateau at >=12 mg.", "population": "Phase 2 pooled: T2D N=361 (26 wk) and obesity N=234 (36 wk); orforglipron 3-45 mg vs placebo (+dulaglutide in T2D).", "comparators": "placebo; dulaglutide 1.5 mg (T2D study)", "endpointType": "surrogate/biomarker", "notes": "Exploratory pooled biomarker analysis. PMID/DOI verified.", "crossRef": "C-ORFOR-CARDIO-LIPID-01", "grade": "moderate", "source": { "citation": "Wharton S et al., Cardiovasc Diabetol, 2025;24(1):240", "url": "https://doi.org/10.1186/s12933-025-02781-x", "identifiers": "PMID 40481478; DOI 10.1186/s12933-025-02781-x", "date": "2025-06-06", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORFOR-CARDIO-LIPID-01", "sourceId": "PMID40481478", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral non-peptide GLP-1RA", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Significant placebo-adjusted decreases in LDL-C, TG, ApoB, ApoC3 (and hsCRP); 12 mg similar to 24/36/45 mg. Exact percentages not in abstract.", "finding": "Orforglipron significantly lowered LDL-C, TG, ApoB and ApoC3 versus placebo in phase 2 (plateau at >=12 mg).", "population": "Phase 2 pooled: T2D N=361 (26 wk), obesity N=234 (36 wk); orforglipron 3-45 mg vs placebo (+dulaglutide in T2D).", "comparators": "placebo; dulaglutide 1.5 mg (T2D study)", "endpointType": "surrogate/biomarker", "notes": "Provides ApoB/ApoC-III axis data for an oral GLP-1RA. PMID/DOI verified.", "crossRef": "C-ORFOR-CARDIO-BP-01", "grade": "moderate", "source": { "citation": "Wharton S et al., Cardiovasc Diabetol, 2025;24(1):240", "url": "https://doi.org/10.1186/s12933-025-02781-x", "identifiers": "PMID 40481478; DOI 10.1186/s12933-025-02781-x", "date": "2025-06-06", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORFOR-VS-ORALSEMA-H2H-01", "sourceId": "PMID41765029", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral non-peptide GLP-1 receptor agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "mixed", "magnitude": "ACHIEVE-3 (open-label, n=1698, 52 wk): HbA1c orforglipron 12/36 mg -1.71/-1.91% vs oral semaglutide 7/14 mg -1.23/-1.47%; orfor 36 vs sema 14 ETD -0.44% (95% CI -0.62 to -0.26) p<0.0001 (non-inferior AND superior). GI AEs 58-59% (orfor) vs 37-45% (sema); AE-discontinuation 9-10% vs 4-5%; pulse +3.7-4.7 vs +1.0-1.5 bpm.", "finding": "Head-to-head, the oral non-peptide orforglipron was non-inferior and superior to ORAL semaglutide on HbA1c, but with more GI adverse events, more discontinuations and a larger heart-rate rise.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "comparative", "notes": "OPEN-LABEL design -> graded moderate, not high. The first oral-vs-oral incretin head-to-head; superior efficacy is paired with worse tolerability and a larger pulse increase.", "crossRef": "", "grade": "moderate", "source": { "citation": "Orforglipron versus oral semaglutide head-to-head (ACHIEVE-3), Lancet 2026", "url": "https://doi.org/10.1016/S0140-6736(26)00202-3", "identifiers": "DOI:10.1016/S0140-6736(26)00202-3", "date": "2026-01-01", "design": "open-label RCT", "maturity": "human-primary", "funding": "Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-ORFORGLIPRON-LANDSCAPE-01", "sourceId": "DOI10.1016/S0140-6736(25)02165-8", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "ATTAIN-1: -12.4% (36 mg) vs -0.9% placebo, 72 wk. ATTAIN-2 (T2D): -10.5% weight, HbA1c -1.8%. ACHIEVE-1 (T2D): HbA1c -1.2/-1.5/-1.5%, weight -4.5/-5.8/-7.6%", "finding": "Once-daily oral non-peptide GLP-1RA (LY3502970, Lilly). In ATTAIN-1 phase 3 obesity (no T2D), 36 mg reduced body weight by 12.4% vs 0.9% placebo at 72 weeks. In ATTAIN-2 (obesity + T2D), top dose gave 10.5% weight loss and HbA1c -1.8%. In ACHIEVE-1 (early T2D), HbA1c fell 1.2/1.5/1.5% (3/12/36 mg) vs 0.4% placebo with weight loss 4.5/5.8/7.6% vs 1.7% placebo.", "population": "ATTAIN-1: obesity/overweight + comorbidity, 72 wk, placebo-controlled (3/12/36 mg). ATTAIN-2: obesity + T2D. ACHIEVE-1: T2D on diet/exercise", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "MECHANISM: oral non-peptide (small-molecule) GLP-1R agonist, once daily, no food/water restriction claimed (vs oral peptide semaglutide). Lilly states safety consistent with injectable class; global regulatory submission stage. GI tolerability typical of class.", "crossRef": "", "grade": "high", "source": { "citation": "Eli Lilly press + ATTAIN-1/ATTAIN-2 (NEJM; Lancet 2025), ACHIEVE-1 (NEJM 2025)", "url": "https://clinicaltrials.gov/study/NCT05869903", "identifiers": "NCT05869903 (ATTAIN-1); NCT05971940 (ACHIEVE-1); ATTAIN-2 DOI 10.1016/S0140-6736(25)02165-8", "date": "2025-08-07", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (disclosed in publication)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-PEMVI-CARDIO-LIPID-01", "sourceId": "CIT:altimmune-momentum-phase-2-ada-2024-abstract-262", "drug": "pemvidutide", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "In subjects with elevated baseline lipids, reductions up to 55.8% TG, 20.0% total cholesterol, 21.8% LDL at week 48.", "finding": "Pemvidutide produced large TG and LDL/total-cholesterol reductions in phase 2 MOMENTUM obesity (glucagon-driven lipid effect).", "population": "Phase 2 MOMENTUM; overweight/obesity; pemvidutide 1.2/1.8/2.4 mg vs placebo; 48 weeks.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Conference/press data; no PubMed PMID located - identifier marked unverified. Large TG effect attributed to glucagon co-agonism.", "crossRef": "", "grade": "low", "source": { "citation": "Altimmune MOMENTUM Phase 2 (ADA 2024, abstract 262-OR)", "url": "https://diabetesjournals.org/diabetes/article/73/Supplement_1/262-OR/155168/", "identifiers": "unverified (Diabetes 2024;73(Suppl 1):262-OR; no PMID located)", "date": "2024-06-01", "design": "conference abstract", "maturity": "conference-abstract", "funding": "industry - Altimmune (sponsor of record; disclosed)", "scopeLimits": "conference/abstract-level; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-PEMVIDUTIDE-BODYCOMP-01", "sourceId": "CIT:altimmune-momentum-phase-2-mri-body-composition-", "drug": "pemvidutide", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Body weight -15.6%; 78.1% fat / 21.9% lean of weight lost (n=50 with full MRI body-composition analysis).", "finding": "MOMENTUM phase 2 MRI-based body-composition substudy: pemvidutide reported ~78.1% of weight lost as fat and ~21.9% as lean mass, framed by the sponsor as 'class-leading' lean-mass preservation.", "population": "MOMENTUM 48-week phase 2 obesity trial; MRI body-composition substudy n=50 pemvidutide; presented ADA 2024 / EASD 2024", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Sponsor press / conference channel; 'class-leading' is a company framing, recorded but not adjudicated. 21.9% lean fraction is numerically below the ~25% class benchmark but methods (MRI vs DXA) differ - not directly comparable. Glucagon-arm lean-preservation claim - records the pole.", "crossRef": "C-TIRZEPATIDE-BODYCOMP-01", "grade": "very-low", "source": { "citation": "Altimmune, MOMENTUM phase 2 MRI body-composition substudy, ADA 2024 / EASD 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-presents-data-phase-2-momentum-trial-pemvidutide", "identifiers": "ADA 2024 oral presentation; EASD 2024 (company press)", "date": "2024-06-23", "design": "prespecified/exploratory secondary of RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-PEMVIDUTIDE-MASLD-WL-24W-01", "sourceId": "PMID41113119", "drug": "pemvidutide", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "MASLD phase-2 (24 wk): pemvidutide weight -6.2% (MASLD context).", "finding": "In a 24-week MASLD trial, pemvidutide produced ~6% weight loss as a secondary outcome.", "population": "Peer-reviewed RCT / meta-analysis", "comparators": "", "endpointType": "efficacy", "notes": "MASLD-context weight secondary, not an obesity-primary result. The pemvidutide obesity-primary (MOMENTUM) remains conference/press-only and non-graduating.", "crossRef": "", "grade": "moderate", "source": { "citation": "Pemvidutide in MASLD, 24-week, J Hepatol Rep 2025", "url": "https://doi.org/10.1016/j.jhepr.2025.101483", "identifiers": "DOI:10.1016/j.jhepr.2025.101483", "date": "2025-10-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "Altimmune", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-PETRELINTIDE-LANDSCAPE-01", "sourceId": "CIT:zealand-pharma-phase-1b-topline-globenewswire-ju", "drug": "petrelintide (ZP8396)", "drugRoot": "petrelintide", "drugSlug": "petrelintide", "drugLabel": "Petrelintide", "drugClass": "long-acting amylin analogue (once-weekly s.c.; mono-agonist)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "phase 1b: up to 8.6% at 16 wk vs 1.7% placebo; ZUPREME-1: up to 10.7% at 42 wk vs 1.7% placebo", "finding": "Phase 1b: 6-week MAD gave ~5.3% and 5.1% weight loss at 0.6/1.2 mg weekly; 16-week MAD up to 8.6% mean vs 1.7% placebo, mild GI events. Phase 2b ZUPREME-1 (42 wk, obesity/overweight without T2D) met its primary endpoint with up to 10.7% mean weight loss vs 1.7% placebo and 'placebo-like' GI tolerability.", "population": "phase 1b MAD: healthy/overweight, 6 and 16 wk; ZUPREME-1: adults obesity/overweight without T2D, 42 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: selective long-acting amylin receptor analogue, monotherapy (no GLP-1 component); positioned as GLP-1-comparable weight loss with improved GI tolerability and lean-mass preservation. Partnered with Roche 2025. ZUPREME-2 (T2D) from April 2025; phase 3 planned H2 2026. Also studied in combination with Roche's GLP-1/GIP dual CT-388. Topline via company press/registry, not peer-reviewed.", "crossRef": "C-CT388-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Zealand Pharma phase 1b topline (GlobeNewswire June 2024); ZUPREME-1 phase 2b topline (Zealand/Roche 2025-2026)", "url": "https://www.zealandpharma.com/pipeline/petrelintide/", "identifiers": "ZP8396; ZUPREME-1 (Zealand Pharma trial)", "date": "2024-06-20", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "press", "funding": "industry - Zealand / Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-PRAMLINTIDE-LANDSCAPE-01", "sourceId": "CIT:pramlintide-symlin-approval-and-reviews-drugbank", "drug": "pramlintide (Symlin)", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (synthetic; short-acting, mealtime s.c.; legacy comparator)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight loss up to ~1.6 kg; modest HbA1c reduction", "finding": "Pramlintide, the first approved amylin analogue (US 2005), used as adjunct to insulin in type 1 and insulin-treated type 2 diabetes, produces modest HbA1c reductions and weight loss (reported up to ~1.6 kg). Acts centrally (area postrema) to induce satiety, suppress prandial glucagon, slow gastric emptying and reduce prandial hyperglycaemia.", "population": "adults with type 1 and insulin-treated type 2 diabetes (approved adjunct-to-insulin indication)", "comparators": "placebo/insulin alone", "endpointType": "surrogate/biomarker", "notes": "Mechanism: rat amylin with R18->H18 substitution; amylin/calcitonin receptor agonist. Legacy/first-generation comparator (mealtime dosing, modest weight effect) against which long-acting amylin analogues (cagrilintide, petrelintide) and co-agonists (amycretin, CagriSema) are positioned. Approved US only, not EU.", "crossRef": "C-CAGRILINTIDE-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Pramlintide (Symlin) approval and reviews; DrugBank DB01278; Vascular Health Risk Manag review", "url": "https://go.drugbank.com/drugs/DB01278", "identifiers": "DrugBank DB01278; FDA approval 2005", "date": "2005-03-16", "design": "preclinical (rodent)", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-RESMETIROM-MASH-MAESTRO-CONTEXT", "sourceId": "PMID38324483", "drug": "resmetirom", "drugRoot": "resmetirom (THR-beta, non-incretin benchmark)", "drugSlug": "resmetirom-thr-beta-non-incretin-benchmark", "drugLabel": "Resmetirom (THR-beta, Non-incretin Benchmark)", "drugClass": "thyroid hormone receptor-beta agonist (NON-incretin context benchmark)", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "NASH resolution without worsening fibrosis 29.9% vs placebo 9.7%", "finding": "CONTEXT BENCHMARK (NON-incretin). Resmetirom (Rezdiffra, Madrigal) is the FIRST FDA-approved MASH drug, approved on the MAESTRO-NASH histological co-primaries. Included as the regulatory/efficacy benchmark against which incretin MASH efficacy is read, NOT as a class finding. Like ESSENCE it gained accelerated approval on histological SURROGATES; hard-outcome confirmation has not yet read out. Cross-trial comparison with ESSENCE is informal only (different populations, no head-to-head).", "population": "MAESTRO-NASH (NCT03900429), phase 3, 3 arms (80/100 mg/placebo), n=966 primary-analysis. Biopsy NASH fibrosis F1B/F2/F3; F4/CIRRHOSIS EXCLUDED. 52 wk.", "comparators": "placebo; resmetirom 80 mg; resmetirom 100 mg", "endpointType": "surrogate/biomarker", "notes": "TAGGED AS CONTEXT, not an incretin-class finding. Provides the regulatory benchmark (first approved MASH drug, same accelerated-approval logic; long-term outcomes not yet read out). ESSENCE numerical resolution/fibrosis rates appear higher, but trials differ (population, F-stage, placebo response) and were not compared head-to-head - record side by side, draw no verdict. Reta relevance: resmetirom sets the bar; incretins add weight/cardiometabolic benefit it lacks, but resmetirom is liver-directed and weight-neutral.", "crossRef": "C2-SEMAGLUTIDE-MASH-01; C-INCRETIN-MASH-F4-GAP", "grade": "moderate", "source": { "citation": "Harrison SA, Bedossa P et al. MAESTRO-NASH. N Engl J Med 2024;390:497-509.", "url": "https://doi.org/10.1056/NEJMoa2309000", "identifiers": "PMID38324483", "date": "2024-02-08", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "industry - Madrigal Pharmaceuticals", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-RETA-CARDIO-01", "sourceId": "NCTNCT06383390", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No results. Event-driven Phase 3 CV + kidney outcomes trial; ~10,000 planned participants; estimated primary completion February 2029; status active, not recruiting.", "finding": "The dedicated retatrutide CV outcomes trial (TRIUMPH-Outcomes) is ONGOING; no hard-outcome MACE or CV-death data have been reported. A registry promissory note, NOT evidence: retatrutide currently has ZERO hard cardiovascular outcome data.", "population": "TRIUMPH-Outcomes (NCT06383390): adults age >=45, BMI >=27, with established ASCVD and/or CKD (HbA1c <=10% if T2D); retatrutide s.c. once weekly (escalated dose) vs placebo; double-blind, event-driven; ~5-year study.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS prior row: corrects the prior speculative '~2027+' to the registry's estimated primary completion of February 2029. Primary outcomes verbatim: (1) time to first of non-fatal MI, non-fatal stroke, CV death, or HF hospitalisation/urgent visit; (2) a major-adverse-kidney-event composite. Registry with no results is very-low (a promissory note). Distinct from TRIUMPH-3 (C-RETA-CARDIO-05). FIREWALL (folded from the dropped sourceless framing note, Council disposition): the GLP-1-class hard-MACE benefit (incl. SELECT in non-diabetic obesity) is frequently read as transferable to retatrutide; that transfer is UNTESTED and non-automatic, because reta adds GIP agonism (shown to add no incremental MACE over a GLP-1RA in SURPASS-CVOT) and glucagon agonism (untested, carrying a sustained-HR debit). NET DIRECTION for retatrutide is two-sided and UNKNOWN until this trial reports (~2029). ENDPOINT NOTE: the primary here is a 4-point composite (adds HF hospitalisation/urgent visit) and is NOT directly comparable to the 3-point MACE class anchors.", "crossRef": "C-RETA-CARDIO-02; C-RETA-CARDIO-05", "grade": "very-low", "source": { "citation": "Eli Lilly, TRIUMPH-Outcomes (ongoing)", "url": "https://clinicaltrials.gov/study/NCT06383390", "identifiers": "NCT06383390", "date": "2024-04-23", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-02", "sourceId": "PMID42209267", "drug": "retatrutide (glucagon/GCGR-arm question)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No outcome data; an open mechanistic-to-outcome question carrying no fabricated number.", "finding": "OPEN QUESTION: no outcome trial isolates a glucagon (GCGR) arm, so the net CV-OUTCOME consequence of glucagon agonism is unresolved. The concern, whether glucagon-driven sustained heart-rate elevation or increased cardiac workload could ERODE the CV benefit established for GLP-1 (with the GIP-containing dual agonist shown CV-safe at whole-molecule level via SURPASS-CVOT, GIP not isolated), is recorded as a tension to be settled by retatrutide's outcome programme, not as a quantified finding.", "population": "No isolating trial exists. The only dedicated triple-agonist CVOT is TRIUMPH-Outcomes (NCT06383390), hard endpoints ~2029.", "comparators": "", "endpointType": "hard-outcome", "notes": "OPEN-QUESTION row; no MACE/CV-death/HF number asserted. The HR-rise / cardiac-workload debit lives in the heart-rate-chronotropy domain (OQ-T7-B), not here; this is the cv-outcomes placeholder noting that no hard-outcome evidence yet adjudicates whether that debit erodes net CV benefit. Both poles given EQUAL standing: (a) GLP-1 benefit + whole-molecule GIP safety may carry through, and glucagon agonism's metabolic/weight/hepatic effects could themselves be CV-neutral or net-favourable; (b) the glucagon HR/workload signal is an unquantified outcome risk. The HR signal is NOT assumed to dominate. SPECIES PROVENANCE (Species/Translation seat): the thread-7/thread-12 HR-rise and GIP-knockout-cardioprotective vectors are substantially RODENT-derived and must not be re-imported here as human-outcome evidence.", "crossRef": "C-RETA-CARDIO-01; C-TIRZ-CARDIO-01; OQ-T7-B", "grade": "moderate", "source": { "citation": "Absence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial record returned; review context, De Fano M et al., Diabetes Obes Metab, 2026", "url": "https://doi.org/10.1111/dom.70888", "identifiers": "PMID42209267", "date": "2026-01-01", "design": "phase-2 RCT", "maturity": "review", "funding": "academic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)", "scopeLimits": "animal data; human relevance uncertain; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-03", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No hard CV-outcome data. Phase-2 primary endpoint was percent change in body weight; the dose-dependent heart-rate rise (peaked ~24 weeks, then declined) is a mechanism signal, not an outcome.", "finding": "The retatrutide phase-2 trial produced NO hard CV-outcome data; MACE and CV death were not endpoints. Its heart-rate rise is a CV-mechanism signal held in the heart-rate / CV-mechanism thread, deliberately not counted in the cv-outcomes domain to avoid double-counting.", "population": "Jastreboff AM et al. phase-2 (NCT04881760): N=338 adults with obesity (entry BMI-based: >=30, or 27-30 with a weight-related condition); retatrutide vs placebo, 48 weeks; double-blind RCT.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "No-data NOTE so the cv-outcomes ledger explicitly states reta phase-2 yields no hard CV outcomes. The HR rise belongs to the heart-rate-chronotropy / CV-mechanism domain (thread-7); cross-ref only, not re-scored as an outcome. As a cv-outcomes record it carries no hard-outcome result (the phase-2 is graded higher in its own weight/mechanism domains).", "crossRef": "C-RETA-CARDIO-01; OQ-T7-B", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-05", "sourceId": "NCTNCT05882045", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No CV-outcome data. Primary endpoint: percent change in body weight at Week 80. Enrolment 1,946; estimated primary completion April 2026; status active, not recruiting.", "finding": "CLARIFYING NOTE: TRIUMPH-3 (NCT05882045) enrols adults with severe obesity (BMI >=35) AND established CVD, but its primary endpoint is percent change in body weight, not MACE. It is a weight-loss trial in a CVD population, NOT a CV outcomes trial; the only dedicated reta CV outcomes (MACE) trial is TRIUMPH-Outcomes (NCT06383390).", "population": "TRIUMPH-3: N=1,946; severe obesity (BMI >=35) with established CVD (prior MI, stroke, or symptomatic PAD); retatrutide s.c. once weekly (two doses) vs placebo; Phase 3 double-blind.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "ADDED to disambiguate TRIUMPH-3 (weight-loss primary in a CVD population) from the true CVOT NCT06383390. No other registered reta trial with a hard CV/MACE primary endpoint was found. VALIDATOR: confirm NCT05882045 primary endpoint is body weight, not MACE.", "crossRef": "C-RETA-CARDIO-01", "grade": "very-low", "source": { "citation": "Eli Lilly. TRIUMPH-3: Phase 3 study of LY3437943 once weekly vs placebo in severe obesity and established CVD. ClinicalTrials.gov, 2023.", "url": "https://clinicaltrials.gov/study/NCT05882045", "identifiers": "NCT05882045", "date": "2023-05-30", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-BP-01", "sourceId": "PMID37366315", "drug": "retatrutide (1-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "Approx -2 to -6 mmHg at lower doses up to ~-6 to -10 mmHg at 12 mg at 48 weeks (exploratory; web-sourced).", "finding": "Retatrutide lowered SBP/DBP dose-dependently (exploratory) in phase 2 obesity.", "population": "N=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "BP exploratory secondary; placebo-adjusted CIs not in abstract; magnitude band web-sourced/indicative. PMID/DOI verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-HR-01", "sourceId": "PMID37366315", "drug": "retatrutide (1-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "At 12 mg ~+6 to +7 bpm (web-sourced ~6.7 bpm), peaking ~week 24, declining toward baseline by weeks 36-48. Mild-to-moderate cardiac arrhythmia incidents noted.", "finding": "Retatrutide caused dose-dependent HR increases peaking at 24 weeks then declining; the largest HR signal observed in the class, with a flagged arrhythmia caution.", "population": "N=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Abstract confirms the dose-dependent-peak-at-24wk pattern but NOT the bpm; ~6.7 bpm at 12 mg is web/secondary-sourced. Arrhythmia signal flagged in review PMID 37902090 (DOI 10.1080/13543784.2023.2276754) as needing CVOTs. PMID/DOI of primary verified.", "crossRef": "C-RETA-CARDIO-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-LIPID-01", "sourceId": "PMID37366315", "drug": "retatrutide (1-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "At 12 mg ~40% mean TG reduction and ~22% LDL-C reduction at 48 weeks (web/secondary-sourced; some sources quote ~30% TG). Exploratory.", "finding": "Retatrutide produced strong dose-dependent triglyceride and LDL lowering in phase 2 obesity (glucagon-agonism-enhanced lipid effect).", "population": "N=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "TG/LDL percentages web/secondary-sourced, not in abstract - treat as indicative. Glucagon-receptor agonism proposed as the driver of strong TG-lowering and hepatic-fat effect. PMID/DOI of primary verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-CARDIO-RENAL-01", "sourceId": "PMID40630318", "drug": "retatrutide (0.5-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "mixed", "magnitude": "T2D: 12 mg UACR -37.0% (95% CI -57.3 to -7.0); eGFR unchanged. Obesity: UACR -28.0% (8 mg), -31.5% (12 mg); eGFR-creatinine +5.3 (8 mg), +8.5 mL/min/1.73m2 (12 mg).", "finding": "Pooled post hoc of two phase 2 trials: higher-dose retatrutide reduced UACR in T2D and obesity, and increased eGFR in obesity but not in T2D.", "population": "Pooled post hoc, 2 phase 2 RCTs; T2D n=281 (wk36, dula comparator) and obesity n=338 (wk48); eGFR >=45.", "comparators": "placebo; dulaglutide 1.5 mg (T2D study)", "endpointType": "other", "notes": "Hypothesis-generating; most participants normoalbuminuric, few with eGFR<60. eGFR rise in obesity (not T2D) is an unexplained dissociation. PMID/DOI verified.", "crossRef": "C-RETA-CARDIO-01", "grade": "moderate", "source": { "citation": "Heerspink HJL et al. (retatrutide kidney), Kidney Int Rep, 2025;10:1980-1992", "url": "https://doi.org/10.1016/j.ekir.2025.03.049", "identifiers": "PMID 40630318; DOI 10.1016/j.ekir.2025.03.049", "date": "2025-04-02", "design": "meta-analysis", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "post-hoc (not prespecified); small sample (N~281)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-HR-ATRIA-01", "sourceId": "PMID40464942", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "positive chronotropy via GCGR-cAMP-PKA (mouse atria); no force-of-contraction rise", "finding": "In isolated mouse right atria, retatrutide itself exerted positive chronotropy that was antagonised by the GCGR antagonist adomeglivant, potentiated by rolipram (PDE4 inhibition) and abolished by the PKA inhibitor H89 - but NOT weakened by propranolol; the authors conclude retatrutide excites beating rate via GCGR, signalling through cAMP/PKA.", "population": "isolated mouse right atria (and left atria for force of contraction)", "comparators": "adomeglivant; rolipram; H89; propranolol", "endpointType": "surrogate/biomarker", "notes": "Reta-DIRECT. Within THIS isolated mouse-atrium assay the chronotropy was abolished by the GCGR antagonist adomeglivant and the PKA inhibitor H89, implicating a GCGR->cAMP/PKA route IN THIS PREPARATION; the study did not run a GIPR- or GLP-1R-isolating contrast, so it does not exclude a GIPR or GLP-1R contribution to retatrutide's chronotropy in vivo (WI-1 Council, OQ-WI1-02). RODENT (mouse atrium): species caveat given the human GCGR null (C-GLUCNAT-HR-04); in-vitro isolated tissue, NOT in-vivo human - no human/clinical attribution is drawn from this datum. Folded from T7-024 (per-receptor-verified); compendium independent audit completed 2026-06-24 (species firewall checked - see validation_evidence).", "crossRef": "C-GLUCNAT-HR-04", "grade": "very-low", "source": { "citation": "Neumann J et al., Naunyn Schmiedebergs Arch Pharmacol 2025;398(12):17147-17160", "url": "https://doi.org/10.1007/s00210-025-04335-0", "identifiers": "PMID:40464942 DOI:10.1007/s00210-025-04335-0", "date": "2025-06-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-LIPID-ANGPTL38-01", "sourceId": "PMID40726454", "drug": "retatrutide (1-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "ANGPTL3/8 fell 47.4% (8 mg) and 44.2% (12 mg) in T2D (both p<0.0001; non-significant at 0.5/4 mg); and 30.2% (1 mg), 50.7% (4 mg), 59.9% (8 mg), 63.4% (12 mg) in obesity/overweight (all p<0.0001). Decreases tracked the concurrent TG and LDL-C falls.", "finding": "In post-hoc analyses of two phase-2 retatrutide trials, circulating ANGPTL3/8 complex concentrations fell dose-dependently and these decreases paralleled the retatrutide-induced reductions in triglycerides and LDL-C.", "population": "Post-hoc analysis of two phase-2 retatrutide RCTs: participants with type 2 diabetes and participants with obesity/overweight without diabetes; ANGPTL3/8 measured by dedicated immunoassay from baseline.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Folded from the thread-7 ledger record T7-041 (PMID 40726454). NET-NEW: fills the ANGPTL gap, previously absent from the compendium. Observation only - the human in-vivo lipid/ANGPTL change is combination-only; per-receptor attribution stays open. IN-VITRO MECHANISM (folded in here on WI-4 audit, NOT a standalone graded record): in the SAME paper, in primary HUMAN hepatocytes (HepatoPAC, BioIVT), glucagon and retatrutide (but NOT GIP or GLP-1) decreased ANGPTL3/8 secretion (glucagon to 55.8% of control, no insulin), and the decrease was negated by a GCGR antagonist antibody - an observation BOUNDED to the hepatocyte model implicating GCGR agonism, NOT an in-vivo human verdict. The authors themselves caution 'our hepatocyte experiments lack in vivo validation ... which limits their translatability'. This in-vitro arm was originally carried as a separate finding (C-RETA-LIPID-ANGPTL38-MECH-01) graded 'low' via a downgrade-only robustness_override; the WI-4 audit found that a STANDALONE in-vitro mechanism finding floors to VERY-LOW by the rubric (ingest IN_VITRO_MARKERS -> very-low; README rubric: in-vitro extrapolated to humans -> very-low), and a one-tier-capped override off the moderate human source could only reach 'low' - a one-tier grade inflation. Rather than carry a dishonestly-graded standalone in-vitro record, the mechanism is folded here as a bounded OBSERVATION (the cell-best human post-hoc evidence carries the cell at moderate). COI: all authors are EMPLOYEES AND SHAREHOLDERS of Eli Lilly and Company (disclosed). Cross-ref existing retatrutide TG/LDL record C-RETA-CARDIO-LIPID-01 (not duplicated here - this record adds the ANGPTL3/8 observable, not the TG/LDL magnitudes).", "crossRef": "C-RETA-CARDIO-LIPID-01", "grade": "moderate", "source": { "citation": "Wen Y, Lemen D, ... Konrad RJ, Diabetes Obes Metab 2025;27(10):5985-5995", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12409240/", "identifiers": "PMID:40726454 DOI:10.1111/dom.16661", "date": "2025-07-29", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-LIPID-NONHDL-CRP-01", "sourceId": "PMID38858523", "drug": "retatrutide (1-12 mg)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "fasting triglycerides reduced by >40% at 48 weeks (p<0.001 vs placebo)", "finding": "In the phase-2a MASLD substudy, retatrutide was associated with a significant reduction in fasting triglycerides (and improved insulin-sensitivity markers); the paper additionally cites improvements in non-HDL cholesterol from other retatrutide trials in people with type 2 diabetes or obesity.", "population": "Phase-2a MASLD substudy of the retatrutide obesity phase-2 trial (NCT04881760); N=98 adults with obesity and MASLD (>=10% liver fat); retatrutide 1-12 mg vs placebo; 48 weeks.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Folded from the thread-7 ledger record T7-040 (PMID 38858523). CORRECTED on independent audit (2026-06-24): the original record claimed the MASLD substudy showed reductions in non-HDL cholesterol, triglycerides AND hsCRP plus BP/glycaemia. The source supports only the triglyceride reduction as an in-substudy lipid result; it attributes non-HDL-C improvement to other (T2D/obesity) retatrutide trials, does NOT report hsCRP at all (the measured panel was K-18, pro-C3, adiponectin, leptin - no CRP), and references BP/glycaemia improvements to the main obesity study, not this substudy. Finding/magnitude rewritten accordingly; hsCRP and the substudy-specific BP/glycaemia/non-HDL claims removed. The existing C-RETA-CARDIO-LIPID-01 carries TG/LDL from the parent Jastreboff trial. Observation only; combination-only attribution.", "crossRef": "C-RETA-CARDIO-LIPID-01", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-SAFETY-GI03", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Lower 2 mg start partially mitigated GI AEs vs 4 mg. At 12 mg (secondary reporting): nausea up to ~60%, vomiting ~26%, diarrhoea ~15%, constipation ~16%; nausea ~14% at lowest dose", "finding": "GI AEs most common, dose-related, mostly mild-to-moderate; partially mitigated by a lower 2 mg (vs 4 mg) starting dose. Nausea showed a clear dose gradient.", "population": "Retatrutide phase 2: 338 adults with obesity; 48 weeks; phase 2 RCT", "comparators": "placebo", "endpointType": "other", "notes": "Explicit titration-mitigation finding. Per-symptom ~values from secondary summaries; confirm vs NEJM tables.", "crossRef": "C-CLASS-SAFETY-GI12", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETA-URATE-01", "sourceId": "PMID42135195", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Retatrutide lowered circulating uric acid dose-dependently in the phase-2 metabolite substudy: 24-wk -13.9 / -16.3 / -22.1% and 48-wk -16.6 / -15.9 / -26.5% at 4/8/12 mg (FDR P<.001 vs baseline and placebo); also lowered in the T2D cohort at 8/12 mg.", "finding": "In the JCEM metabolite substudy of the two phase-2 retatrutide trials, retatrutide lowered circulating uric acid dose-dependently versus baseline and placebo, consistent with the weight-mediated class pattern.", "population": "Retatrutide phase-2 obesity + T2D metabolomics substudy (Pearson et al., post hoc of NCT04881760 / NCT05929066).", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "NON-MONOTONIC at 48 wk (the 8 mg arm attenuated vs 4 mg), yet the article describes the effect as 'sustained' - flagged as a wording-vs-data nuance. Biochemical surrogate, post hoc/exploratory metabolomics, confounded with weight loss; Lilly-sponsored, ~10/11 authors Lilly-affiliated. The ONLY retatrutide urate datum in the corpus; primary reta trials report no urate/gout endpoint (see the two absences).", "crossRef": "", "grade": "moderate", "source": { "citation": "Pearson SM et al., J Clin Endocrinol Metab 2026 (metabolomics); PubMed null result 2026 (clamp/tracer)", "url": "https://doi.org/10.1210/clinem/dgag201", "identifiers": "PMID:42135195", "date": "2026-05-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "post-hoc (not prespecified); small sample (N~282)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-APP-01", "sourceId": "PMID40916752", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "Prespecified EXPLORATORY analysis (T2D, n=275, 36 wk; Appetite-VAS + Eating Inventory): retatrutide >=4 mg reduced overall appetite, hunger and prospective food consumption vs placebo (p<0.05); 8/12 mg reduced perceived hunger and disinhibition (tendency to overeat), correlated with weight loss (r~0.28-0.36); differences vs the active comparator dulaglutide were less consistent. The PIVOTAL obesity phase-2 trial (n=338, up to -24% weight) reported NO craving or appetite endpoint at all.", "finding": "Retatrutide's ONLY appetite/eating-behaviour data is a prespecified exploratory analysis in T2D (appetite VAS + Eating Inventory) showing reduced appetite, hunger and disinhibition; it has NO craving-specific instrument, NO neuroimaging, and its pivotal obesity trial measured no craving at all. So retatrutide 'food noise' reduction is INFERRED by class analogy, NOT demonstrated.", "population": "Prespecified exploratory analysis of the retatrutide phase-2 T2D trial (n=275, 36 wk); reta 0.5-12 mg vs placebo and dulaglutide 1.5 mg.", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "The reta 'food noise' gap: the most potent agent has the THINNEST direct craving evidence - exploratory, different population (T2D not obesity), no craving instrument, no fMRI, inconsistent vs an active GLP-1 comparator. Do NOT present reta food-noise reduction as demonstrated. Cross-ref C-CLASS-APP-FOODNOISE-01.", "crossRef": "C-CLASS-APP-FOODNOISE-01", "grade": "moderate", "source": { "citation": "Kanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998", "url": "https://doi.org/10.1111/dom.70063", "identifiers": "PMID:40916752", "date": "2025-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "not multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-APP-REBOUND-01", "sourceId": "CIT:self-reported-side-effects-among-reddit-users-ta", "drug": "retatrutide (on-treatment appetite-rebound folk claim)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "n/a", "magnitude": "The only source is a non-peer-reviewed medRxiv preprint (Penn, 2026.05.28.26352819): of 13,589 Reddit users reporting current (grey-market) retatrutide use, 7,823 had >=1 mapped symptom, and after appetite-SUPPRESSION terms were excluded 'increased appetite' was the single most-reported category - the inverse of the GI-dominated phase-2 trial profile. The reta phase-2 trial (Jastreboff NEJM 2023) reports NO increased-appetite AE at any dose and monotonic dose-dependent weight loss (-24.2% at 12 mg).", "finding": "FOLK-CLAIM VERDICT ('appetite/food noise comes ROARING BACK on retatrutide, on treatment'): UNPROVEN. The self-report SIGNAL is real (a striking, oft-repeated observation), but the causal claim is unsupported: (1) the only source is a non-peer-reviewed Reddit text-mining preprint of an unregulated grey-market population (selection/recall/dosing-error/contamination bias); (2) no controlled trial shows paradoxical on-treatment increased appetite; (3) the proposed 'glucagon' mechanism is BACKWARDS - glucagon-receptor agonism SUPPRESSES appetite. Plausibly explained by inconsistent grey-market dosing, normal physiological hunger as the body nears a new set-point, or reporting artefact. NOTE: distinct from the REAL post-discontinuation appetite rebound (D4).", "population": "Non-peer-reviewed medRxiv Reddit text-mining preprint (grey-market reta users); contrasted with the reta phase-2 trial AE profile.", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "GRADE very-low, NON-GRADUATING (preprint, self-report, grey-market population). Belief-vs-reality: a genuine, intriguing self-report signal that is currently UNPROVEN as a pharmacological effect and whose proposed glucagon mechanism contradicts glucagon's known anorexigenic action. Log as a flagged low-tier pharmacovigilance hypothesis pending peer review/trial confirmation. Distinguish on-treatment hunger-return (this, unproven) from post-discontinuation rebound (real, C-CLASS-MAINT-01/02 + the regain rows). Cross-ref the food-noise verdict.", "crossRef": "C-CLASS-APP-FOODNOISE-01; C-RETATRUTIDE-APP-01", "grade": "very-low", "source": { "citation": "Self-Reported Side Effects Among Reddit Users Taking Unapproved Retatrutide. medRxiv 2026.05.28.26352819 (PREPRINT, non-peer-reviewed, NOT PubMed-indexed; non-standard DOI prefix 10.64898). Contrast: Jastreboff AM et al., NEJM 2023, PMID 37366315 (no increased-appetite AE).", "url": "https://www.medrxiv.org/content/10.64898/2026.05.28.26352819v1", "identifiers": "CIT:reta-appetite-rebound-medrxiv-preprint-2026", "date": "2026-06-03", "design": "pharmacovigilance / disproportionality", "maturity": "preprint", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-BODYCOMP-01", "sourceId": "PMID40609566", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "total fat mass -23.2% (DXA, week 36)", "finding": "Retatrutide phase-2 T2D DXA substudy: fat mass fell dose-dependently; the lean-mass conclusion is a SECONDARY, proportional-only claim ('proportion of lean-mass loss similar to other obesity treatments'), read by the sponsor as reassurance. CRITICAL: no ABSOLUTE lean-kg is reported, and proportional parity at a larger total loss is fully compatible with the LARGEST absolute lean-kg loss of any agent. Completer-only, T2D, fat-primary endpoint.", "population": "Substudy of the retatrutide phase-2 T2D RCT (NCT04867785), double-blind placebo- and dulaglutide-controlled; 189 enrolled to substudy, 103 with paired baseline+week-36 DXA (completer-only); DXA at week 36.", "comparators": "placebo; dulaglutide", "endpointType": "imaging/physiological surrogate", "notes": "DEEPENED (D2): foregrounds the decision-relevant gap - no absolute reta lean-kg anywhere, and the favourable lean conclusion is the sponsor's secondary proportional reassurance, NOT a powered equivalence result (thread-5 C9, OQ-T5-C). PMID DISAMBIGUATION (independent validation): the canonical reta Coskun substudy is PMID 40609566 (DOI 10.1016/S2213-8587(25)00092-0). A prior corpus note had carried PMID 40318682 for this paper - that is WRONG: 40318682 is a DIFFERENT paper (Sattar et al., SURPASS-3 MRI tirzepatide muscle composition, DOI 10.1016/S2213-8587(25)00027-0), NOT a duplicate. ATTRIBUTION (Council Methodologist): this is a WHOLE-DRUG DXA readout; it neither isolates nor implicates the GCGR arm - the GCGR-causes-net-lean-loss hypothesis is unresolved (thread-5) and cannot be inferred from a triple-agonist composite. Read WITH C-RETATRUTIDE-BODYCOMP-03 (the double absence), never alone. Cross-ref T5-001.", "crossRef": "C-RETATRUTIDE-BODYCOMP-03; T5-001", "grade": "moderate", "source": { "citation": "Coskun T et al. (Eli Lilly), Lancet Diabetes Endocrinol, 2025", "url": "https://doi.org/10.1016/S2213-8587(25)00092-0", "identifiers": "PMID40609566", "date": "2025-07-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-BODYCOMP-02", "sourceId": "DOI10.1038/S41591-024-03018-2", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Hepatic fat (MRI-PDFF) substantial reduction (liver-fat figures in hepatic-MASH domain); body-weight reduction up to 16.9% at 36 weeks in parent phase 2.", "finding": "Phase 2a MASLD substudy used MRI-PDFF to quantify hepatic fat alongside body-composition assessment; retatrutide markedly reduced liver fat content (ectopic-fat depot adjacent to body-composition remit).", "population": "Pre-specified substudy of phase 2 obesity trial, participants with MASLD; MRI-PDFF", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Ectopic/liver-fat depot; primary numbers belong in hepatic-mash domain but logged here as adjacent body-composition imaging. Cross-ref hepatic-mash records.", "crossRef": "C-RETATRUTIDE-BODYCOMP-01", "grade": "moderate", "source": { "citation": "Sanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMC11271400; DOI 10.1038/s41591-024-03018-2", "date": 2024, "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (disclosed; retatrutide MASLD substudy)", "scopeLimits": "small sample (N~98)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-BODYCOMP-03", "sourceId": "PMID38843460", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "n/a - not measured. Obesity phase-2 (PMID 37366315) reported body weight only (LSM up to -24.2% at 12 mg, 48 wk), NO DXA. T2D DXA substudy (PMID 40609566) reported fat-mass % only, NO absolute lean-kg and NO function. Zero retatrutide grip-strength / gait-speed / SPPB / 6MWD data.", "finding": "RETATRUTIDE GAP (double absence): (1) the phase-2 OBESITY trial reported NO DXA/body-composition, so there is NO obesity-population reta lean-mass data at the 12 mg dose; the only reta DXA is the lower-weight-loss T2D substudy. (2) NO physical-function or muscle-strength data exist for retatrutide at all. CONSEQUENCE (Council Red-team): because retatrutide loses the MOST total weight of any agent (~24%) at an apparently constant ~75/25 fat:lean split, the arithmetic implies the LARGEST absolute lean-kg loss of any agent (thread-5 OQ-T5-C), yet it is unmeasured; and reta UNIQUELY adds a glucagon (GCGR) arm whose catabolic amino-acid/ureagenesis axis (thread-5) is a mechanistic reason its absolute lean loss could EXCEED dual/mono agents. Reta is therefore plausibly highest-absolute-lean-loss AND least-evidenced, NOT neutral-because-silent. Whether reta's lean-mass loss is harmful (true sarcopenia) or adaptive is UNTESTED for both obesity-magnitude mass and muscle function.", "population": "Retatrutide programme to date: phase-2 obesity (Jastreboff, NEJM 2023, PMID 37366315, weight only) and phase-2 T2D DXA substudy (Coskun, Lancet D&E 2025, PMID 40609566, fat-mass primary); no function endpoint in any reported reta trial.", "comparators": "placebo; dulaglutide", "endpointType": "symptom/PRO", "notes": "Explicit reta gap (the absence is the finding); anchored to the Drucker safety review (a real source naming the gap) rather than left sourceless. Mirrors thread-5 OQ-T5-B (T2D reassurance transported onto obesity loss), OQ-T5-C (absolute lean-kg unquantified) and gap #4 (MRI muscle volume + grip/strength absent). The proportional reassurance in C-RETATRUTIDE-BODYCOMP-01 is DXA mass, not function. Cross-ref C9.", "crossRef": "C-RETATRUTIDE-BODYCOMP-01; C-RETATRUTIDE-BODYCOMP-02; C-CLASS-BODYCOMP-08; T5-001", "grade": "moderate", "source": { "citation": "Gap row derived from absence across the retatrutide phase-2 reports (PMID 37366315 weight-only; PMID 40609566 fat-primary DXA) and class safety reviews (Drucker, Diabetes Care 2024, PMID 38843460, naming reta as an under-characterised muscle-strength domain)", "url": "https://doi.org/10.2337/dci24-0003", "identifiers": "PMID38843460", "date": "2026-06-21", "design": "prespecified/exploratory secondary of RCT", "maturity": "review", "funding": "academic - Canadian Institutes for Health Research (CIHR grant 154321), Drucker review", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-BONE-ABSENCE-MASLD-01", "sourceId": "PMID38858523", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "ABSENCE: the retatrutide phase-2a MASLD trial reported NO DXA/BMD, bone-turnover or fracture endpoint.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial (Sanyal 2024) did not report any DXA/BMD, bone-turnover or fracture endpoint.", "population": "Retatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide bone effect can be asserted OR excluded. Reinforces the documented retatrutide bone-outcome void; cross-refs the obesity-trial absence.", "crossRef": "C-RETATRUTIDE-BONE-ABSENCE-OBESITY-01", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-BONE-ABSENCE-OBESITY-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "ABSENCE: the retatrutide phase-2 obesity trial reported NO DXA/BMD, bone-turnover-marker or fracture endpoint; adverse events were gastrointestinal plus a dose-dependent heart-rate increase only.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial (Jastreboff 2023) did not report any DXA/BMD, bone-turnover or fracture endpoint - no retatrutide bone effect can be asserted or excluded; all retatrutide bone inference is indirect class-extrapolation.", "population": "Retatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present in the trial report.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide bone effect can be asserted OR excluded. All retatrutide bone inference is indirect class-extrapolation. Mirrors the reta iron absence on the same source.", "crossRef": "C-RETATRUTIDE-BONE-ABSENCE-MASLD-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-CNS-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "n/a", "magnitude": "No dedicated CNS / psychiatric / addiction / cognition endpoint reported. Phase-2 safety was GI-dominant + dose-dependent heart-rate rise; no PHQ-9 / C-SSRS / addiction / cognition result published for retatrutide.", "finding": "RETATRUTIDE GAP: retatrutide has essentially NO dedicated CNS, addiction, cognition or psychiatric data beyond routine adverse-event capture in its two phase-2 trials. The absence is the finding. Any class CNS effect attributed to retatrutide is a class-transfer expectation, not a reta result - and reta's GLUCAGON arm (central glucagon/energy-balance/mood circuitry) is a CNS-relevant differentiator that is entirely unstudied, so even the class transfer may not capture it. Central glucagon circuitry intersects mood/satiety/stress pathways and could move neuropsychiatric outcomes in EITHER direction - the sign is UNKNOWN, not presumed benign. Routine adverse-event capture in the phase-2 trials is NOT a psychiatric-safety clearance for retatrutide, only an absence of dedicated data.", "population": "Reta phase-2 obesity (Jastreboff, NCT04881760, N=338) + T2D (Rosenstock, NCT04867785, N=281); psychiatric AEs captured only as routine treatment-emergent events, not instrumented.", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "symptom/PRO", "notes": "NEUTRAL gap. The phase-2 trials are robust but carry NO dedicated neuropsychiatric data, so for THIS domain the row is a gap (UNKNOWN, not negative). No reta suicidality/addiction/cognition signal has been reported, but equally none has been looked for. The glucagon-arm CNS axis is unstudied - flag. VALIDATOR: confirm PMID 37366315/37385280 report no dedicated CNS endpoint.", "crossRef": "C-CLASS-CNS-05; C-CLASS-CNS-04", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-EE-01", "sourceId": "DOI10.1056/NEJMOA2301972", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "n/a", "magnitude": "Energy expenditure was NOT measured in the cited human phase-2 trial; a glucagon-mediated EE increase is a PROPOSED preclinical mechanism only (preclinical evidence mixed).", "finding": "Glucagon-mediated increased energy expenditure is PROPOSED for retatrutide (mechanistic/preclinical reviews); not measured in the cited human phase-2 trial.", "population": "Preclinical (rodent) models with calorie-intake-matched controls; reported via reviews/secondary sources", "comparators": "calorie-intake-matched control", "endpointType": "imaging/physiological surrogate", "notes": "IMPORTANT GAP: I could not locate a dedicated human calorimetry / whole-room EE trial for retatrutide. The 'increased energy expenditure' claim is preclinical and glucagon-mechanism-theoretical, surfaced via reviews and secondary descriptions, not from human indirect calorimetry. Distinct from the GLP-1/GIP duals because the glucagon arm is hypothesised to raise EE - this is the OPEN question the cartography flags, not a verdict. Confirm primary preclinical source before treating as human-primary.", "crossRef": "C-GLP1CLASS-EE-01", "grade": "very-low", "source": { "citation": "Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389:514-526 (and preclinical/mechanistic descriptions)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2301972", "identifiers": "DOI 10.1056/NEJMoa2301972", "date": "2023-06-26", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-EE-RUNSHOT-01", "sourceId": "PMID26434748", "drug": "retatrutide ('runs hot' folk claim)", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Glucagon is a genuine human thermogenic hormone: acute glucagon infusion raises resting energy expenditure by ~15% (a ~200 kcal/day equivalent - the paper states the percentage, the kcal is a derivation), BAT-independently and without raising circulating noradrenaline (Salem 2016). Retatrutide is the only late-stage obesity agent activating the glucagon receptor at therapeutic doses. BUT body temperature/sweating was NOT a measured endpoint in the reta phase-2 trials, and neither flags hyperhidrosis/'feeling hot' as a prominent AE.", "finding": "FOLK-CLAIM VERDICT ('retatrutide runs hot / sweating / feels hot, via glucagon'): MIXED - the MECHANISM is real and plausibly reta-distinct (glucagon thermogenesis is textbook human physiology, and reta is the only glucagon-arm agent in late development), but the reta-DIRECT evidence is thin-to-absent (no controlled thermometry/sweating measurement; not a prominent named AE in phase-2). So the 'runs hot' symptom is INFERRED from the mechanism, not demonstrated in patients.", "population": "Human glucagon-infusion thermogenesis study (Salem 2016) for the mechanism; reta phase-2 obesity/T2D trials (no temperature endpoint) for the direct-data gap.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "GRADE: mechanism moderate (human infusion study); reta-direct symptom UNPROVEN (not measured). Belief-vs-reality: this folk attribution is mechanistically MORE credible than most, but the leap to 'reta raises body temperature in patients' is inferred, not shown - do not state as a documented clinical effect. Links the glucagon-thermogenesis mechanism (energy-expenditure threads) to the lay claim. Cross-ref C-RETATRUTIDE-SAFETY-DYSESTHESIA-01 (the other reta-distinct sensory/autonomic signal).", "crossRef": "C-RETATRUTIDE-SAFETY-DYSESTHESIA-01", "grade": "moderate", "source": { "citation": "Salem V et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab 2016 (PMID 26434748). Reta phase-2: Jastreboff NEJM 2023 (PMID 37366315), Rosenstock Lancet 2023 (PMID 37385280) - no temperature endpoint.", "url": "https://doi.org/10.1111/dom.12585", "identifiers": "PMID26434748", "date": "2016-09-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic-MRC/BBSRC/NIHR/Wellcome Trust", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-GOUT-ABSENCE-MASLD-01", "sourceId": "PMID38858523", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ABSENCE: the retatrutide phase-2a MASLD trial reported NO uric-acid or gout endpoint.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial (Sanyal 2024) did not report any uric-acid or gout endpoint.", "population": "Retatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for any uric-acid/gout endpoint - none present.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide gout-OUTCOME effect can be asserted OR excluded. Reinforces the documented retatrutide gout-outcome void; cross-refs the obesity-trial absence.", "crossRef": "C-RETATRUTIDE-GOUT-ABSENCE-OBESITY-01", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-GOUT-ABSENCE-OBESITY-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ABSENCE: the retatrutide phase-2 obesity trial reported NO uric-acid or gout endpoint; urate data exist only in the separate JCEM metabolite substudy.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial (Jastreboff 2023) did not report any uric-acid or gout endpoint; the only retatrutide urate data come from the separate JCEM metabolite substudy.", "population": "Retatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any uric-acid/gout endpoint - none present in the trial report.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide gout-OUTCOME effect can be asserted OR excluded from this trial. Clinical gout-outcome data for retatrutide are a complete void; the substudy urate datum (C-RETA-URATE-01) is biochemical only.", "crossRef": "C-RETATRUTIDE-GOUT-ABSENCE-MASLD-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-IRON-ABSENCE-MASLD-01", "sourceId": "PMID38858523", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ABSENCE: the phase-2a MASLD trial reported NO iron/ferritin/hepcidin/anaemia/haemoglobin endpoint; biomarker panel was ALT/AST/FIB-4/K-18/ELF/pro-C3; no iron variable anywhere including the AE table.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial did not report any iron, ferritin, hepcidin, anaemia or haemoglobin endpoint; its biomarker panel was ALT/AST/FIB-4/K-18/ELF/pro-C3 and no iron variable appears anywhere, including the adverse-event table.", "population": "Retatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for iron/ferritin/hepcidin/anaemia/haemoglobin reporting - none present.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "This is an ABSENCE (not measured, not a measured-null): no retatrutide iron effect can be asserted OR excluded from this trial. All retatrutide iron inference is indirect class-extrapolation.", "crossRef": "", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-IRON-ABSENCE-OBESITY-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ABSENCE: the phase-2 obesity trial reported NO iron/ferritin/hepcidin/anaemia endpoint; adverse events were gastrointestinal plus a dose-dependent heart-rate increase only.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial did not report any iron, ferritin, hepcidin or anaemia endpoint; its adverse events were gastrointestinal plus a dose-dependent heart-rate increase only, with no iron variable reported.", "population": "Retatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for iron/ferritin/hepcidin/anaemia reporting - none present.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide iron effect can be asserted OR excluded. All retatrutide iron inference is indirect class-extrapolation.", "crossRef": "C-RETATRUTIDE-IRON-ABSENCE-MASLD-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-LANDSCAPE-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "LS mean weight change at 48 weeks -24.2% vs placebo -2.1%", "finding": "Triple GIP/GLP-1/glucagon agonist (LY3437943, Eli Lilly). In phase 2 obesity, once-weekly s.c. retatrutide produced large dose-dependent weight loss; phase 3 TRIUMPH subsequently reported weight loss up to ~29% at 68 weeks. Balanced agonist at GIPR, GLP-1R and GCGR, the glucagon arm proposed to add an energy-expenditure component atop incretin-driven appetite suppression.", "population": "Phase 2 NCT04881760: N=338 adults, BMI >=30 or 27-<30 with weight-related condition, 48 wk, placebo-controlled. TRIUMPH-4 NCT05931367: phase 3, 68 wk, obesity + knee OA. TRIUMPH-1: phase 3, 80 wk, obesity/overweight.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: triple GIP/GLP-1/GCGR agonist; the only triple agonist in phase 3 as of mid-2026. Phase 2 obesity is the journal anchor; phase 3 TRIUMPH-1/-4 are press-tagged. TRIUMPH is an 8-trial registrational programme (obesity, T2D, OSA, MASLD/MASH, knee OA, CV outcomes). Dose-dependent heart-rate increases peaked at 24 weeks then declined.", "crossRef": "C-RETATRUTIDE-LANDSCAPE-02; C-RETATRUTIDE-LANDSCAPE-03", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-LANDSCAPE-02", "sourceId": "DOI10.1016/S0140-6736(23)01053-X", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Phase 2 (T2D): HbA1c reduction up to ~2.0-2.2 percentage points; body weight reduction ~16.9% at 12 mg at 36 weeks. HbA1c greater than placebo at all but 0.5 mg, and greater than dulaglutide 1.5 mg at the 8 mg slow-escalation and 12 mg doses.", "finding": "In a phase 2 trial in adults with type 2 diabetes, retatrutide reduced HbA1c and body weight versus both placebo and active comparator dulaglutide 1.5 mg.", "population": "Phase 2 NCT04867785: adults with T2D, USA, randomised double-blind, placebo- and dulaglutide-1.5mg-controlled, 36 wk (24-wk primary).", "comparators": "placebo; dulaglutide", "endpointType": "surrogate/biomarker", "notes": "Notable as a rare obesity-class agent showing strong glycaemic efficacy despite a glucagon-receptor arm (glucagon agonism would naively raise glucose); net effect is HbA1c lowering, attributed to dominant GLP-1/GIP action plus weight loss. Active dulaglutide comparator = within-class head-to-head.", "crossRef": "C-RETATRUTIDE-LANDSCAPE-01", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 (retatrutide phase 2 in T2D)", "url": "https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01053-X/abstract", "identifiers": "DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (disclosed in publication)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-LANDSCAPE-03", "sourceId": "DOI10.1038/S41591-024-03018-2", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple receptor agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Liver fat (relative change) at 48 weeks: -81.7% (8 mg), -86.0% (12 mg) vs -4.6% placebo. Normal liver fat (<5%) in ~89% (8 mg) and ~93% (12 mg).", "finding": "In a phase 2a MASLD substudy, retatrutide produced very large reductions in liver fat with a high proportion of participants reaching normal liver-fat content.", "population": "N=98 adults with obesity and elevated liver fat (MASLD), substudy of phase 2 obesity trial NCT04881760, retatrutide 1/4/8/12 mg vs placebo, 48 wk.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Glucagon arm is the proposed driver of the outsized hepatic-fat effect (increases hepatic lipid oxidation). Reported as among the largest liver-fat reductions seen for any agent in development. Open full text via PMC.", "crossRef": "C-RETATRUTIDE-LANDSCAPE-01", "grade": "moderate", "source": { "citation": "Sanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMC11271400; DOI 10.1038/s41591-024-03018-2", "date": 2024, "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (disclosed; retatrutide MASLD substudy)", "scopeLimits": "small sample (N~98)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-MAINT-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "n/a", "magnitude": "No off-treatment data. On-treatment 48-wk loss: -24.2% (12 mg), -22.8% (8 mg) vs -2.1% placebo, with the weight curve NOT plateaued at week 48.", "finding": "RETATRUTIDE GAP: no maintenance, withdrawal/regain or intermittent-dosing data specific to retatrutide exist. The phase-2 obesity trial reported continuous on-treatment loss to 48 weeks (up to -24.2%) with weight still declining at trial end, but contained NO withdrawal or off-treatment arm. Reta's regain kinetics are UNKNOWN and must be inferred from the GLP-1/GIP class - a CLASS-TRANSFER expectation (reta would be expected to regain like the class), NOT a reta result. The steep, non-plateauing curve concerns the CEILING of loss, NOT regain kinetics; the proportion and absolute magnitude of any reta regain are UNQUANTIFIED and untested. Reta's glucagon arm (an energy-expenditure component absent from the GLP-1/GIP class) makes the class-transfer NON-AUTOMATIC in mechanism as well as magnitude - its off-treatment behaviour cannot be assumed to track a pure incretin in either direction. If regain is disproportionately fat (the C-CLASS-MAINT-04 gap), the agent that loses the most is the one whose loss-regain cycle could most degrade the lean:fat ratio (cross-ref D2) - the highest-stakes, untested instance of that gap.", "population": "Reta phase-2 obesity (Jastreboff, NEJM 2023, NCT04881760): N=338; 48 weeks on-treatment; no withdrawal arm.", "comparators": "placebo", "endpointType": "other", "notes": "RETATRUTIDE-SPECIFIC GAP (class-transfer expectation folded in, clearly tagged NOT a reta result). The programme's core drug has NO regain/maintenance evidence of its own; maintenance/regain behaviour is currently borrowed from sema/tirz withdrawal trials. Robustness rates the trial; for THIS domain the row carries no reta evidence. Awaits TRIUMPH-6. VALIDATOR: confirm PMID 37366315 has no off-treatment arm.", "crossRef": "C-RETATRUTIDE-MAINT-02; C-SEMAGLUTIDE-MAINT-01; C-TIRZEPATIDE-MAINT-01; C-CLASS-MAINT-04", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-MAINT-02", "sourceId": "NCTNCT06859268", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "n/a", "magnitude": "No results. Re-randomisation maintenance design: ~80-week open lead-in on retatrutide, then re-randomise to continue dose 1 / escalate to dose 2 / switch to placebo for 36 weeks. Enrolment ~643; primary endpoint percent change in body weight; status active, not recruiting; estimated primary completion April 2028.", "finding": "REGISTRY (no results): TRIUMPH-6 (NCT06859268) is the registered phase-3b retatrutide weight-MAINTENANCE trial with a continued-vs-withdrawal (re-randomisation) design - the first reta trial designed to measure maintenance vs withdrawal of weight reduction, i.e. the trial whose future readout would fill the reta regain gap.", "population": "TRIUMPH-6 (NCT06859268): adults with obesity and a history of unsuccessful dietary weight loss, without diabetes; retatrutide lead-in then re-randomise (continue dose 1 / escalate dose 2 / placebo); phase-3b double-blind.", "comparators": "placebo; retatrutide (continued); retatrutide (escalated)", "endpointType": "other", "notes": "Registered per the D4 remit; confirmed on clinicaltrials.gov as the reta maintenance / continued-vs-withdrawal trial, primary completion April 2028. Promissory note (very-low). VALIDATOR: confirm NCT06859268 design + completion date.", "crossRef": "C-RETATRUTIDE-MAINT-01", "grade": "very-low", "source": { "citation": "Eli Lilly. TRIUMPH-6: maintenance of weight reduction with retatrutide. ClinicalTrials.gov, confirmed 2026-06-21.", "url": "https://clinicaltrials.gov/study/NCT06859268", "identifiers": "NCT06859268", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-MASH-TRIAL-GAP", "sourceId": "CIT:no-dedicated-reta-mash-histology-trial-located-i", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "n/a", "magnitude": "No dedicated retatrutide MASH histology trial identified (registered or published).", "finding": "REGISTRATIONAL GAP: no dedicated retatrutide MASH / MASH-with-fibrosis phase-2b or phase-3 histology trial could be identified. PubMed returns no reta histological MASH/steatohepatitis trial, and the reta phase-3 (TRIUMPH) programme targets obesity, T2D, knee osteoarthritis and cardiovascular outcomes - not a biopsy MASH-resolution/fibrosis endpoint. Unlike semaglutide (ESSENCE), tirzepatide (SYNERGY-NASH), survodutide and pemvidutide (IMPACT), reta has no liver-histology registrational trial. Stated as a GAP, not finessed.", "population": "n/a - registry/landscape gap statement.", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Per Thread 8, reta-direct histological confirmation of MASH/fibrosis benefit is pending (estimated ~2032). Until a dedicated biopsy-endpoint trial reports, reta's hepatic position is liver-FAT (imaging surrogate) ONLY. This row makes the absence explicit and auditable; identifier is a synthesis marker, never a fabricated NCT. If a reta MASH NCT is later confirmed, register it as a separate registry/no-results row.", "crossRef": "C2-RETATRUTIDE-MASH-01; C-CLASS-MASH-SURROGATE-GAP", "grade": "very-low", "source": { "citation": "No dedicated reta MASH-histology trial located in PubMed or via trial-registry knowledge as of 2026-06; reta phase-3 TRIUMPH is obesity/T2D/OA/CV oriented. Identifier null because the item is a NEGATIVE.", "url": "", "identifiers": "CIT:retatrutide-mash-trial-gap-2026", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "n/a - absence-of-evidence landscape note (no study, no sponsor)", "scopeLimits": "no outcome data yet (ongoing); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-MICROBIOME-ABSENCE-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "EXPLICIT ABSENCE: no retatrutide gut-microbiome datum (human or animal) exists. Reviewed the retatrutide evidence base - no microbiome study (compositional, FMT, or mechanistic) of any kind has been reported; all verified microbiome evidence is liraglutide / semaglutide / exenatide / dulaglutide. Not measured -> can be neither asserted NOR excluded. Do NOT impute from retatrutide's obesity/MASLD data.", "finding": "EXPLICIT ABSENCE: there is no retatrutide gut-microbiome data of any kind - human or animal. Unlike liraglutide and semaglutide (rodent + small human compositional studies), retatrutide's microbiome effects are a complete void, not a measured-null, and cannot be inferred from its weight-loss data.", "population": "Retatrutide evidence base reviewed for any gut-microbiome indication (pinned to the phase-2 obesity trial, Jastreboff et al., NCT04881760, as the reviewed-for-indication anchor) - none present.", "comparators": "placebo", "endpointType": "measured-null", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide microbiome effect can be asserted OR excluded. Complete void despite retatrutide producing the largest weight loss (highest a-priori interest). Routed to OQ-MICROBIOME-B. Do NOT impute from obesity/MASLD data.", "crossRef": "C-CLASS-MICROBIOME-NOCAUSE-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-MICRONUTRIENT-ABSENCE-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ABSENCE: the retatrutide phase-2 obesity trial reported NO vitamin-D, B12, folate, magnesium or calcium (non-iron micronutrient) endpoint; adverse events were gastrointestinal plus a dose-dependent heart-rate increase only.", "finding": "EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial did not report any non-iron micronutrient (vitamin D/B12/folate/magnesium/calcium) endpoint - no retatrutide micronutrient effect can be asserted or excluded.", "population": "Retatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any non-iron micronutrient (vitamin D/B12/folate/Mg/Ca) endpoint - none present.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide micronutrient effect can be asserted OR excluded. Complements the reta iron absence on the same source; all reta micronutrient inference is indirect class-extrapolation.", "crossRef": "C-RETATRUTIDE-IRON-ABSENCE-OBESITY-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-NULL-0.5MG-01", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon tri-agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "no-change", "magnitude": "Phase-2 T2D: retatrutide 0.5 mg HbA1c -0.43% (SE 0.20) vs placebo -0.01% (NS); weight -3.19% vs placebo -3.00% (NS) - the only dose not separating from placebo (all >=4 mg arms p<0.0001).", "finding": "In the phase-2 T2D dose-ranging trial, retatrutide's lowest (0.5 mg) dose produced a measured null - no significant HbA1c or weight separation from placebo - defining the bottom of the dose-response.", "population": "Peer-reviewed RCT (measured null)", "comparators": "placebo", "endpointType": "measured-null", "notes": "The ONLY true retatrutide measured null in the corpus: a sub-therapeutic dose-floor effect, NOT 'retatrutide does not work'.", "crossRef": "", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-OSA-01", "sourceId": "NCTNCT05929066", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "No results yet. Designated PRIMARY OSA endpoint: change from baseline in AHI (events/hr) in the nested moderate-to-severe OSA subset (AHI >=15 on polysomnography at screening). TRIUMPH-1 (NCT05929066, without T2D, N~2335, primary completion ~Apr 2026); TRIUMPH-2 (NCT05929079, with T2D, N~1000, ~May 2026). OSA-cohort sub-N not separately disclosed in the registry.", "finding": "Retatrutide DOES have dedicated, registrational OSA endpoints: the TRIUMPH phase-3 programme nests moderate-to-severe OSA cohorts with change in AHI as a designated primary endpoint (TRIUMPH-1 and TRIUMPH-2), framed registrationally by the published TRIUMPH design paper. STATUS: trials active/completed-recruitment, AHI readout pending (~2026). This is a registry/no-results promissory note, NOT a gap - and reta has NO published AHI/OSA outcome data, so nothing here implies an observed reduction.", "population": "TRIUMPH-1 (NCT05929066): adults without T2D, obesity/overweight, OSA subset AHI >=15 on PSG, N~2335, phase-3 double-blind placebo-controlled, weekly s.c. retatrutide vs placebo. TRIUMPH-2 (NCT05929079): adults with T2D, OSA subset, N~1000.", "comparators": "placebo", "endpointType": "other", "notes": "NON-GRADUATING promissory note (very-low). PREMISE CORRECTION (load-bearing): reta is NOT absent from the OSA path - it has a designated registrational AHI primary endpoint in two TRIUMPH trials. What must NOT be overstated: reta has NO published AHI/OSA outcome data; nothing implies an observed AHI reduction. Companion to the existing TRIUMPH-2 glycaemic registry row C2-RETATRUTIDE-GLY-05. VALIDATOR: confirm NCT05929066/05929079 list OSA + AHI-as-primary, and PMID 41090431 frames TRIUMPH as registrational for OSA.", "crossRef": "C2-RETATRUTIDE-GLY-05; C-RETATRUTIDE-OSA-02; C-CLASS-OSA-LANDSCAPE-01; C-CLASS-OSA-MECHANISM", "grade": "very-low", "source": { "citation": "ClinicalTrials.gov TRIUMPH-1 (NCT05929066) and TRIUMPH-2 (NCT05929079), Eli Lilly; registrational OSA framing in Giblin K et al., Diabetes Obes Metab 2025;28(1):83-93 (PMID 41090431, DOI 10.1111/dom.70209). Accessed 2026-06-21.", "url": "https://clinicaltrials.gov/study/NCT05929066", "identifiers": "NCT05929066", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-OSA-02", "sourceId": "CIT:position-derived-from-triumph-design-giblin-k-et", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "No data. EXPECTATION only: given reta's class-leading weight loss (up to ~24% at 48 wk in phase-2), IF OSA benefit is weight-mediated (the dominant hypothesis), reta would plausibly produce the largest AHI reductions of any incretin. This is an inference, NOT an observed result; no AHI number can be attached to reta.", "finding": "RETATRUTIDE-DIRECT OSA POSITION: reta has no published OSA/AHI outcome data. Its OSA relevance rests on (a) the registrational TRIUMPH OSA endpoints (results pending) and (b) the inference that, because OSA benefit in this class appears largely weight-mediated, the agent with the largest weight loss should deliver the largest AHI reduction. Stated as an EXPECTATION conditional on weight-mediation - not an outcome reta has demonstrated.", "population": "n/a (positional/inferential row). Weight-loss anchor: reta phase-2 (Jastreboff 2023, obesity, 48 wk) up to ~24% mean weight loss (weight-loss domain).", "comparators": "", "endpointType": "other", "notes": "NON-GRADUATING. HARD RULE: do NOT imply reta has OSA outcomes - it has none. The 'largest AHI reduction in class' is a weight-mediated EXPECTATION fully contingent on the weight-mediation question (C-CLASS-OSA-MECHANISM): if OSA benefit has a substantial weight-INDEPENDENT component, reta's potency advantage would NOT automatically translate into proportionally larger AHI reductions.", "crossRef": "C-RETATRUTIDE-OSA-01; C-CLASS-OSA-MECHANISM; C-CLASS-OSA-LANDSCAPE-01", "grade": "very-low", "source": { "citation": "Position derived from TRIUMPH design (Giblin K et al., Diabetes Obes Metab 2025, PMID 41090431) and reta phase-2 weight-loss data; no OSA outcome source exists for retatrutide.", "url": "", "identifiers": "CIT:retatrutide-osa-position-2026", "date": "2026-06-21", "design": "narrative review", "maturity": "review", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-SAFETY-CONS01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "GI AEs ~35% of reta participants in T2D (13% at 0.5 mg to 50% at 8 mg fast-escalation) vs 13% placebo; GI dose-related, mostly mild-moderate; dose-dependent HR rise peaking ~24 wk then declining (magnitude in thread-7). No MTC/pancreatitis/NAION/biliary events reported; no severe hypoglycaemia; no deaths.", "finding": "RETATRUTIDE DIRECT SAFETY position: across the two phase-2 trials the profile is GI-DOMINANT + a DOSE-DEPENDENT HEART-RATE rise, with NO MTC/pancreatitis/NAION/biliary events reported - but these are SHORT (36-48 wk), small per-arm trials, UNDERPOWERED for rare events, so the absence of a signal is NOT clearance. Reta has NO long-term safety data (phase-3 TRIUMPH ongoing).", "population": "Phase-2: obesity (Jastreboff, n=338, 48 wk, 1-12 mg) + T2D (Rosenstock, n=281, 36 wk, 0.5-12 mg, placebo + dulaglutide).", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "safety-event/signal", "notes": "ABSENCE != CLEARANCE (hard rule): no MTC/pancreatitis/NAION/biliary in phase-2 reflects short underpowered exposure, not safety. RETA-RELEVANT/AMPLIFIED signals: (1) GI/biliary/gallbladder - RELEVANT, likely AMPLIFIED (reta is most potent, largest weight loss, biliary is weight-loss-coupled); (2) early-worsening retinopathy - RELEVANT via rapid large glucose-lowering in T2D (cross-ref RETINOPATHY-CONS01); (3) NAION - class-transfer (reta is a GLP-1 agonist; cross-ref NAION-CONS01); (4) MTC - class boxed-warning labelling (rodent-basis); (5) HR rise - RETA-SPECIFIC, dose-dependent (thread-7), outside the class-signal taxonomy; (6) lean-mass/bone - weight-loss-coupled, may be amplified (cross-ref D2). UNSTUDIED for reta: NAION, pancreatitis, MTC, ileus, AKI, suicidality, aspiration - class-transfer reasoning only. GRADE: phase-2 RCT = moderate, but the rare-event arm is effectively very-low-power. VALIDATOR: confirm 37366315/37385280 report no dedicated rare-event signal + the GI/HR profile.", "crossRef": "C-CLASS-SAFETY-NAION-CONS01; C-CLASS-SAFETY-RETINOPATHY-CONS01; C-CLASS-SAFETY-BIL-CONS01; C-CLASS-SAFETY-STRUCTURE01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-SAFETY-DYSESTHESIA-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Phase-2 obesity trial (peer-reviewed anchor): cutaneous hyperesthesia / skin sensitivity ~7% retatrutide vs ~1% placebo, none severe/serious, none causing discontinuation. Phase-3 TRIUMPH-4 TOPLINE (2026, company-reported, NOT yet peer-reviewed): dysesthesia 8.8% at 9 mg and 20.9% at 12 mg vs 0.7% placebo - clearly dose-dependent (~2.4x from 9->12 mg), generally mild/self-limiting, rarely causing discontinuation.", "finding": "FOLK-CLAIM VERDICT ('retatrutide-specific dysesthesia / skin tingling-buzzing, in 5-15% of users, not in the other two'): TRUE / CONFIRMED - and it OVERTURNS the prior assumption that this was baseless folk chatter. Dysesthesia is a NAMED, DOSE-DEPENDENT, placebo-differentiated, retatrutide-CLASS-SPECIFIC sensory signal (no GLP-1/GIP equivalent), surfaced by the folk-claims loop and NOT previously in the safety dossier (D6/Thread 14). The lay '5-15%' figure if anything UNDERSTATES the 12 mg rate (~21%). Mechanism is UNPROVEN (a glucagon-receptor effect is the leading hypothesis given dose-dependence + class-specificity; rapid weight loss / B-vitamin / electrolyte contributions are partial confounders at best).", "population": "Retatrutide phase-2 obesity trial (skin hyperesthesia ~7%) + phase-3 TRIUMPH-4 topline (dysesthesia 8.8/20.9% at 9/12 mg); no comparable signal for semaglutide or tirzepatide.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "GRADE: phase-2 skin-hyperesthesia ~7% is the peer-reviewed anchor (moderate). The TRIUMPH-4 dysesthesia figures (8.8/20.9%) are PRESS/TOPLINE - NON-GRADUATING until peer-reviewed publication; flagged accordingly. IMPORTANT: this is a real reta-distinct safety signal the structured D6 safety dossier missed and the folk-claims loop found - a candidate addition to Thread 14 once TRIUMPH-4 publishes. Mechanism unproven. Cross-ref the reta-direct safety position (C-RETATRUTIDE-SAFETY-CONS01) and the heart-rate signal (thread-7). [VALIDATION: the ~7% phase-2 cutaneous-hyperesthesia rate is a full-text AE-table figure (not in the abstract); the phase-2 dose-dependent HR rise IS abstract-confirmed. TRIUMPH-4 dysesthesia confirmed as an 11 Dec 2025 Eli Lilly topline press release.]", "crossRef": "C-RETATRUTIDE-SAFETY-CONS01; C-RETATRUTIDE-EE-RUNSHOT-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-T1D-ABSENCE-01", "sourceId": "PMID37366315", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "ABSENCE: no retatrutide type-1-diabetes efficacy or safety datum exists. Reviewed the retatrutide evidence base (phase-2 obesity and other programmes) - no T1D trial, substudy, or adjunct-to-insulin datum has been reported; not measured, cannot be asserted OR excluded.", "finding": "EXPLICIT ABSENCE: there is no retatrutide data in type-1 diabetes of any kind. Unlike liraglutide (two pivotal RCTs) and tirzepatide (one phase-2 trial), retatrutide has not been studied as an insulin adjunct in T1D - a complete void, not a measured-null.", "population": "Retatrutide evidence base reviewed for any type-1-diabetes indication (pinned to the phase-2 obesity trial, Jastreboff et al., NCT04881760, as the reviewed-for-indication anchor) - none present.", "comparators": "placebo", "endpointType": "measured-null", "notes": "ABSENCE (not measured, not a measured-null): no retatrutide T1D effect can be asserted OR excluded. Complete void - the most under-studied agent in this population; routed to OQ-T1D-B. Do NOT impute from retatrutide's obesity/MASLD data.", "crossRef": "C-TIRZ-T1D-01", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526", "url": "https://doi.org/10.1056/NEJMoa2301972", "identifiers": "PMID 37366315; DOI 10.1056/NEJMoa2301972; NCT04881760", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-TRANSCEND-WL-01", "sourceId": "PMID42250575", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon tri-agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -15.3% vs placebo -2.6%", "finding": "In retatrutide's first phase-3 trial, monotherapy produced 11.5-15.3% weight loss in type-2 diabetes; the glycaemic arm (HbA1c) is recorded separately (C2-RETATRUTIDE-GLY-02).", "population": "TRANSCEND-T2D-1 (NCT06354660): 537 adults with type-2 diabetes inadequately controlled by diet and exercise, retatrutide 4/9/12 mg vs placebo 1:1:1:1; 40-week phase-3 randomised double-blind placebo-controlled monotherapy RCT at 48 sites (USA/Mexico/India).", "comparators": "", "endpointType": "efficacy", "notes": "Reta's first phase-3 to graduate - a major maturity step up from the earlier dose-finding programme. T2D (not pure obesity) population. Shares source PMID 42250575 with the glycaemic finding.", "crossRef": "C2-RETATRUTIDE-GLY-02", "grade": "high", "source": { "citation": "Bajaj HS et al., Lancet, 2026", "url": "https://doi.org/10.1016/S0140-6736(26)00967-0", "identifiers": "PMID42250575", "date": "2026-06-06", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-RETATRUTIDE-TRIUMPH1-TOPLINE-01", "sourceId": "CIT:lilly-triumph-1-topline-pr-2026-05-21", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "up to 28.3% weight loss at 80 wk (12 mg); 45.3% achieving >=30%; up to 30.3% at 104 wk in the high-BMI extension; all doses met primary + key secondary endpoints (topline, press-grade)", "finding": "Eli Lilly TRIUMPH-1 (NCT05929066) Phase 3 topline press release: retatrutide produced up to 28.3% weight loss at 80 weeks (12 mg), with 45.3% achieving at least 30% loss, rising to up to 30.3% at 104 weeks in the high-BMI extension; all doses reportedly met the primary and key secondary endpoints. PRESS/TOPLINE (non-graduating): corporate-announced, not peer-reviewed, not posted to ClinicalTrials.gov (hasResults=FALSE as of 2026-06-21), and carrying NO mechanism detail (no DXA, EE or per-receptor data). The magnitude confirms the Phase-2 reading held in Phase 3 but does not bear on the open mechanism question.", "population": "TRIUMPH-1 (NCT05929066): n=2,339, obesity without diabetes, 80 weeks +/- high-BMI extension to 104 weeks", "comparators": "placebo", "endpointType": "press-topline", "notes": "Promoted from CIR-012 (provenance register, 2026-06-21). Press/topline tier, non-graduating until peer-reviewed publication (to be promoted to human-primary on publication, as was done for TRANSCEND-T2D-1/Bajaj per CIR-007). At very-low it is exempt from the high/moderate funding-locator floor; issuer recorded honestly as Eli Lilly (trial sponsor).", "crossRef": "", "grade": "very-low", "source": { "citation": "Eli Lilly, TRIUMPH-1 (retatrutide) Phase 3 topline press release, PRNewswire, 21 May 2026 (NCT05929066)", "url": "https://investor.lilly.com/news-releases/news-release-details/lillys-retatrutide-showed-significant-weight-loss-triumph-1", "identifiers": "Eli Lilly PRNewswire topline 2026-05-21; NCT05929066 (hasResults=FALSE as of 2026-06-21)", "date": "2026-05-21", "design": "phase-2 RCT (pipeline)", "maturity": "press", "funding": "industry - Eli Lilly (trial sponsor; corporate topline announcement of its own TRIUMPH-1 trial)", "scopeLimits": "press/topline only - no peer-reviewed publication; no DXA/EE/per-receptor mechanism detail; results not posted to ClinicalTrials.gov (hasResults=FALSE 2026-06-21)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-SEMA-ADMIN-MISSED-SC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Ozempic: within 5 days of the missed dose", "finding": "For Ozempic, a missed dose should be administered as soon as possible within 5 days after the missed dose; if more than 5 days have elapsed, skip the missed dose and resume at the next regularly scheduled dose.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "Ozempic US PI 2.1. Restricted to the Ozempic rule, which is what this label supports; the distinct Wegovy missed-dose rule (>2 days / 48 h to the next dose) lives in the Wegovy label and is recorded separately at C-SEMA-ADMIN-MISSED-WEGOVY-01.", "crossRef": "C-SEMA-ADMIN-MISSED-WEGOVY-01", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-ADMIN-MISSED-WEGOVY-01", "sourceId": "CIT:wegovy-us-pi-dailymed-f5e548d0", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Wegovy: administer if the next scheduled dose is >2 days (48 h) away", "finding": "For Wegovy, if a dose is missed and the next scheduled dose is more than 2 days (48 hours) away, administer it as soon as possible; if the next scheduled dose is less than 2 days away, skip the missed dose and resume on the regularly scheduled day.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "Wegovy US PI 2.1. The Wegovy missed-dose rule differs from Ozempic's (within 5 days); the Ozempic rule is recorded at C-SEMA-ADMIN-MISSED-SC-01. Split out so each clause rests on the label that actually supports it.", "crossRef": "C-SEMA-ADMIN-MISSED-SC-01", "grade": "high", "source": { "citation": "Wegovy (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "identifiers": "DailyMed setid f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-ADMIN-ORAL-01", "sourceId": "CIT:rybelsus-us-pi-dailymed-27f15fac", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Fasting, AM, <=120 mL water, 30-min wait before food/drink/other oral drugs", "finding": "Oral semaglutide must be taken fasting in the morning with a small sip of water and a 30-minute wait before food, other drinks or other oral medicines.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "Rybelsus PI 2.", "crossRef": "", "grade": "high", "source": { "citation": "Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98", "identifiers": "DailyMed setid 27f15fac-7d98-4114-a2ec-92494a91da98", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-ADMIN-SC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "s.c. abdomen/thigh/upper arm, weekly, any time, +/- food, rotate sites", "finding": "Subcutaneous semaglutide is injected once weekly into the abdomen, thigh or upper arm with site rotation, on any day, with or without food.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-01", "sourceId": "PMID37952131", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE 6.5% (569/8803) vs 8.0% (701/8801); HR 0.80 (95% CI 0.72-0.90; P<0.001); ARR ~1.5pp over mean 39.8 months. MI the largest single component; CV death not significant on hierarchical testing.", "finding": "In adults aged >=45 with pre-existing CVD and overweight/obesity (BMI >=27) but WITHOUT diabetes, once-weekly s.c. semaglutide 2.4 mg reduced 3-point MACE (CV death, non-fatal MI, non-fatal stroke) versus placebo.", "population": "SELECT: N=17,604; established CVD + overweight/obesity, no diabetes; multicentre double-blind placebo-controlled event-driven superiority RCT; mean follow-up 39.8 months.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS the prior one-line SELECT row with the HR and event rates. First GLP-1RA CVOT in a non-diabetic obesity population. Weight-independence framing carried in companion analysis (C-SEMA-CARDIO-05). Cross-ref the T2D sema CVOTs.", "crossRef": "C-SEMA-CARDIO-02; C-SEMA-CARDIO-04; C-SEMA-CARDIO-05", "grade": "high", "source": { "citation": "Lincoff AM et al. (SELECT), NEJM, 2023", "url": "https://doi.org/10.1056/NEJMoa2307563", "identifiers": "PMID 37952131; DOI 10.1056/NEJMoa2307563; NCT03574597", "date": "2023-11-11", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-02", "sourceId": "PMID27633186", "drug": "semaglutide (s.c.)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.74 (95% CI 0.58-0.95; P<0.001 non-inferiority, P=0.02 superiority); event rate 6.6% vs 8.9%. Benefit stroke/MI-driven (non-fatal stroke HR ~0.61); CV death neutral (HR ~0.98).", "finding": "In T2D at high CV risk, s.c. semaglutide reduced first MACE versus placebo, meeting non-inferiority then superiority; reduction driven mainly by non-fatal stroke and MI, with CV death unchanged.", "population": "SUSTAIN-6: N=3297; T2D high CV risk; double-blind placebo-controlled pre-approval CV-safety RCT; median 2.1 years.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS prior row with component decomposition (stroke/MI-driven, CV death neutral). Contrast LEADER, where CV death WAS reduced. Powered for non-inferiority; a retinopathy-complication signal noted in trial.", "crossRef": "C-LIRA-CARDIO-01; C-SEMA-CARDIO-01", "grade": "high", "source": { "citation": "Marso SP et al. (SUSTAIN-6), NEJM, 2016", "url": "https://doi.org/10.1056/NEJMoa1607141", "identifiers": "PMID 27633186; DOI 10.1056/NEJMoa1607141; NCT01720446", "date": "2016-09-15", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-03", "sourceId": "PMID31185157", "drug": "semaglutide (oral)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "MACE HR 0.79 (95% CI 0.57-1.11; P<0.001 non-inferiority; superiority NOT met). MACE 3.8% vs 4.8%. CV death and all-cause death nominally lower (secondary). Median 15.9 months.", "finding": "In T2D at high CV risk, once-daily oral semaglutide was non-inferior to placebo for MACE but did NOT demonstrate superiority (CV-safety trial, underpowered for superiority).", "population": "PIONEER 6: N=3183; T2D high CV risk; double-blind placebo-controlled CV-safety RCT; median 15.9 months.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "BOTH-POLES: a non-inferiority (NOT superiority) oral-sema result; the design was CV-safety. Definitive oral-sema superiority came later in SOUL (C-SEMA-CARDIO-04). DEEPENS prior row with HR and CI-crossing-1 detail.", "crossRef": "C-SEMA-CARDIO-04", "grade": "high", "source": { "citation": "Husain M et al. (PIONEER 6), NEJM, 2019", "url": "https://doi.org/10.1056/NEJMoa1901118", "identifiers": "PMID 31185157; DOI 10.1056/NEJMoa1901118; NCT02692716", "date": "2019-06-11", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-04", "sourceId": "PMID40162642", "drug": "semaglutide (oral)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "MACE HR 0.86 (95% CI 0.77-0.96; P=0.006); 12.0% (3.1/100PY) vs 13.8% (3.7/100PY). Confirmatory secondary major-kidney-disease composite NOT significant. Mean follow-up 47.5 months.", "finding": "In T2D with established ASCVD, CKD, or both, oral semaglutide 14 mg reduced MACE versus placebo in a dedicated superiority CVOT; the kidney composite did not differ.", "population": "SOUL: N=9650; T2D age >=50, HbA1c 6.5-10.0%, with ASCVD and/or CKD; double-blind placebo-controlled event-driven superiority RCT; mean follow-up 47.5 months.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "DEEPENS the prior SOUL row (which carried the NCT only) with the published primary result. Establishes oral-sema SUPERIORITY (contrast PIONEER-6 non-inferiority). A prespecified sub-analysis (Circulation 2025, PMID 40156843) found benefit consistent regardless of baseline SGLT2i use. Kidney composite not met (unlike FLOW).", "crossRef": "C-SEMA-CARDIO-03; C-SEMA-CARDIO-06", "grade": "high", "source": { "citation": "McGuire DK, Marx N, Buse JB et al., N Engl J Med, 2025", "url": "https://doi.org/10.1056/NEJMoa2501006", "identifiers": "PMID40162642", "date": "2025-03-29", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "kidney confirmatory-secondary not met", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-05", "sourceId": "PMID38740993", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "Weight at 208 weeks -10.2% vs -1.5%; waist -7.7 vs -1.3 cm (P<0.0001); clinically meaningful weight loss across every baseline BMI class. The trial's 20% MACE RRR (HR 0.80) is restated as context, NOT re-derived by subgroup here.", "finding": "Prespecified SELECT analysis: semaglutide produced sustained weight loss across every baseline BMI category to 4 years (208 weeks). The trial's headline 20% MACE reduction is restated as context; this paper reports weight-by-BMI, not a per-subgroup MACE analysis.", "population": "SELECT prespecified weight/BMI secondary analysis (prespecified secondary of the N=17,604 double-blind RCT); up to 208 weeks.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "GRADE: prespecified-secondary, anthropometric (surrogate) endpoint, so this grades MODERATE, NOT a hard-CVOT-equivalent (independent validation, 2026-06-21). BOTH-POLES / weight-independence context: the wider SELECT literature reports the MACE benefit emerged early and was largely NOT explained by weight-loss magnitude (a separate mediation analysis, NOT resolved here and NOT established by this paper). This paper documents the durable weight loss across BMI classes that the narrative rests on; it does not report MACE by subgroup.", "crossRef": "C-SEMA-CARDIO-01", "grade": "moderate", "source": { "citation": "Ryan DH, Lingvay I, Deanfield J et al., Nat Med, 2024", "url": "https://doi.org/10.1038/s41591-024-02996-7", "identifiers": "PMID38740993", "date": "2024-05-13", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (SELECT sponsor)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-06", "sourceId": "PMID38785209", "drug": "semaglutide (s.c.)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "Primary kidney composite HR 0.76 (95% CI 0.66-0.88; P=0.0003); CV death HR 0.71 (0.56-0.89); MACE HR 0.82 (0.68-0.98; P=0.029); all-cause death HR 0.80 (0.67-0.95; P=0.01). Median 3.4 years; stopped early for efficacy.", "finding": "CROSS-DOMAIN (kidney trial with CV components): in T2D with CKD, s.c. semaglutide 1.0 mg reduced the major-kidney-disease composite (which includes CV death) and separately reduced CV death, MACE and all-cause death.", "population": "FLOW: N=3533; T2D with CKD (eGFR 25-75, raised UACR); double-blind placebo-controlled RCT; median 3.4 years (stopped early at interim).", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "GRADE: for its CV components this row is MODERATE, not a hard-MACE CVOT-equivalent (Council, Evidence-grader): the CV endpoints are SECONDARY in a renal-PRIMARY trial that was STOPPED EARLY for efficacy (two independent softening factors; estimates likely inflated). The renal primary (HR 0.76) leads the magnitude; the CV-death HR 0.71 is the most extreme single CV-death estimate in the domain and rests on an interrupted secondary analysis, so it must NOT be weighted as a CV-outcome CVOT in any pooled or narrative CV claim. Contrast SOUL, where the kidney composite was not met.", "crossRef": "C-SEMA-CARDIO-04", "grade": "moderate", "source": { "citation": "Perkovic V et al., N Engl J Med, 2024", "url": "https://doi.org/10.1056/NEJMoa2403347", "identifiers": "PMID38785209", "date": "2024-05-24", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (FLOW sponsor)", "scopeLimits": "stopped early for efficacy (may inflate estimate)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-07", "sourceId": "PMID41138739", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "decrease", "magnitude": "Prespecified SELECT adiposity/mediation analysis: of the 20% MACE reduction (SELECT primary HR 0.80, 95% CI 0.72-0.90), an estimated ~33% was MEDIATED through waist-circumference reduction (waist-adjusted HR 0.86, 95% CI 0.77-0.97) - implying ~67% is weight/waist-INDEPENDENT. No linear trend linked week-20 weight loss to subsequent MACE in the semaglutide arm; greater week-20 waist reduction WAS associated with lower subsequent MACE. Per-5-kg lower BASELINE weight HR 0.96 (0.94-0.99). In placebo, weight loss was paradoxically associated with increased MACE.", "finding": "In the prespecified SELECT mediation analysis, semaglutide's cardiovascular benefit was largely INDEPENDENT of baseline adiposity and of the amount of weight lost - roughly two-thirds of the MACE reduction was not explained by waist-circumference change - indicating mechanisms of CV benefit beyond adiposity reduction. CRITICAL: this is the evidence the popular 'works even without weight loss' claim rests on, and it is SEMAGLUTIDE-SPECIFIC; there is NO equivalent tirzepatide mediation analysis, so the weight-independent CV claim must NOT be transferred to tirzepatide (the SURMOUNT-MMO obesity CV trial is ongoing).", "population": "Prespecified analysis of SELECT (NCT03574597): n=17,604 adults >=45 y, BMI >=27, with established CVD and WITHOUT diabetes; semaglutide 2.4 mg weekly vs placebo; 41 countries; primary outcome time-to-first MACE (CV death, non-fatal MI, non-fatal stroke). Mediation via time-varying adjustment for waist/weight change + week-20 and week-104 landmarks.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "GRADE moderate: a prespecified mediation analysis of a high-quality CVOT, but mediation rests on causal-inference assumptions (time-varying confounding) and is a secondary analysis - directional, not a primary causal proof. The SELECT primary MACE result (HR 0.80) is C-SEMA-CARDIO-01 (PMID 37952131). This row is the ANCHOR for checking the cross-drug 'tirzepatide reduces CV risk even without weight loss' claim: the weight-independence belongs to SEMAGLUTIDE (SELECT), not tirzepatide. Cross-ref C-SEMA-CARDIO-01 (SELECT primary), C-TIRZ-CARDIO-01 (SURPASS-CVOT non-inferiority), C-TIRZ-CARDIO-03 (SURMOUNT-MMO ongoing).", "crossRef": "C-SEMA-CARDIO-01; C-SEMA-CARDIO-05; C-TIRZ-CARDIO-01; C-TIRZ-CARDIO-03", "grade": "moderate", "source": { "citation": "Deanfield J, Lincoff AM, Kahn SE et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet 2025;406(10516):2257-2268.", "url": "https://doi.org/10.1016/S0140-6736(25)01375-3", "identifiers": "PMID41138739", "date": "2025-11-15", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "no outcome data yet (ongoing); possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-BP-01", "sourceId": "PMID36691308", "drug": "semaglutide (2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "SBP reductions ~-3 to -6 mmHg vs placebo (office BP); review-level, per-trial CIs not extracted.", "finding": "Once-weekly semaglutide 2.4 mg reduced office SBP/DBP versus placebo across the STEP 1-5 programme.", "population": "Adults with overweight/obesity, STEP 1-5; most 68 weeks; RCT.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Review summary, not a dedicated ABPM trial. Magnitude approximate; confirm against individual STEP papers. PMID/DOI verified.", "crossRef": "", "grade": "low", "source": { "citation": "Amaro A et al. (STEP cardiometabolic review), Postgrad Med, 2022;134(sup1):18-27", "url": "https://doi.org/10.1080/00325481.2022.2147325", "identifiers": "PMID 36691308; DOI 10.1080/00325481.2022.2147325", "date": "2022-01-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-HF-01", "sourceId": "PMID37622681", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "increase", "magnitude": "KCCQ-CSS +16.6 vs +8.7; difference 7.8 (95% CI 4.8 to 10.9; P<0.001). Co-primary weight: -13.3% vs -2.6% (diff -10.7 pp). 6MWD diff +20.3 m. CRP treatment ratio 0.61. Hierarchical composite win ratio 1.72 (1.37-2.15). Serious AEs 13.3% vs 26.7%.", "finding": "STEP-HFpEF: in HFpEF with obesity but without diabetes, semaglutide improved HF symptoms/physical limitations (KCCQ-CSS) versus placebo at 52 weeks.", "population": "N=529, HFpEF (EF >=45%), BMI >=30, no T2D; 52 weeks; RCT vs placebo.", "comparators": "placebo", "endpointType": "symptom/PRO", "notes": "Symptom/functional trial, not powered for hard HF outcomes. NT-proBNP magnitude (~-20.9% vs -5.3%) web-sourced, unverified against primary text. PMID/DOI verified.", "crossRef": "", "grade": "high", "source": { "citation": "Kosiborod MN et al. (STEP-HFpEF), NEJM, 2023;389:1069-1084", "url": "https://doi.org/10.1056/NEJMoa2306963", "identifiers": "PMID 37622681; DOI 10.1056/NEJMoa2306963; NCT04788511", "date": "2023-08-25", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "identifier not fully verified; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-HF-02", "sourceId": "PMID38587233", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "increase", "magnitude": "KCCQ-CSS +13.7 vs +6.4; diff 7.3 (95% CI 4.1 to 10.4; P<0.001). Weight diff -6.4 pp. 6MWD diff +14.3 m (P=0.008). Composite win ratio 1.58 (1.29-1.94). CRP ratio 0.67. Serious AEs 17.7% vs 28.8%.", "finding": "STEP-HFpEF DM: in HFpEF with obesity AND T2D, semaglutide improved KCCQ-CSS, weight, 6MWD and inflammation versus placebo at 52 weeks.", "population": "N=616, HFpEF with BMI >=30 and T2D; 52 weeks; RCT vs placebo.", "comparators": "placebo", "endpointType": "symptom/PRO", "notes": "KCCQ-CSS gain numerically smaller than non-diabetic STEP-HFpEF. PMID/DOI verified.", "crossRef": "C-SEMA-CARDIO-HF-01", "grade": "high", "source": { "citation": "Kosiborod MN et al. (STEP-HFpEF DM), NEJM, 2024;390:1394-1407", "url": "https://doi.org/10.1056/NEJMoa2313917", "identifiers": "PMID 38587233; DOI 10.1056/NEJMoa2313917; NCT04916470", "date": "2024-04-06", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-HF-03", "sourceId": "PMID39222642", "drug": "semaglutide (2.4 mg; 1.0 mg in FLOW)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "decrease", "magnitude": "CV death or worsening HF: 5.4% vs 7.5%; HR 0.69 (95% CI 0.53-0.89; p=0.0045). Worsening HF events: 2.8% vs 4.7%; HR 0.59 (0.41-0.82). CV death alone: HR 0.82 (0.57-1.16; p=0.25).", "finding": "Pooled post-hoc (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM): in participants with HFpEF history, semaglutide reduced the composite of CV death or worsening HF events, and worsening HF events alone; no significant effect on CV death alone.", "population": "N=3,743 with HFpEF history pooled from four RCTs; 1914 sema vs 1829 placebo; ITT.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Post-hoc pooled, not a prespecified powered HF-outcome trial; HFpEF partly investigator-reported in SELECT/FLOW. PMID/DOI verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Kosiborod MN et al., Lancet, 2024;404:949-961", "url": "https://doi.org/10.1016/S0140-6736(24)01643-X", "identifiers": "PMID 39222642; DOI 10.1016/S0140-6736(24)01643-X", "date": "2024-08-30", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-HR-01", "sourceId": "DOI10.1056/NEJMOA1607141", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "~+1 to +4 bpm; SUSTAIN-6 placebo-corrected +2.75 bpm (0.5 mg) and +3.2 bpm (1.0 mg).", "finding": "Semaglutide produces a modest resting heart-rate rise versus placebo (class chronotropic effect).", "population": "T2D (SUSTAIN-6) and obesity (STEP) populations; s.c. semaglutide vs placebo.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "SUSTAIN-6 bpm figures from secondary/abstract reporting, not independently PubMed-verified this pass. HR rise not linked to excess cardiac events in trial reporting.", "crossRef": "", "grade": "low", "source": { "citation": "Marso SP et al. (SUSTAIN-6), NEJM, 2016;375:1834-1844; plus class HR summaries", "url": "https://doi.org/10.1056/NEJMoa1607141", "identifiers": "DOI 10.1056/NEJMoa1607141", "date": "2016-11-10", "design": "narrative review", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-LIPID-01", "sourceId": "PMID36691308", "drug": "semaglutide (2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Favourable lipid changes across STEP 1-5 (review-level; exact percentages not extracted).", "finding": "Semaglutide 2.4 mg improved the lipid profile (TG, total/LDL cholesterol) versus placebo across the STEP programme.", "population": "Adults with overweight/obesity, STEP 1-5; 68 weeks; RCT.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Review summary; semaglutide lipid effects generally milder than glucagon co-agonists (no direct glucagon-driven hepatic TG effect). PMID/DOI verified.", "crossRef": "C-SEMA-CARDIO-BP-01", "grade": "low", "source": { "citation": "Amaro A et al. (STEP cardiometabolic review), Postgrad Med, 2022;134(sup1):18-27", "url": "https://doi.org/10.1080/00325481.2022.2147325", "identifiers": "PMID 36691308; DOI 10.1080/00325481.2022.2147325", "date": "2022-01-01", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-RENAL-01", "sourceId": "DOI10.1056/NEJMOA2403347", "drug": "semaglutide (s.c. 1.0 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Composite (kidney failure, >=50% eGFR loss, kidney/CV death): HR 0.76 (95% CI 0.66 to 0.88; p=0.0003), 24% RRR. Kidney-specific composite HR 0.79 (0.66-0.94). CV death HR 0.71 (0.56-0.89). eGFR total slope less steep by 1.16 mL/min/1.73m2/yr (95% CI 0.86-1.47).", "finding": "FLOW: in T2D + CKD, semaglutide reduced the primary composite kidney outcome versus placebo; trial stopped early for efficacy. eGFR slope also less steep.", "population": "FLOW: N=3,533 T2D + CKD; median follow-up 3.4 years; double-blind RCT vs placebo.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Stopped early for efficacy (may inflate estimate); limited baseline SGLT2i use. eGFR-slope figure web-sourced. DOI/NCT confirmed; PMID unverified.", "crossRef": "", "grade": "high", "source": { "citation": "Perkovic V et al. (FLOW), NEJM, 2024", "url": "https://doi.org/10.1056/NEJMoa2403347", "identifiers": "PMID 38785209; DOI 10.1056/NEJMoa2403347; NCT03819153 [VERIFIED 2026-06-20]", "date": "2024-05-24", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (disclosed in publication)", "scopeLimits": "identifier not fully verified; magnitude web/secondary-sourced; stopped early for efficacy (may inflate estimate)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CARDIO-RENAL-02", "sourceId": "PMID27633186", "drug": "semaglutide (s.c. 0.5/1.0 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "New/worsening nephropathy 3.8% vs 6.1%; HR 0.64 (95% CI 0.46 to 0.88; p=0.005); driven by reduced new macroalbuminuria.", "finding": "SUSTAIN-6 prespecified secondary: lower rate of new or worsening nephropathy with semaglutide versus placebo.", "population": "SUSTAIN-6: N=3,297 T2D; 104 weeks; RCT.", "comparators": "placebo", "endpointType": "other", "notes": "Component of a microvascular secondary outcome. Exact percentages/HR web-sourced; abstract states only that rates were lower. PMID/DOI verified.", "crossRef": "C-SEMA-CARDIO-02", "grade": "high", "source": { "citation": "Marso SP et al. (SUSTAIN-6), NEJM, 2016", "url": "https://doi.org/10.1056/NEJMoa1607141", "identifiers": "PMID 27633186; DOI 10.1056/NEJMoa1607141; NCT01720446", "date": "2016-09-15", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-CONTRA-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "US: MTC/MEN2 (boxed warning) + serious hypersensitivity; EU: hypersensitivity only", "finding": "Semaglutide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and for serious hypersensitivity; the EU contraindication is hypersensitivity only (the MTC/MEN2 boxed warning is a US construct).", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "contraindication", "notes": "US PI 4 / EU SmPC 4.3. Regional contrast preserved.", "crossRef": "C-SEMA-SAFETY-MTC09", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DDI-GASTRIC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Delays gastric emptying; no clinically relevant effect on oral-drug absorption", "finding": "Semaglutide delays gastric emptying and can theoretically affect oral-drug absorption, but did not alter the absorption of orally administered medications to a clinically relevant degree.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "US PI 7. Ozempic advises 'caution'; Wegovy advises 'monitor the effects of oral medications'.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DDI-LEVOTHYROXINE-01", "sourceId": "CIT:rybelsus-us-pi-dailymed-27f15fac", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "increase", "magnitude": "Levothyroxine exposure +33% (90% CI 1.25-1.42) with oral semaglutide", "finding": "Oral semaglutide increased levothyroxine exposure by about 33% in a drug-interaction study; this is an oral-semaglutide (SNAC co-formulation) interaction, not stated for the injectable products.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "Rybelsus PI 7.", "crossRef": "", "grade": "high", "source": { "citation": "Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98", "identifiers": "DailyMed setid 27f15fac-7d98-4114-a2ec-92494a91da98", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DDI-OC-01", "sourceId": "CIT:ozempic-eu-smpc-emc-9750", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "No clinically relevant change in ethinylestradiol/levonorgestrel exposure", "finding": "Semaglutide does not reduce the effectiveness of combined oral contraceptives to a clinically relevant degree; no additional contraceptive method is required.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "EU Ozempic SmPC 4.5. CONTRAST with tirzepatide, whose label advises a barrier/non-oral method (see C-TIRZ-SAFETY-CONTRA04). Drug-specific, not a class fact.", "crossRef": "C-TIRZ-SAFETY-CONTRA04", "grade": "high", "source": { "citation": "Ozempic (semaglutide) EU Summary of Product Characteristics (EMA)", "url": "https://www.medicines.org.uk/emc/product/9750/smpc", "identifiers": "EMC product 9750 (EMA Annex I)", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DOSE-OZEMPIC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Titrate 0.25 -> 0.5 -> 1 -> max 2 mg once weekly", "finding": "Ozempic is titrated from a 0.25 mg starter to a maximum of 2 mg once weekly.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.1. CORRECTED: a previously-suspected 'EU max 1 mg' discrepancy is OUTDATED - the EU Ozempic SmPC now states weekly doses above 2 mg are not recommended, so both regions cap at 2 mg; no US/EU max-dose discrepancy.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DOSE-RYBELSUS-01", "sourceId": "CIT:rybelsus-us-pi-dailymed-27f15fac", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "3 (starter) -> 7 -> max 14 mg once daily", "finding": "Rybelsus is titrated 3 -> 7 -> 14 mg once daily; the 3 mg dose is a non-therapeutic starter and 14 mg the maximum.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "Rybelsus PI 2. The combined US label also lists distinct higher-strength oral OZEMPIC tablets (1.5/4/9 mg) - do not attribute those to Rybelsus.", "crossRef": "", "grade": "high", "source": { "citation": "Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98", "identifiers": "DailyMed setid 27f15fac-7d98-4114-a2ec-92494a91da98", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-DOSE-WEGOVY-01", "sourceId": "CIT:wegovy-us-pi-dailymed-f5e548d0", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "16-week titration to maintenance 2.4 mg (or 1.7 mg) once weekly", "finding": "Wegovy is titrated over 16+ weeks to a maintenance dose of 2.4 mg once weekly (1.7 mg an allowed fallback).", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.1 (Table 1). EU concordant.", "crossRef": "", "grade": "high", "source": { "citation": "Wegovy (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "identifiers": "DailyMed setid f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-HF-CRP-01", "sourceId": "PMID39217564", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "decrease", "magnitude": "CRP reduced across all baseline strata; weight-independent (p-interaction 0.91)", "finding": "In a secondary analysis of the STEP-HFpEF programme, inflammation (CRP >=2 mg/L) was present in 71% of obesity-related HFpEF patients; semaglutide reduced CRP more than placebo across all baseline CRP strata, and the CRP fall was largely INDEPENDENT of the magnitude of weight loss.", "population": "secondary analysis of pooled STEP-HFpEF programme, HFpEF + obesity", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "GLP-1R class. The anti-inflammatory limb of the HFpEF mechanism and a (weak) weight-INDEPENDENT signal: CRP fall did not track weight-loss magnitude. Secondary analysis; surrogate (CRP); sponsor-authored (Novo Nordisk). Distinct PMID from the STEP-HFpEF primaries. Folded from T12-GLP1R-04 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-SEMA-CARDIO-HF-01", "grade": "moderate", "source": { "citation": "Verma S et al., J Am Coll Cardiol 2024;84(17):1646-1662 (STEP-HFpEF inflammation analysis)", "url": "https://doi.org/10.1016/j.jacc.2024.08.028", "identifiers": "PMID:39217564 DOI:10.1016/j.jacc.2024.08.028 NCT04788511 NCT04916470", "date": "2024-10-22", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; sponsor-authored)", "scopeLimits": "surrogate/exploratory endpoint; sponsor-authored COI (Novo Nordisk)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-HF-ECHO-01", "sourceId": "PMID39217567", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "decrease", "magnitude": "LA volume -6.13 mL (95% CI -9.85 to -2.41); RV area -1.99 cm2; E/A -0.14; LV systolic unchanged", "finding": "In a prespecified echocardiography substudy of the pooled STEP-HFpEF programme (491 of 1145 participants), semaglutide 2.4 mg attenuated left-atrial remodelling (LA volume difference -6.13 mL, p=0.0013) and right-ventricular enlargement and improved diastolic indices, with no change in LV mass or systolic function; greater weight loss correlated with greater LA-volume reduction.", "population": "prespecified echo substudy of pooled STEP-HFpEF + STEP-HFpEF DM, 491 of 1145 participants, HFpEF + obesity, 52 wk", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "GLP-1R class. STRUCTURAL correlate of the HFpEF benefit (reverse atrial/RV remodelling, improved diastolic filling) distinguishing it from a purely symptomatic effect; LV systolic effect NULL, consistent with the HFrEF failure to benefit. Substudy; sponsor-authored (Novo Nordisk). Distinct substudy PMID from the STEP-HFpEF primaries already in the corpus. Folded from T12-GLP1R-03 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-SEMA-CARDIO-HF-01", "grade": "moderate", "source": { "citation": "Solomon SD et al., J Am Coll Cardiol 2024;84(17):1587-1602 (STEP-HFpEF echo substudy)", "url": "https://doi.org/10.1016/j.jacc.2024.08.021", "identifiers": "PMID:39217567 DOI:10.1016/j.jacc.2024.08.021 NCT04788511 NCT04916470", "date": "2024-10-22", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; sponsor-authored)", "scopeLimits": "surrogate/exploratory endpoint; sponsor-authored COI (Novo Nordisk)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-IMMUNO-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "ADA ~1% (Ozempic, 32/3150) / ~3% (Wegovy, 50/1709); no clinically significant PK effect", "finding": "Anti-semaglutide antibodies develop in roughly 1-3% of patients with no identified clinically significant effect on pharmacokinetics.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "immunogenicity", "notes": "US PI 12.6. ADA incidence is HIGHLY ASSAY- AND TRIAL-POOL-DEPENDENT (Ozempic glycaemic pool vs Wegovy 68-wk obesity pool); the 1%-vs-3% step is not a head-to-head, and the cross-drug contrast with tirzepatide (~51-65%) is partly an assay artefact - do not state as a clean biological comparison.", "crossRef": "C-TIRZ-IMMUNO-01", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-IRON-01", "sourceId": "PMID40116342", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "10 weeks of semaglutide cut the post-oral-iron-load serum iron rise from ~19% to ~8% (p=0.013); TSAT rise attenuated to 7%; median relative reduction ~13%; 17.6% (9/51) lost >=30% of absorption.", "finding": "In 51 people with type-2 diabetes, 10 weeks of semaglutide attenuated (did not abolish) the post-oral-iron-load serum iron rise, consistent with reduced intestinal iron absorption on the drug.", "population": "51 people with type-2 diabetes; single-arm uncontrolled observational pre-post study (no control arm), 10 weeks; post-oral-iron-load serum-iron and TSAT measurement (NCT06629688).", "comparators": "within-subject baseline (no control arm)", "endpointType": "safety-event/signal", "notes": "Small single-arm pilot, no control, 10 weeks; absorption attenuated not abolished. MANDATORY: do NOT assert the mechanism is proven to be genuine malabsorption rather than an acute-phase effect - that stronger restatement was REFUTED 0-3 in adversarial review; hepcidin and inflammation were not measured.", "crossRef": "", "grade": "low", "source": { "citation": "Melis M et al. Effect of semaglutide on intestinal iron absorption in type-2 diabetes: a pilot study. Diabetes Obes Metab 2025.", "url": "https://doi.org/10.1111/dom.16368", "identifiers": "PMID 40116342 / DOI 10.1111/dom.16368 / PMC12046454 / NCT06629688", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-IRON-02", "sourceId": "PMID40116342", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Authors attribute the reduced absorption (hedged 'may') to delayed gastric emptying / altered GI motility; warn of possible iron-deficiency/anaemia risk in susceptible patients; suggest iron-status monitoring.", "finding": "The authors attribute the reduced iron absorption (author-hedged 'may') to delayed gastric emptying / altered GI motility, warn it could contribute to iron deficiency or anaemia in susceptible patients, and suggest monitoring iron status.", "population": "51 people with type-2 diabetes; single-arm uncontrolled observational pre-post study (no control arm), 10 weeks; post-oral-iron-load serum-iron and TSAT measurement (NCT06629688).", "comparators": "within-subject baseline (no control arm)", "endpointType": "safety-event/signal", "notes": "Author interpretation, hedged. Same small single-arm pilot; mechanism attribution is hypothesis, not proven.", "crossRef": "C-SEMA-IRON-01", "grade": "low", "source": { "citation": "Melis M et al. Effect of semaglutide on intestinal iron absorption in type-2 diabetes: a pilot study. Diabetes Obes Metab 2025.", "url": "https://doi.org/10.1111/dom.16368", "identifiers": "PMID 40116342 / DOI 10.1111/dom.16368 / PMC12046454 / NCT06629688", "date": 2025, "design": "observational cohort", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-LACTATION-EU-01", "sourceId": "CIT:ozempic-eu-smpc-emc-9750", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "EU: should not be used during breast-feeding", "finding": "The EU SmPC states semaglutide should not be used during breast-feeding.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/lactation", "notes": "EU Ozempic SmPC 4.6. REGIONAL CONTRAST: opposite posture to the US benefit/risk framing, and opposite to tirzepatide's EU 'could be considered' (C-TIRZ-LACTATION-EU-01).", "crossRef": "C-SEMA-LACTATION-US-01; C-TIRZ-LACTATION-EU-01", "grade": "high", "source": { "citation": "Ozempic (semaglutide) EU Summary of Product Characteristics (EMA)", "url": "https://www.medicines.org.uk/emc/product/9750/smpc", "identifiers": "EMC product 9750 (EMA Annex I)", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-LACTATION-US-01", "sourceId": "CIT:wegovy-us-pi-dailymed-f5e548d0", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "No human milk data; rat milk 3-12x below maternal plasma", "finding": "US labelling states there are no data on the presence of semaglutide in human milk; in lactating rats it was detected in milk at 3-12-fold lower levels than maternal plasma, and advises weighing breastfeeding benefits against clinical need.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/lactation", "notes": "US PI 8.2. Label HEDGE (no human data) - does not imply a measured human milk level. Fills the prior breastfeeding corpus blank (OQ-REPRO-A). EU posture differs - see C-SEMA-LACTATION-EU-01.", "crossRef": "C-SEMA-LACTATION-EU-01", "grade": "high", "source": { "citation": "Wegovy (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "identifiers": "DailyMed setid f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-MICROBIOME-01", "sourceId": "PMID41132642", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "Small uncontrolled human study (15 Chinese type-2-diabetes patients on metformin, 12-week single-arm semaglutide): 16S showed structural (beta-diversity) shifts - phylum-level Firmicutes decreased and Bacteroidota/Actinobacteriota/Proteobacteria increased; genus-level Bifidobacterium increased and Klebsiella decreased. The authors explicitly concede the single-arm no-control design CANNOT establish causation and that appetite/diet modulation is a confounder.", "finding": "A small 12-week single-arm study in 15 type-2-diabetes patients found semaglutide changed gut-microbiota composition (e.g. more Bifidobacterium, less Firmicutes), but with no control group and an appetite/diet confound the authors themselves say causation cannot be established.", "population": "15 Chinese type-2-diabetes patients poorly controlled on metformin; 12-week single-arm semaglutide; 16S rRNA, n=15 (no control arm).", "comparators": "baseline (pre-treatment)", "endpointType": "mechanistic/physiological", "notes": "HUMAN but n=15, single-arm, no control -> low (species floor exempted by the human-cohort tokens; NOT inflated above low). Authors concede no causation + appetite/diet confound. Direction:no-change tags this as a compositional/mechanism finding, not an efficacy direction. Read with the structural no-causation finding.", "crossRef": "C-CLASS-MICROBIOME-NOCAUSE-01", "grade": "low", "source": { "citation": "Chen Y, Shan Y, Wang T, Liu Z, Zhao Z, He Y. The Effect of Semaglutide on Gut Microbiota in Chinese Patients with Type 2 Diabetes Poorly Controlled by Metformin. Diabetes Metab Syndr Obes 2025;18:3865-3881.", "url": "https://doi.org/10.2147/DMSO.S537001", "identifiers": "DOI:10.2147/DMSO.S537001", "date": "2025-10", "design": "unspecified", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (n=15); single-arm (no control); short duration (12wk); appetite/diet confound", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-MICROBIOME-RODENT-01", "sourceId": "PMID39148685", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "Semaglutide shifts gut-microbiota composition in obese mice: in HFD C57BL/6J mice, 12 weeks of semaglutide reversed HFD-induced compositional changes (16S), with the shifted taxa correlating with reduced pro-inflammatory cytokines and improved cognition. This is a rodent 16S compositional/correlational result - it does NOT show the microbiome shift causes the metabolic or behavioural effect.", "finding": "In obese mice, semaglutide reversed diet-induced gut-microbiota changes (16S), with the shifted taxa correlating with lower inflammation - but this is a compositional/correlational rodent finding, not evidence that the microbiome mediates semaglutide's effects.", "population": "High-fat-diet C57BL/6J obese mice; 12-week semaglutide vs HFD/normal-chow controls; 16S rRNA (Feng 2024 PeerJ).", "comparators": "high-fat-diet control; normal-chow control", "endpointType": "mechanistic/physiological", "notes": "RODENT, very-low. Semaglutide pole of the cross-agent compositional reproducibility. 16S-only, correlational, food-intake confounded. Corroborates C-CLASS-MICROBIOME-01 (liraglutide side).", "crossRef": "C-CLASS-MICROBIOME-01", "grade": "very-low", "source": { "citation": "Feng J, Teng Z, Yang Y, Liu J, Chen S. Effects of semaglutide on gut microbiota, cognitive function and inflammation in obese mice. PeerJ 2024;12:e17891.", "url": "https://doi.org/10.7717/peerj.17891", "identifiers": "DOI:10.7717/peerj.17891", "date": "2024-08", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; 16S compositional only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-NULL-ALZHEIMERS-01", "sourceId": "PMID41865758", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "no-change", "magnitude": "evoke + evoke+ (n=3808, early symptomatic AD): CDR-SB difference -0.08 (95% CI -0.35 to 0.20) p=0.57 (evoke) and 0.10 (-0.17 to 0.38) p=0.46 (evoke+); both trials discontinued for negative outcome; biomarkers improved without clinical benefit.", "finding": "In two fully-powered phase-3 trials, oral semaglutide did NOT slow clinical progression of early Alzheimer's disease versus placebo (primary endpoint CDR-SB) - a measured null that reverses the optimistic epidemiological GLP-1/dementia-association literature.", "population": "evoke and evoke+ (NCT04777396, NCT04777409): 3808 participants with early symptomatic Alzheimer's disease, oral semaglutide up to 14 mg once daily vs placebo; two multicentre randomised double-blind placebo-controlled phase-3 trials across 566 sites in 40 countries.", "comparators": "placebo", "endpointType": "measured-null", "notes": "MEASURED NULL (not a gap): fully-powered primary-endpoint failure. READ-ACROSS BOUNDARY: this is ORAL SEMAGLUTIDE in early AD; do NOT generalise to 'GLP-1s do not work in dementia' nor attribute to tirzepatide/retatrutide (neither tested in AD).", "crossRef": "", "grade": "high", "source": { "citation": "Cummings et al., Oral semaglutide in early symptomatic Alzheimer's disease (evoke and evoke+), Lancet 2026", "url": "https://doi.org/10.1016/S0140-6736(26)00459-9", "identifiers": "DOI:10.1016/S0140-6736(26)00459-9", "date": "2026-03-19", "design": "double-blind RCT", "maturity": "human-primary", "funding": "Novo Nordisk", "scopeLimits": "industry-sponsored; primary endpoint negative", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-NULL-CVDEATH-SELECT-01", "sourceId": "PMID37952131", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "SELECT (n=17,604): cardiovascular-death component HR 0.85 (95% CI 0.71-1.01), CI crosses 1 - did not independently reach significance (appendix-sourced). Context: composite MACE HR 0.80 (0.72-0.90) and all-cause death HR 0.81 (0.71-0.93) WERE significant.", "finding": "In SELECT, semaglutide's cardiovascular-death component did not independently reach significance, despite a positive composite MACE and a significant all-cause-mortality reduction - a component null, NOT evidence that semaglutide fails to reduce CV death.", "population": "Peer-reviewed RCT (measured null)", "comparators": "placebo", "endpointType": "measured-null", "notes": "BOTH-POLED: the point estimate (0.85) is protective-leaning within a positive trial. The CV-death HR is from the SELECT supplementary appendix, not the primary abstract.", "crossRef": "C-SEMA-CARDIO-01; C-SEMA-CARDIO-07", "grade": "high", "source": { "citation": "Lincoff AM et al. (SELECT), NEJM, 2023", "url": "https://doi.org/10.1056/NEJMoa2307563", "identifiers": "PMID 37952131; DOI 10.1056/NEJMoa2307563; NCT03574597", "date": "2023-11-11", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-NULL-PIONEER6-COMPONENTS-01", "sourceId": "PMID31185157", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "PIONEER-6: non-fatal MI HR 1.18 (95% CI 0.73-1.90), non-fatal stroke HR 0.74 (0.35-1.57) - both CIs cross 1 (measured component nulls). MACE HR 0.79 (0.57-1.11) non-inferior; superiority not tested (non-inferiority safety design).", "finding": "In PIONEER-6, oral semaglutide showed no significant effect on the individual non-fatal MI or stroke components; the MACE 'non-superiority' is a design feature of a non-inferiority safety trial, not a measured efficacy null.", "population": "Peer-reviewed RCT (measured null)", "comparators": "placebo", "endpointType": "measured-null", "notes": "MEASURED component nulls (wide CIs, both-poled). The MACE-superiority is NEVER-MEASURED-AT-POWER and is already recorded in C-SEMA-CARDIO-03 - this row adds only the component detail.", "crossRef": "C-SEMA-CARDIO-03", "grade": "high", "source": { "citation": "Husain M et al. (PIONEER 6), NEJM, 2019", "url": "https://doi.org/10.1056/NEJMoa1901118", "identifiers": "PMID 31185157; DOI 10.1056/NEJMoa1901118; NCT02692716", "date": "2019-06-11", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-OASIS4-WL-01", "sourceId": "PMID40934115", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -13.6% vs placebo -2.2%", "finding": "The lower-dose (25 mg) registrational oral-semaglutide obesity trial gave ~14% weight loss.", "population": "OASIS-4 (NCT05564117): 307 adults without diabetes, BMI >=30 (or >=27 with an obesity-related complication), oral semaglutide 25 mg vs placebo 2:1; 71-week registrational randomised double-blind placebo-controlled RCT at 22 sites in four countries.", "comparators": "", "endpointType": "efficacy", "notes": "Registrational programme; the NEJM article-type metadata field is mis-tagged at a lower study phase, but this is the registrational 25 mg pivotal trial - graded high on its true double-blind RCT design.", "crossRef": "", "grade": "high", "source": { "citation": "Oral semaglutide 25 mg for obesity (OASIS-4), NEJM 2025", "url": "https://doi.org/10.1056/NEJMoa2500969", "identifiers": "DOI:10.1056/NEJMoa2500969", "date": "2025-09-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-ORAL-SAFETY-GI04", "sourceId": "PMID31186300", "drug": "oral semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (oral)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "PIONEER 1: trial-product discontinuations 2.3-7.4% (oral semaglutide 3/7/14 mg) vs 2.2% placebo. Mild-to-moderate transient GI events most common AE", "finding": "GI effects (esp. nausea, vomiting) most frequent AEs across the PIONEER programme; mild-to-moderate, faded with time. PIONEER 1 trial-product discontinuations dose-related.", "population": "PIONEER 1: 703 adults with T2D on diet/exercise; 26 weeks; phase 3a RCT, oral semaglutide 3/7/14 mg vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "PMID/DOI and discontinuation range CONFIRMED directly via PubMed (corrects fork's earlier review-channel tag). Per-symptom nausea rates (e.g. 16.0% on 14 mg) from broader PIONEER reporting.", "crossRef": "C-SEMA-SAFETY-GI01", "grade": "high", "source": { "citation": "Aroda VR et al., Diabetes Care 2019 (PIONEER 1)", "url": "https://doi.org/10.2337/dc19-0749", "identifiers": "PMID:31186300 / DOI:10.2337/dc19-0749 / NCT02906930", "date": "2019-06-11", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-BIOAVAIL-ORAL-01", "sourceId": "CIT:rybelsus-us-pi-dailymed-27f15fac", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Oral absolute bioavailability ~0.4-1%, SNAC-dependent", "finding": "Oral semaglutide (Rybelsus) has a very low absolute bioavailability (~0.4-1%) and requires the SNAC absorption enhancer; absorption is highly sensitive to fasting/water conditions.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "Rybelsus PI 12.3.", "crossRef": "", "grade": "high", "source": { "citation": "Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98", "identifiers": "DailyMed setid 27f15fac-7d98-4114-a2ec-92494a91da98", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-BIOAVAIL-SC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Absolute s.c. bioavailability 89%", "finding": "Subcutaneous semaglutide has an absolute bioavailability of 89%.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-EXCR-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Excreted urine + faeces; ~3% intact in urine", "finding": "Semaglutide-related material is excreted via urine and faeces, with ~3% of the dose excreted as intact semaglutide in urine.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-HALFLIFE-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Elimination half-life ~1 week; drug present in circulation ~5 weeks (Ozempic) / ~5-7 weeks (Wegovy)", "finding": "Subcutaneous semaglutide has an elimination half-life of approximately one week, the basis for once-weekly dosing and the prolonged washout.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3. EU SmPC states '~1 week'; a numeric terminal half-life of ~148 h appears in the EPAR assessment report (NOT the SmPC) and is held pending an EPAR source row.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-METAB-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Proteolytic cleavage + beta-oxidation of fatty-acid sidechain; not CYP", "finding": "Semaglutide is cleared mainly by metabolism via proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty-acid side chain, not by CYP enzymes.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3. Label does not provide an explicit 'not a CYP substrate' sentence; absence of named CYP interactions is implied.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-SS-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Steady state after 4-5 weeks of once-weekly dosing", "finding": "Steady-state semaglutide exposure is reached after 4-5 weeks of once-weekly administration.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "Ozempic PI 12.3. The Wegovy render omitted the interval, so this is scoped to Ozempic, not asserted as a Wegovy-labelled fact.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PK-VD-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Apparent Vd ~12.5 L (s.c.) / ~8 L (oral); >99% albumin-bound", "finding": "Semaglutide has a small volume of distribution consistent with high (>99%) albumin binding.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3 (s.c.); Rybelsus 12.3 (oral). Apparent (s.c.) and absolute (oral) Vd are different parameters; not conflated.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-PREG-LABEL-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "increase", "magnitude": "Animal embryofetal mortality, structural anomalies, growth reduction (rat/rabbit/monkey) at/below MRHD; human data insufficient", "finding": "Animal reproduction studies show embryofetal mortality, structural abnormalities and growth alterations across rat, rabbit and monkey at exposures at or below the human dose; the label states human data are insufficient to establish a drug-associated risk and to discontinue when pregnancy is recognised.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "reproductive-tox", "notes": "US PI 8.1. The animal harm is a positive finding; the human-risk conclusion is a label hedge ('insufficient').", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-REG-GCGR-NEGATIVE-01", "sourceId": "CIT:ozempic-nda-209637-pharmtox-refid-4134195", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "no human glucagon-receptor binding; broad receptor-profile assay showed no >50% inhibition/stimulation at any other receptor (only a non-specific thyroid-hormone-receptor result)", "finding": "FDA Ozempic Pharm/Tox review confirms semaglutide does not bind the human glucagon receptor, and a broad receptor-profile assay showed no greater-than-50% activity at any other receptor. The GLP-1 monoagonist comparator is GCGR-negative, completing (with the tirzepatide GCGR-silence datum) the receptor-level elimination: the glucagon arm is the sole added pharmacology in retatrutide versus both characterised duals.", "population": "In-vitro human receptor binding/selectivity assays (FDA NDA 209637 Pharm/Tox, Sec 4.2 Secondary Pharmacology, p.31)", "comparators": "broad receptor panel", "endpointType": "pharmacology-receptor", "notes": "Promoted from sweep SW-REG-02 (2026-06-21). Load-bearing for glucagon-attribution-by-elimination: the GLP-1-mono comparator carries no GCGR contamination.", "crossRef": "", "grade": "low", "source": { "citation": "FDA Ozempic NDA 209637 Pharmacology/Toxicology Review, Reference ID 4134195 (reviewer Basso)", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000PharmR.pdf", "identifiers": "FDA Reference ID 4134195 (NDA 209637)", "date": "2017-12-05", "design": "in-vitro / cell-line / SAR", "maturity": "regulatory-doc", "funding": "industry - Novo Nordisk (applicant/manufacturer; FDA Pharm/Tox review of Novo's NDA 209637 submission)", "scopeLimits": "in-vitro receptor assay; human relevance via pharmacology only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-REG-RMR-INTAKE-01", "sourceId": "CIT:ozempic-nda-209637-clinpharm-refid-4142722", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "decrease", "magnitude": "resting metabolic rate significantly LOWER on semaglutide vs placebo (treatment difference -601.9 kJ/24h); energy intake ~24% lower", "finding": "FDA Ozempic Clinical Pharmacology review: in obese non-diabetics semaglutide weight loss was driven by ~24% lower energy intake, NOT energy expenditure - resting metabolic rate was significantly lower on semaglutide (-601.9 kJ/24h), and the reviewer concluded weight loss is more related to appetite/intake than to expenditure. Supports 'EE not demonstrably raised (chronic GLP-1-mono)', NOT a causal EE-suppression claim: the post-hoc lower RMR is mass-confounded (lower RMR is the trivial consequence of lower mass).", "population": "Obese non-diabetic adults, Study NN9535-3685 (FDA NDA 209637 ClinPharm PD section, p.45-47)", "comparators": "placebo", "endpointType": "physiological-surrogate", "notes": "Promoted from sweep SW-REG-04 (2026-06-21). Audit caveats: MODERATE, sponsor-derived, POST-HOC RMR; red-team mass-confounded - directional only, no causal EE-suppression claim. Chronic GLP-1-mono baseline: intake-driven, EE not raised.", "crossRef": "C-CLASS-RODENT-EEDEFENCE-01", "grade": "moderate", "source": { "citation": "FDA Ozempic NDA 209637 Clinical Pharmacology Review, Reference ID 4142722, Study NN9535-3685", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf", "identifiers": "FDA Reference ID 4142722 (NDA 209637)", "date": "2017-12-05", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "industry - Novo Nordisk (applicant/manufacturer; FDA Clinical Pharmacology review of Novo's NDA 209637 submission)", "scopeLimits": "post-hoc / exploratory RMR-intake analysis; mass-confounded (lower RMR tracks lower mass)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-BIL03", "sourceId": "PMID40189856", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Semaglutide gallbladder/cholelithiasis RR ~2.6 (1.40-4.82); tirzepatide biliary NS", "finding": "In obesity without diabetes, semaglutide increased gallbladder disorders (esp. cholelithiasis) >2.6-fold, whereas tirzepatide showed no significant biliary risk; neither significantly increased hepatic or pancreatic AEs.", "population": "13 RCTs, 26,894 obese participants without diabetes; meta-analysis", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Notable divergence: biliary signal attached to semaglutide but not tirzepatide in obesity-only; why left open.", "crossRef": "C-TIRZ-SAFETY-BIL02; C-CLASS-SAFETY-BIL01", "grade": "moderate", "source": { "citation": "Safwan M et al., Ann Saudi Med 2025", "url": "https://doi.org/10.5144/0256-4947.2025.129", "identifiers": "PMID:40189856 / DOI:10.5144/0256-4947.2025.129", "date": "2025-04-03", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic/independent - no funding (None)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-BIL15", "sourceId": "PMID41639322", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Bile-duct cancer (n=4) ROR 2.30, IC 0.23, PRR 2.30. Among 442 neoplasms: pancreatic 70, breast 28, MTC 15, thyroid 14, bile-duct 6", "finding": "VigiBase disproportionality identified a potential signal between semaglutide and bile-duct cancer (cholangiocarcinoma); pancreatic cancer was the most frequent neoplasm reported.", "population": "VigiBase ICSRs 1 Jan 2009-31 Jul 2023; disproportionality", "comparators": "VigiBase background", "endpointType": "safety-event/signal", "notes": "Emerging/contested bile-duct signal; small n (4 cases); causality cannot be established.", "crossRef": "C-SEMA-SAFETY-BIL03; C-CLASS-SAFETY-MTC14", "grade": "very-low", "source": { "citation": "Kaur RJ et al., Indian J Gastroenterol 2026", "url": "https://doi.org/10.1007/s12664-025-01891-4", "identifiers": "PMID:41639322 / DOI:10.1007/s12664-025-01891-4", "date": "2026-02-04", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE01", "sourceId": "PMID38958939", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "T2D: 36-mo cumulative 8.9% vs 1.8%, HR 4.28 (1.62-11.29). Overweight/obese: 6.7% vs 0.8%, HR 7.64 (2.21-26.36)", "finding": "Index signal-raising cohort: patients on semaglutide had markedly higher cumulative NAION incidence than those on non-GLP-1 RA medications, in both T2D and overweight/obese populations.", "population": "Retrospective matched cohort, single neuro-ophthalmology registry (Mass Eye and Ear); 710 T2D, 979 overweight/obese; Dec 2017-Nov 2023", "comparators": "non-GLP-1 RA antidiabetics; non-GLP-1 RA weight-loss meds", "endpointType": "safety-event/signal", "notes": "Triggered the regulatory reviews. Single-centre referral-enriched population; absolute incidence not generalisable; causality not established.", "crossRef": "C-SEMA-SAFETY-EYE02; C-SEMA-SAFETY-EYE05; C-CLASS-SAFETY-EYE06; C-SEMA-SAFETY-EYE08", "grade": "low", "source": { "citation": "Hathaway JT et al., JAMA Ophthalmol 2024", "url": "https://doi.org/10.1001/jamaophthalmol.2024.2296", "identifiers": "PMID:38958939 / DOI:10.1001/jamaophthalmol.2024.2296", "date": "2024-08-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE02", "sourceId": "PMID39696569", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "~Doubled 5-yr NAION risk (HR approx 2.2)", "finding": "Danish nationwide cohort (signal-confirming): once-weekly semaglutide roughly doubled five-year NAION risk in T2D.", "population": "Danish nationwide registry, 424,152 persons with T2D", "comparators": "non-semaglutide T2D", "endpointType": "safety-event/signal", "notes": "Population-based replication; far lower absolute incidence than the referral-centre study. HR magnitude to confirm vs full text.", "crossRef": "C-SEMA-SAFETY-EYE01", "grade": "low", "source": { "citation": "Danish cohort, Int J Retina Vitreous 2024", "url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657653/", "identifiers": "PMID 39696569; DOI 10.1186/s40942-024-00620-x [VERIFIED 2026-06-20]", "date": "2024-12-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "identifier not fully verified; single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE04", "sourceId": "PMID40146102", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "1-yr HR 1.94 (0.93-4.02, NS); 2-yr HR 2.39 (1.37-4.18); 3-yr 2.44 (1.44-4.12); 4-yr 2.05 (1.26-3.34)", "finding": "TriNetX global cohort (time-dependent): no NAION increase up to 1 year, but elevated risk at 2-4 years in diabetes.", "population": "TriNetX; 174,584 semaglutide vs 174,584 non-GLP-1 RA with diabetes; Oct 2019-Dec 2023", "comparators": "non-GLP-1 RA antidiabetics", "endpointType": "safety-event/signal", "notes": "Null early, significant from 2 yr; follow-up length drives the signal. Risk also raised with concomitant hypertension.", "crossRef": "C-SEMA-SAFETY-EYE01; C-SEMA-SAFETY-EYE05; C-CLASS-SAFETY-EYE06", "grade": "low", "source": { "citation": "Hsu AY et al., JAMA Ophthalmol 2025", "url": "https://doi.org/10.1001/jamaophthalmol.2025.0349", "identifiers": "PMID:40146102 / DOI:10.1001/jamaophthalmol.2025.0349", "date": "2025-05-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE05", "sourceId": "PMID41217382", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "T2D: OR 0.36 (0.25-0.51); overweight/obesity OR 0.10 (0.01-1.35, NS); 2447 NAION events among 1,212,775", "finding": "REFUTING/NULL pole: in a large racially diverse Military Health System cohort, semaglutide associated with LOWER odds of NAION in T2D and no significant difference in overweight/obesity.", "population": "Military Health System beneficiaries; 973,529 T2D + 239,246 overweight/obese; Dec 2017-Sep 2023", "comparators": "non-GLP-1 RA medications; PDE-5 inhibitors (subset)", "endpointType": "safety-event/signal", "notes": "Directly contradicts the signal cohorts; authors conclude NAION risk should not preclude use.", "crossRef": "C-SEMA-SAFETY-EYE01; C-CLASS-SAFETY-EYE06", "grade": "low", "source": { "citation": "Lieberman RA et al., Mil Med 2026", "url": "https://doi.org/10.1093/milmed/usaf522", "identifiers": "PMID:41217382 / DOI:10.1093/milmed/usaf522", "date": "2026-05-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE07", "sourceId": "PMID42201355", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "1-yr pooled HR 3.36 (1.44-7.84, I2 97%); 2-yr 2.37 (1.46-3.85, I2 0%); 3-yr 2.37 (1.45-3.87)", "finding": "SIGNAL-confirming meta-analysis (T2D-restricted): semaglutide associated with increased NAION risk vs non-GLP-1RAs, persisting across follow-up windows.", "population": "Meta-analysis; 8 retrospective cohorts (14,255,247 participants), mean age 59.3 yr", "comparators": "non-GLP-1 RA medications", "endpointType": "safety-event/signal", "notes": "Very high 1-yr heterogeneity (I2 97%). Tensioned against the null class meta-analysis (same year, opposite conclusion, differing inclusion).", "crossRef": "C-CLASS-SAFETY-EYE06; C-SEMA-SAFETY-EYE01", "grade": "moderate", "source": { "citation": "Lampsas S et al., Graefes Arch Clin Exp Ophthalmol 2026", "url": "https://doi.org/10.1007/s00417-026-07291-4", "identifiers": "PMID:42201355 / DOI:10.1007/s00417-026-07291-4", "date": "2026-05-27", "design": "meta-analysis", "maturity": "review", "funding": "academic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-EYE08", "sourceId": "CIT:ema-prac-highlights-2-5-june-2025-who-safety-com", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "NAION listed 'very rare' (up to 1 in 10,000); applies to Ozempic, Rybelsus, Wegovy", "finding": "Regulatory: EMA PRAC concluded its review and recommended adding NAION to semaglutide product information as a 'very rare' side effect; WHO issued a confirmatory signal.", "population": "EU regulatory review of all NAION data for semaglutide", "comparators": "", "endpointType": "safety-event/signal", "notes": "Review opened Jan 2025, concluded Jun 2025. UK MHRA Drug Safety Update 5 Feb 2026. 'Very rare' sits between high-HR signal studies and null cohorts.", "crossRef": "C-SEMA-SAFETY-EYE01; C-CLASS-SAFETY-EYE09", "grade": "high", "source": { "citation": "EMA PRAC highlights 2-5 June 2025; WHO safety communication 27 June 2025", "url": "https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-2-5-june-2025", "identifiers": "EMA PRAC June 2025", "date": "2025-06-05", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-GI01", "sourceId": "PMID33567185", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "GI-related discontinuation 4.5% (59/1306) semaglutide vs 0.8% (5/655) placebo", "finding": "Nausea and diarrhoea most common AEs; transient, mild-to-moderate. More semaglutide than placebo participants discontinued for GI events.", "population": "STEP 1: 1961 adults, overweight/obesity, no diabetes; 68 weeks; double-blind RCT", "comparators": "placebo", "endpointType": "other", "notes": "Abstract gives discontinuation figure not per-symptom rates.", "crossRef": "C-LIRA-SAFETY-GI06; C-TIRZ-SAFETY-GI02", "grade": "high", "source": { "citation": "Wilding JPH et al., NEJM 2021 (STEP 1)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2032183", "identifiers": "PMID 33567185; DOI 10.1056/NEJMoa2032183; NCT03548935", "date": "2021-02-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-ILEUS11", "sourceId": "PMID41596262", "drug": "semaglutide (and GLP-1RA class)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "RCT network meta-analysis (Chen et al., Int J Mol Sci 2026): intestinal-obstruction risk NOT elevated for most GLP-1 agents; liraglutide possibly protective (OR 0.44, 95% CI 0.24-0.81).", "finding": "A randomised-trials network meta-analysis found intestinal-obstruction risk not elevated for most GLP-1 agents (liraglutide possibly protective), corroborating the weak/very-low post-marketing spontaneous-report obstruction signal.", "population": "RCT network meta-analysis (Chen et al., Int J Mol Sci 2026; the anchor source) of intestinal-obstruction risk across GLP-1 agents, read against the weaker post-marketing spontaneous-report signal.", "comparators": "placebo/active comparators in RCTs; post-marketing spontaneous-report background", "endpointType": "safety-event/signal", "notes": "Signal-vs-null tension: a spontaneous-report signal exists but trial-level evidence does not confirm elevated mechanical-obstruction risk. [VALIDATION 2026-06-21: the prior CIT placeholder is resolved to PMID41596262 / DOI 10.3390/ijms27020608 for the RCT-network-meta component. The previously-bundled spontaneous-report counts (SIO n=19, ileus n=17, paralytic ileus n=8) could NOT be resolved to a specific source and have been dropped; OQ-D6-D updated.]", "crossRef": "C-CLASS-SAFETY-ILEUS10", "grade": "moderate", "source": { "citation": "Chen JJ et al. Risk of intestinal obstruction with GLP-1 receptor agonists: a randomised-trials network meta-analysis. Int J Mol Sci 2026;27(2):608.", "url": "https://doi.org/10.3390/ijms27020608", "identifiers": "PMID41596262", "date": "2026-01-15", "design": "network meta-analysis", "maturity": "human-primary", "funding": "academic/independent - no external funding", "scopeLimits": "network meta-analysis of RCTs for a rare event; obstruction risk not elevated for most agents", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-MH03", "sourceId": "PMID38182782", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Incident SI HR 0.27 (0.20-0.36); recurrent SI HR 0.44 (0.32-0.60). 6-month incident SI 0.11% (sema) vs 0.43% (comparator)", "finding": "Real-world propensity-matched cohort (TriNetX EHR): semaglutide associated with LOWER risk of incident and recurrent suicidal ideation vs non-GLP1R anti-obesity meds; replicated in T2DM.", "population": "240,618 overweight/obese (mean 50.1y, 72.6% female); replicated in 1,589,855 T2DM; retrospective cohort emulation, 6-month follow-up", "comparators": "non-GLP1R anti-obesity medications; non-GLP1R anti-diabetes medications", "endpointType": "safety-event/signal", "notes": "Per PubMed. Protective-direction pole; key evidence cited by both FDA and EMA. Retrospective EHR (confounding by indication/channelling possible).", "crossRef": "C-CLASS-SAFETY-MH01; C-CLASS-SAFETY-MH02", "grade": "low", "source": { "citation": "Wang W, Volkow ND, Berger NA, Davis PB, Kaelber DC, Xu R. Nat Med 2024;30(1):168-176", "url": "https://doi.org/10.1038/s41591-023-02672-2", "identifiers": "PMID:38182782 / DOI:10.1038/s41591-023-02672-2", "date": "2024-01-05", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-MH09", "sourceId": "PMID39226070", "drug": "semaglutide (and GLP-1 RA class)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "PHQ-9 wk68 mean 2.0 (sema) vs 2.4 (placebo); treatment diff -0.56 (95% CI -0.81 to -0.32; P<0.001); OR 0.63 (0.50-0.79) for shift to more severe PHQ-9 category; SI/behaviour <=1%, no difference; pooled N=3681", "finding": "Across the STEP programme (RCT data), depression-symptom endorsement on PHQ-9 similar/lower for semaglutide 2.4 mg vs placebo; pooled analysis found no clinically meaningful difference in incident significant depressive symptoms and no PHQ-9 worsening.", "population": "Post-hoc analysis of the pooled STEP 1/2/3/5 placebo-controlled RCTs in adults with obesity (PHQ-9 psychiatric-safety endpoints).", "comparators": "placebo", "endpointType": "symptom/PRO", "notes": "RCT-level no-signal pole, post-hoc psychiatric-safety analysis. [VERIFIED 2026-06-20]: identifier resolved to PMID 39226070; prior magnitude (3.4% vs 5.0% endorsement) did not match paper and was corrected to PHQ-9 mean diff / shift OR.", "crossRef": "C-TIRZ-SAFETY-MH08", "grade": "moderate", "source": { "citation": "Wadden TA et al., JAMA Intern Med 2024 (STEP 1/2/3/5 psychiatric post hoc)", "url": "https://doi.org/10.1001/jamainternmed.2024.4346", "identifiers": "PMID 39226070; DOI 10.1001/jamainternmed.2024.4346", "date": "2024-08-26", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-MTC09", "sourceId": "CIT:ozempic-wegovy-semaglutide-us-prescribing-inform", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Dose/duration-dependent increase in rodent C-cell adenomas/carcinomas (qualitative; rodent)", "finding": "FDA boxed warning: in mice and rats semaglutide caused dose- and treatment-duration-dependent thyroid C-cell tumours (adenomas/carcinomas) at clinically relevant exposures; contraindicated with personal/family history of MTC or MEN 2. Human relevance not determined.", "population": "Lifetime rodent carcinogenicity studies; regulatory label", "comparators": "vehicle control", "endpointType": "safety-event/signal", "notes": "Rodent-primary signal anchoring the class boxed warning; human relevance explicitly 'not determined'.", "crossRef": "C-LIRA-SAFETY-MTC08; C-TIRZ-SAFETY-MTC10; C-CLASS-SAFETY-MTC11", "grade": "high", "source": { "citation": "Ozempic/Wegovy (semaglutide) US Prescribing Information, FDA", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209637s035,209637s037lbl.pdf", "identifiers": "Drugs@FDA NDA 209637/215256 (Boxed Warning)", "date": "2025-01-01", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-PV06", "sourceId": "PMID38943656", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "10 unexpected serious adverse signals (disproportionality/Bayesian)", "finding": "FAERS flagged unexpected signals for semaglutide incl. pancreatic cancer, intestinal obstruction (ileus), cholecystitis and polycystic ovary.", "population": "FAERS Q1 2018-Q4 2023; disproportionality", "comparators": "FAERS background", "endpointType": "safety-event/signal", "notes": "Disproportionality != causality. Cholecystitis/pancreatic-cancer signals concordant with biliary/pancreatic records.", "crossRef": "C-SEMA-SAFETY-BIL03", "grade": "very-low", "source": { "citation": "Du Y et al., J Diabetes Investig 2024", "url": "https://doi.org/10.1111/jdi.14229", "identifiers": "PMID:38943656 / DOI:10.1111/jdi.14229", "date": "2024-06-29", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "disproportionality: reporting != incidence/causality", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-REGAIN14", "sourceId": "PMID35441470", "drug": "semaglutide (2.4 mg s.c.)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Week 0-68 mean loss 17.3% (SD 9.3); regained 11.6 percentage points by week 120 (net loss 5.6% [SD 8.9] vs placebo net 0.1%); placebo regained 1.9 pts", "finding": "One year after withdrawal of semaglutide 2.4 mg plus lifestyle intervention, participants regained about two-thirds of lost weight and cardiometabolic improvements reverted towards baseline.", "population": "STEP 1 trial extension (NCT03548935), off-treatment, n=327 subset, adults without diabetes", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Per PubMed; numbers CONFIRMED via metadata. Frames obesity as chronic relapsing. Weight-regain straddles safety-other and weight-loss domains.", "crossRef": "C-TIRZ-SAFETY-REGAIN15 (weight-loss domain: durability/rebound)", "grade": "low", "source": { "citation": "Wilding JPH et al., Diabetes Obes Metab 2022", "url": "https://doi.org/10.1111/dom.14725", "identifiers": "PMID:35441470 / DOI:10.1111/dom.14725 / PMC9542252", "date": "2022-05-19", "design": "observational cohort", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-RETINO10", "sourceId": "PMID27633186", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Retinopathy complications HR 1.76 (1.11-2.78; P=0.02); 3.0% vs 1.8%", "finding": "Diabetic retinopathy complications significantly more frequent with semaglutide than placebo in SUSTAIN-6 (early-worsening signal).", "population": "SUSTAIN-6 RCT; 3297 T2D at high CV risk; semaglutide 0.5/1.0 mg vs placebo, 104 weeks", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Widely attributed to rapid glucose-lowering ('early worsening') in pre-existing retinopathy/poor control rather than a direct drug effect; mechanism left open. Prompted the FOCUS trial.", "crossRef": "C-SEMA-SAFETY-RETINO11", "grade": "high", "source": { "citation": "Marso SP et al. (SUSTAIN-6), NEJM, 2016", "url": "https://doi.org/10.1056/NEJMoa1607141", "identifiers": "PMID 27633186; DOI 10.1056/NEJMoa1607141; NCT01720446", "date": "2016-09-15", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SAFETY-RETINO11", "sourceId": "NCTNCT03811561", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Planned ~5-yr follow-up of DR progression; primary endpoint first DR-progression event. Result UNCONFIRMED in this pass", "finding": "Dedicated long-term retinopathy trial (FOCUS) evaluated semaglutide effect on diabetic retinopathy progression over ~5 years.", "population": "FOCUS RCT, ~1500 T2D with diabetic retinopathy, semaglutide 1.0 mg s.c. weekly vs placebo, ~5 yr", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Registry identifier cited; full results NOT opened this pass, so magnitude is UNCONFIRMED and flagged. Direction 'mixed' pending data. [RE-CHECK 2026-06-22: registry record confirmed against ClinicalTrials.gov NCT03811561 - official title 'Long-term Effects of Semaglutide on Diabetic Retinopathy in Subjects With Type 2 Diabetes', status ACTIVE (not recruiting), n~1500, semaglutide 0.25->1.0 mg s.c. weekly vs placebo, primary endpoint >=3-step ETDRS subject-level DR progression by Year 5, hasResults=FALSE, estimated completion 2027-11-07. The finding claims only that the trial EXISTS and what it evaluates - that design/existential claim is now VERIFIED against the primary registry. The OUTCOME remains genuinely unreported (no results posted), so magnitude stays UNCONFIRMED and direction 'mixed pending data'; do NOT cite a FOCUS result.]", "crossRef": "C-SEMA-SAFETY-RETINO10", "grade": "very-low", "source": { "citation": "FOCUS trial, ClinicalTrials.gov", "url": "https://clinicaltrials.gov/study/NCT03811561", "identifiers": "NCT03811561", "date": "2019-01-22", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SPECIALPOP-ELDERLY-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "No overall efficacy difference by age", "finding": "No overall difference in effectiveness was observed between older (>=65) and younger adults; greater sensitivity of some older individuals cannot be ruled out.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/elderly", "notes": "US PI 8.5. The Wegovy 75+ fracture observation is split out as C-SEMA-WEGOVY-FRACTURE-ELDERLY-01.", "crossRef": "C-SEMA-WEGOVY-FRACTURE-ELDERLY-01", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SPECIALPOP-HEPATIC-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "US: no dose adjustment; EU more restrictive in severe", "finding": "US labelling specifies no dose adjustment for hepatic impairment (no clinically relevant PK change).", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/hepatic", "notes": "US PI 8.7. EU more restrictive in severe hepatic impairment (noted, not primary-sourced here).", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SPECIALPOP-PAED-01", "sourceId": "CIT:wegovy-us-pi-dailymed-f5e548d0", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "Wegovy established >=12 y (obesity); Ozempic adults only", "finding": "Wegovy is established in adolescents aged 12 and older with obesity; Ozempic has no established paediatric use.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/paediatric", "notes": "US PI 8.4. Product-specific cut-off.", "crossRef": "", "grade": "high", "source": { "citation": "Wegovy (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "identifiers": "DailyMed setid f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-SPECIALPOP-RENAL-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "US: no dose adjustment incl. ESRD; EU: more restrictive in severe", "finding": "US labelling specifies no dose adjustment for renal impairment including ESRD (no clinically relevant PK change). 'No dose adjustment' is a label instruction, not a measured null.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/renal", "notes": "US PI 8.6. EU materials are more restrictive in SEVERE renal impairment ('use not recommended') per the EU SmPC; that EU clause is noted but not the primary source here.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-WASHOUT-01", "sourceId": "CIT:ozempic-us-pi-dailymed-adec4fd2", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "Discontinue >=2 months before a planned pregnancy", "finding": "US labelling advises discontinuing semaglutide at least 2 months before a planned pregnancy because of its long half-life.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/pregnancy", "notes": "US PI 8.3. Scoped to US; the EU pre-conception interval is not section-confirmed here. Fills OQ-REPRO-B.", "crossRef": "", "grade": "high", "source": { "citation": "Ozempic (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79", "identifiers": "DailyMed setid adec4fd2-6858-4c99-91d4-531f5f2a2d79", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMA-WEGOVY-FRACTURE-ELDERLY-01", "sourceId": "CIT:wegovy-us-pi-dailymed-f5e548d0", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Wegovy 75+: hip/pelvis fractures 2.4% (17/703) vs 0.6% (4/663) placebo", "finding": "In the cardiovascular-outcomes trial, Wegovy-treated patients aged >=75 reported numerically more hip/pelvis fractures than placebo (2.4% vs 0.6%); small numerators, post-hoc, causality NOT established.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "safety-event/signal", "notes": "US PI 8.5 (Wegovy/obesity-specific). Must NOT generalise to 'semaglutide' or to Ozempic.", "crossRef": "", "grade": "high", "source": { "citation": "Wegovy (semaglutide) US Prescribing Information, Novo Nordisk", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "identifiers": "DailyMed setid f5e548d0-cc79-4c34-a3f5-e20a5b8b6564", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-APP-05", "sourceId": "PMID36655300", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "ad libitum energy intake -35%", "finding": "Semaglutide 2.4 mg reduces food cravings and improves control of eating on the VALIDATED Control of Eating Questionnaire, with improvements sustained to 2 years - the instrument-grade evidence underlying the lay 'food noise' claim for semaglutide.", "population": "STEP-5 CoEQ subgroup (n=174, 104 wk) + mechanism-of-action RCT (n=72, 20 wk); adults with overweight/obesity; semaglutide 2.4 mg vs placebo.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "The deepest, longest, most-replicated craving dataset of the three drugs. CoEQ and the Food Craving Inventory are validated craving instruments; they overlap with but are not identical to 'food noise' as an intrusive-rumination construct (see C-CLASS-APP-FOODNOISE-01). Cross-ref the appetite-intake intake rows (C2-SEMAGLUTIDE-APP-01..04).", "crossRef": "C-CLASS-APP-FOODNOISE-01; C2-SEMAGLUTIDE-APP-01", "grade": "high", "source": { "citation": "Wharton S et al. Two-year effect of semaglutide 2.4 mg on control of eating (STEP 5 CoEQ). Obesity 2023;31(3):703-715 (with Friedrichsen M et al., Diabetes Obes Metab 2021, PMID 33269530, the MoA RCT).", "url": "https://doi.org/10.1002/oby.23673", "identifiers": "PMID36655300", "date": "2023-01-19", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "small sample (N~174)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-BODYCOMP-01", "sourceId": "PMID41068996", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Weight -10% (M7), -13% (M12); fat mass -14% (M7), -18% (M12); lean mass -3 kg at M7 then stable; handgrip +4.5 kg at M12; sarcopenic obesity 49%->33%.", "finding": "SEMALEAN prospective study: semaglutide 2.4 mg reduced total fat mass with an initial lean-mass decline that stabilised after 7 months; handgrip strength improved and prevalence of sarcopenic obesity fell from 49% to 33%; REE normalised to lean mass rose from M7 to M12.", "population": "n=115 enrolled / 106 completers with obesity (68.9% female, mean BMI 46.3); DXA + handgrip + REE at M0, M7, M12; prospective single-arm", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "Single-arm, no placebo. Reports functional improvement (handgrip) and reduced sarcopenic-obesity prevalence despite absolute lean-mass loss - records the muscle-quality/function pole. T2D and prior-GLP-1 subgroups showed attenuated responses.", "crossRef": "", "grade": "moderate", "source": { "citation": "Alissou M et al. (SEMALEAN), Diabetes Obes Metab, 2025", "url": "https://doi.org/10.1111/dom.70141", "identifiers": "PMID 41068996; DOI 10.1111/dom.70141", "date": "2025-10-09", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic/investigator - no external funding declared (NOT industry/Novo Nordisk)", "scopeLimits": "small sample (N~115)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-BODYCOMP-02", "sourceId": "PMID31897524", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Total fat mass -3.4 kg (sema) vs -2.6 kg (cana) (ETD -0.79 kg, NS); total lean mass -2.3 kg (sema) vs -1.5 kg (cana) (ETD -0.78 kg, NS); lean-mass proportion +1.2 pp (sema).", "finding": "SUSTAIN 8 DXA substudy: semaglutide 1.0 mg vs canagliflozin 300 mg in T2D reduced total fat mass, lean mass and visceral fat; proportion of lean mass rose ~1.2 percentage points; changes in visceral fat and fat-to-lean ratio comparable between arms.", "population": "n=178 randomised to DXA substudy (sema n=88, cana n=90); 114 with end-of-treatment data; T2D on metformin; 52 weeks; RCT (NCT03136484)", "comparators": "canagliflozin", "endpointType": "imaging/physiological surrogate", "notes": "Active comparator (SGLT2i), no placebo arm; authors note absolute body-composition impact is speculative without placebo. Head-to-head GLP-1 vs SGLT2i.", "crossRef": "", "grade": "moderate", "source": { "citation": "McCrimmon RJ et al., Diabetologia, 2020", "url": "https://doi.org/10.1007/s00125-019-05065-8", "identifiers": "PMID 31897524; DOI 10.1007/s00125-019-05065-8; NCT03136484", "date": "2020-01-02", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "small sample (N~178)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-BODYCOMP-03", "sourceId": "PMID39168573", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Reduction in epicardial adipose tissue reported (letter; exact volume figures in primary letter, not fully extracted here).", "finding": "STOP randomised trial (T2D): semaglutide reduced epicardial adipose tissue vs comparator over the trial period (epicardial-fat-specific RCT readout).", "population": "STOP (Semaglutide Treatment effect On coronary atherosclerosis Progression) randomised trial in T2D; CT-based epicardial adipose tissue", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Research-letter format (abstract not available in PubMed record); exact EAT magnitude to be confirmed from full letter. Epicardial-fat-specific RCT for semaglutide.", "crossRef": "", "grade": "moderate", "source": { "citation": "Manubolu VS et al. (STOP trial), J Am Coll Cardiol, 2024", "url": "https://doi.org/10.1016/j.jacc.2024.05.065", "identifiers": "PMID 39168573; DOI 10.1016/j.jacc.2024.05.065", "date": "2024-08-27", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "academic / non-commercial (STOP; investigator-initiated; disclosed)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-CNS-01", "sourceId": "PMID39937469", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Grams of alcohol in lab self-administration task beta -0.48 (95% CI -0.85 to -0.11; P=.01); weekly craving beta -0.39 (P=.01); drinks/drinking-day beta -0.41 (P=.04); greater reduction in heavy drinking over time. NO effect on average drinks/day or number of drinking days. Cigarettes/day (smoker subsample) beta -0.10 (P=.005).", "finding": "ADDICTION (alcohol) - the key RCT: in adults with alcohol use disorder, once-weekly low-dose semaglutide reduced alcohol consumed in a laboratory self-administration task and reduced craving, drinks-per-drinking-day and heavy drinking versus placebo, but did NOT change overall drinking frequency. A within-trial smoker subsample also cut cigarettes/day.", "population": "Hendershot AUD RCT (NCT05520775): N=48 non-treatment-seeking adults with AUD; phase-2 double-blind RCT, 9 weeks; semaglutide titrated to 1.0 mg vs placebo; single US centre.", "comparators": "placebo", "endpointType": "other", "notes": "The largest human addiction RCT BUT graded MODERATE, not high: the PRIMARY endpoint is a SURROGATE laboratory self-administration task, and the real-world endpoints (average drinks/day, number of drinking days) were NULL; small N=48, 9 weeks, low dose only, non-treatment-seeking. Positive on craving/lab-task, NULL on real-world frequency - do NOT read as proof semaglutide cuts drinking. Reward-circuit mechanism inferred not measured here (see the rodent mechanism row). Cross-ref the exenatide AUD RCT (which was NEGATIVE on its primary).", "crossRef": "C-EXENATIDE-CNS-01; C-CLASS-CNS-03", "grade": "low", "source": { "citation": "Hendershot CS, Bremmer MP, Paladino MB et al., JAMA Psychiatry, 2025", "url": "https://doi.org/10.1001/jamapsychiatry.2024.4789", "identifiers": "PMID39937469", "date": "2025-04-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain; small sample (N~48); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-CNS-02", "sourceId": "PMID38806481", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "50-56% lower risk of both incident and recurrent AUD over 12 months vs other anti-obesity medications; replicated in 598,803 T2D patients.", "finding": "ADDICTION (alcohol) - the largest real-world signal: in an EHR cohort, semaglutide vs other anti-obesity medications was associated with substantially lower risk of incident and recurrent alcohol use disorder, consistent across subgroups and replicated in T2D. ASSOCIATION ONLY (LOW): confounding-by-indication is unresolved and the signal is NOT corroborated by the semaglutide AUD RCT, which was null on real-world drinking frequency.", "population": "Wang/Xu EHR cohort: N=83,825 obesity (+598,803 T2D replication); 12-month retrospective cohort; semaglutide vs other anti-obesity meds.", "comparators": "other anti-obesity medications", "endpointType": "other", "notes": "Large magnitude (50-56%) but design floors it to LOW: confounding-by-indication is the central threat (people prescribed semaglutide differ systematically), AUD is diagnosis-coded not measured drinking, 12 months only. Directionally concordant with the Hendershot RCT but cannot establish causality. An Author Correction was issued. VALIDATOR: confirm PMID 38806481 + correction 38890337.", "crossRef": "C-SEMAGLUTIDE-CNS-01; C-CLASS-CNS-01", "grade": "low", "source": { "citation": "Wang W, Volkow ND, Berger NA et al., Nat Commun, 2024 (Author Correction PMID 38890337)", "url": "https://doi.org/10.1038/s41467-024-48780-6", "identifiers": "PMID38806481", "date": "2024-05-28", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-CNS-03", "sourceId": "PMID39074369", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "decrease", "magnitude": "Medical encounter for tobacco-use-disorder diagnosis: HR 0.68 (0.63-0.74) vs insulin (strongest) to HR 0.88 (0.81-0.96) vs other GLP-1RAs (weakest but significant); reduced cessation-medication prescriptions/counselling; divergence mostly within 30 days.", "finding": "ADDICTION (tobacco): in a target-trial-emulation EHR study of T2D + tobacco use disorder, semaglutide was associated with lower TUD-related healthcare measures versus seven other antidiabetes classes, including other GLP-1RAs.", "population": "Wang/Xu target-trial emulation (US EHR): N=222,942 new antidiabetes users incl. 5,967 semaglutide with T2D+TUD; 12 months; vs 7 comparator classes.", "comparators": "insulin; metformin; DPP-4 inhibitors; SGLT2 inhibitors; sulfonylureas; thiazolidinediones; other GLP-1 receptor agonists", "endpointType": "other", "notes": "Largest real-world tobacco signal; LOW - confounding-by-indication, the endpoint is healthcare ENCOUNTERS (a proxy, not biochemically-verified abstinence), very early divergence. Directionally consistent with the exenatide smoking RCT. VALIDATOR: confirm PMID 39074369.", "crossRef": "C-EXENATIDE-CNS-02", "grade": "low", "source": { "citation": "Wang W, Volkow ND, Berger NA et al., Ann Intern Med, 2024", "url": "https://doi.org/10.7326/M23-2718", "identifiers": "PMID39074369", "date": "2024-07-30", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-CNS-04", "sourceId": "NCTNCT04777396", "drug": "semaglutide (oral)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "cns-neuropsychiatric", "domainLabel": "cns-neuropsychiatric", "domainSlug": "cns-neuropsychiatric", "direction": "no-change", "magnitude": "Primary endpoint (CDR-SB change) NOT met vs placebo; biomarkers improved but did not translate to slowed clinical progression; 1-year extension discontinued. Combined N=3,808 (EVOKE 1,855 + EVOKE+ 1,953). Exact figures pending CTAD Dec 2025 / peer review.", "finding": "NEURODEGENERATION (Alzheimer's) - the load-bearing NEGATIVE readout: the EVOKE and EVOKE+ phase-3 trials of oral semaglutide in early Alzheimer's did NOT slow disease progression (CDR-SB primary not met) despite company-reported improvement in AD biomarkers - a biomarker/clinical dissociation. The largest GLP-1-in-AD result to date.", "population": "EVOKE (NCT04777396) + EVOKE+ (NCT04777409): amyloid-positive early AD (MCI / mild dementia), age 55-85; phase-3 double-blind placebo-controlled; ~2 years.", "comparators": "placebo", "endpointType": "other", "notes": "LOAD-BEARING NEGATIVE. Contrary to common framing, EVOKE has READ OUT (24 Nov 2025) and was NEGATIVE on the primary clinical endpoint despite a positive biomarker signal. Robustness floored to VERY-LOW: the source is a company (Novo Nordisk, the sponsor) PRESS topline with no PMID/DOI (NON-GRADUATING). COI: the sponsor is reporting its own negative result, and the 'biomarkers improved' claim is sponsor-asserted with figures pending CTAD Dec 2025. The design is a pivotal phase-3, so RE-ASSESS on peer-reviewed publication (potential ceiling high IF endpoint/design integrity is confirmed - do NOT pre-stamp a grade off a press release; peer review could reveal subgroup-salvage spin). Both NCTs confirmed Completed. The positive epidemiology sits at the OTHER pole and was NOT confirmed by this RCT.", "crossRef": "C-LIRAGLUTIDE-CNS-01; C-CLASS-CNS-04", "grade": "very-low", "source": { "citation": "Novo Nordisk topline announcement, 24 Nov 2025 (EVOKE/EVOKE+); CTAD Dec 2025; peer-reviewed paper pending", "url": "https://clinicaltrials.gov/study/NCT04777396", "identifiers": "NCT04777396", "date": "2025-11-24", "design": "trial registry (ongoing/no-data)", "maturity": "press", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C-SEMAGLUTIDE-EE-01", "sourceId": "PMID41405347", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "WAT browning, sympathetic innervation, locomotor activity all increased vs pair-fed; hypothermia rescued; sex-dependent (greater in females); 4-week treatment", "finding": "In diet-induced obese rats with a pair-fed (intake-matched) control, semaglutide produced weight loss beyond caloric restriction alone and, across adipose depots, promoted white adipose tissue browning, smaller adipocytes and enhanced sympathetic innervation - changes largely absent in pair-fed rats. Semaglutide rescued caloric-restriction-associated hypothermia, reduced the small fall in circulating thyroid hormones, potentiated local thyroid input, and sustained increased locomotor activity. Effects were more potent in females.", "population": "Diet-induced obese rats; semaglutide vs ad libitum control vs intake-matched (pair-fed); sex-stratified", "comparators": "ad libitum control; pair-fed control", "endpointType": "imaging/physiological surrogate", "notes": "Food-intake-INDEPENDENT WAT browning/thermogenesis for semaglutide in rodents (pair-fed design), plus a sex-difference signal. Stands against the human class finding that GLP-1 monotherapy shows no EE effect beyond weight loss (C-GLP1CLASS-EE-01) - record both poles; species + endpoint (tissue browning vs whole-body EE) differ. PMC12710457 open. Per PubMed.", "crossRef": "C-GLP1CLASS-EE-01; C-SEMAGLUTIDE-EE-02", "grade": "very-low", "source": { "citation": "Byun S, Sotzen MR, Knappenberger MA, et al. Advantage of Semaglutide: Comprehensive Analysis of Metabolic Impact of Semaglutide-Treated and Pair-Fed Rats. Compr Physiol. 2025;15(6):e70083", "url": "https://doi.org/10.1002/cph4.70083", "identifiers": "PMID 41405347; DOI 10.1002/cph4.70083", "date": "2025-12-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-EE-02", "sourceId": "PMID38493915", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "2-3 fold increase in adipocyte glucose uptake; increased beige adipogenesis and thermogenic capacity ex vivo; N=8", "finding": "In a small human study (T2DM, subcutaneous fat biopsy before and after 6-month semaglutide), therapy restored adipose-derived stem cell proliferation and increased both white and beige adipogenesis ex vivo, with lipid-droplet fragmentation in beige adipocytes. Newly formed beige adipocytes used glucose for canonical thermogenesis; both white and beige adipocytes showed 2-3 fold higher glucose uptake. Insulin sensitivity (HOMA-IR, M-index) was unchanged.", "population": "T2DM patients, N=8, subcutaneous adipose biopsy at baseline and after 6 months semaglutide; adipose-derived stem cells studied ex vivo", "comparators": "within-subject baseline", "endpointType": "imaging/physiological surrogate", "notes": "Human ex-vivo (biopsy-derived) beige-adipogenesis signal for semaglutide; small N, no comparator arm. Endpoint is adipose-progenitor/thermogenic capacity, not whole-body EE - complements rather than contradicts C-GLP1CLASS-EE-01. Per PubMed.", "crossRef": "C-SEMAGLUTIDE-EE-01", "grade": "moderate", "source": { "citation": "Stafeev I, Agareva M, Michurina S, et al. Semaglutide 6-months therapy of type 2 diabetes mellitus restores adipose progenitors potential to develop metabolically active adipocytes. Eur J Pharmacol. 2024;970:176476", "url": "https://doi.org/10.1016/j.ejphar.2024.176476", "identifiers": "PMID 38493915; DOI 10.1016/j.ejphar.2024.176476", "date": "2024-03-15", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic-Russian Science Foundation (grant 22-15-00365)", "scopeLimits": "small sample (N~8)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-HEALTHECON-CEA-01", "sourceId": "PMID39882599", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "ICER $136,271/QALY at US list price; $32,219/QALY under an empirically-estimated 48% rebate scenario (2023 USD; healthcare-sector perspective; lifetime horizon; 3% discount). Per 100,000 treated: 2,791 non-fatal MIs, 3,000 coronary revascularisations, 487 non-fatal strokes and 115 CV deaths avoided; +0.218 QALYs; +$29,767 lifetime cost. Mean treatment duration modelled 2.79 years.", "finding": "In a MANUFACTURER-SPONSORED (Novo Nordisk) Markov cost-effectiveness model of semaglutide 2.4 mg in the SELECT population (overweight/obese with established CV disease, no diabetes), semaglutide was reported cost-effective at US list price against a $150,000/QALY willingness-to-pay threshold. Context-only economic observation; the headline result is highly price-assumption-dependent and sponsor-authored, so it is paired here with the independent competing null.", "population": "Cohort-level Markov state-transition cost-effectiveness model; simulated 100,000 subjects aligned to SELECT (NCT03574597) baseline; healthcare-sector perspective; USA; sponsor Novo Nordisk (four of ten authors Novo employees, others Novo-commissioned HEOR Ltd).", "comparators": "placebo; standard of care", "endpointType": "hard-outcome", "notes": "WI-3 NEW-GATHER (cost-effectiveness / QALY, CV-disease obesity setting). Context-only modelling study, not an efficacy/mechanism claim or recommendation. GRADE low by rule (cost-effectiveness model). COI / sponsor-authorship flag (Constitution 1.8): sponsor (Novo Nordisk) authored, advancing the sponsor-favourable 'cost-effective at list price' conclusion - down-weighted at point of use and deliberately paired with the INDEPENDENT competing null (C-TIRZEPATIDE-HEALTHECON-CEA-01, academic, which finds semaglutide NOT cost-effective at net price, ICER $467,676/QALY in the general-obesity setting). The two are not in direct contradiction (different populations: SELECT CV-disease cohort with modelled CV-event savings vs general obesity; different WTP thresholds $150k vs $100k; list vs net price) - record both poles and the price-assumption dependence per Constitution 1.10. scope_limits: model assumptions, list-price sensitivity (rebate scenario swings the ICER ~4x), sponsor COI, generalisability of SELECT to broader population (authors' own caveat).", "crossRef": "C-TIRZEPATIDE-HEALTHECON-CEA-01; C-CLASS-MAINT-ADHERENCE-01", "grade": "low", "source": { "citation": "McEwan P, Bog M, Faurby M, Foos V, Lingvay I, Lubker C, Miller R, Toliver JC, Yeates F, Lincoff AM. Cost-effectiveness of semaglutide in people with obesity and cardiovascular disease without diabetes. J Med Econ 2025;28(1):268-278 (Novo Nordisk-sponsored).", "url": "https://doi.org/10.1080/13696998.2025.2459529", "identifiers": "PMID39882599 DOI10.1080/13696998.2025.2459529", "date": "2025-02-12", "design": "cost-effectiveness Markov model", "maturity": "human-primary", "funding": "industry - Novo Nordisk (sponsor-authored cost-effectiveness model; COI-flagged per Constitution 1.8)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-LANDSCAPE-01", "sourceId": "PMID33567185", "drug": "semaglutide (subcutaneous)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor monoagonist (peptide, once-weekly s.c.)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-14.9% vs -2.4% body weight (treatment-policy); approx -15.3 kg; HbA1c also reduced in T2D STEP 2 cohort", "finding": "Once-weekly subcutaneous semaglutide 2.4 mg produced a mean body-weight change of -14.9% vs -2.4% with placebo at week 68 (treatment-policy estimand; -17.3% vs -2.0% on the trial-product estimand); 86.4% reached >=5% weight loss vs 31.5% placebo.", "population": "STEP 1: 1961 adults, BMI >=30 (or >=27 with comorbidity), without diabetes, 68 weeks, randomised double-blind vs placebo, adjunct to lifestyle", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: selective GLP-1 receptor agonist, acylated peptide with albumin binding giving ~1 week half-life. Marketed as Wegovy (obesity, 2.4 mg) and Ozempic (T2D, up to 2.0 mg); approved US/EU. Glycaemic anchor: STEP 2 / SUSTAIN show HbA1c reductions ~1.5-1.8%. Headline weight figure varies by estimand (-14.9% treatment-policy vs -17.3% trial-product) - both recorded, no resolution.", "crossRef": "C-SEMAGLUTIDE-LANDSCAPE-02", "grade": "high", "source": { "citation": "Wilding JPH et al., NEJM 2021 (STEP 1)", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2032183", "identifiers": "PMID 33567185; DOI 10.1056/NEJMoa2032183; NCT03548935", "date": "2021-02-10", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-LANDSCAPE-02", "sourceId": "DOI10.1016/S0140-6736(23)01185-6", "drug": "semaglutide (oral)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor monoagonist (peptide, once-daily oral with SNAC absorption enhancer)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "body weight -15.1% vs placebo -2.4% (OASIS 1)", "finding": "Once-daily oral semaglutide 50 mg produced a mean body-weight change of -15.1% vs -2.4% placebo at week 68 (treatment-policy; -17.4% trial-product). In T2D (PIONEER PLUS) oral 50 mg gave ~2.0 percentage-point HbA1c reduction.", "population": "OASIS 1: adults with overweight/obesity without T2D, 9 countries, 68 weeks, randomised double-blind vs placebo; PIONEER PLUS: T2D, baseline HbA1c >=8%", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: same molecule as s.c. semaglutide, formulated with SNAC for oral gastric absorption; oral bioavailability low/variable, hence high mg doses (14/25/50 mg). Original PIONEER programme (3/7/14 mg) marketed as Rybelsus (T2D); oral 25/50 mg obesity dosing later filed. GI AEs ~80% vs 46% placebo (OASIS 1).", "crossRef": "C-SEMAGLUTIDE-LANDSCAPE-01", "grade": "high", "source": { "citation": "Knop CR et al., Lancet 2023 (OASIS 1)", "url": "https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01185-6/abstract", "identifiers": "DOI 10.1016/S0140-6736(23)01185-6; NCT05035095", "date": "2023-06-25", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (disclosed in publication)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-MAINT-01", "sourceId": "PMID33755728", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "Week 20->68: +6.9% regain (switch to placebo) vs -7.9% continued loss (semaglutide); difference -14.8pp (95% CI -16.0 to -13.5; P<0.001). Continued-arm advantages: waist -9.7 cm, SBP -3.9 mmHg.", "finding": "STEP-4 randomised-withdrawal RCT: adults who had lost a mean 10.6% during a 20-week semaglutide run-in were re-randomised (2:1) at week 20 to continue semaglutide 2.4 mg or switch to placebo. Those switched to placebo REGAINED weight (+6.9%) while those continuing kept losing (-7.9%); waist/BP gains were preserved only with continued treatment. The headline is regain-on-withdrawal; the continued arm is the maintenance counterpart.", "population": "STEP-4 (NCT03548987): N=803 randomised; adults BMI >=30 (or >=27 + comorbidity) without diabetes; double-blind phase-3a withdrawal at week 20; 48 weeks post-randomisation.", "comparators": "placebo (switch from semaglutide)", "endpointType": "other", "notes": "Canonical randomised-withdrawal regain figure for semaglutide (+6.9% over 48 wk). Counterpart to the on-treatment weight-loss rows: loss is maintained only while treatment continues. Authors frame as supporting continued treatment for maintenance. Pairs with the STEP-1 extension (longer off-treatment arc + cardiometabolic reversal). VALIDATOR: confirm PMID 33755728 + the +6.9/-7.9 figures.", "crossRef": "C-SEMAGLUTIDE-MAINT-02; C-TIRZEPATIDE-MAINT-01", "grade": "moderate", "source": { "citation": "Rubino D, Abrahamsson N, Davies M et al., JAMA, 2021 (STEP 4)", "url": "https://doi.org/10.1001/jama.2021.3224", "identifiers": "PMID33755728", "date": "2021-04-13", "design": "randomised-withdrawal RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-MAINT-02", "sourceId": "PMID35441470", "drug": "semaglutide (s.c. 2.4 mg)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "Week 68->120 (1 yr off-treatment): regained 11.6pp (SD 7.7) of lost weight on semaglutide vs 1.9pp placebo; net wk0-120 loss 5.6% (semaglutide) vs 0.1% placebo; ~two-thirds of the 17.3% on-treatment loss regained. Cardiometabolic variables (waist, BP, lipids, HbA1c) reverted towards baseline.", "finding": "STEP-1 off-treatment extension: after BOTH semaglutide and lifestyle were stopped at week 68, participants regained ~two-thirds of lost weight (11.6 of 17.3 pp) by week 120, and on-treatment cardiometabolic improvements reverted towards baseline. The clearest class documentation of cardiometabolic REVERSAL on regain.", "population": "STEP-1 extension (NCT03548935): exploratory subset N=327; adults with obesity without diabetes; off-treatment observational follow-up after the 68-week RCT.", "comparators": "placebo (also withdrawn)", "endpointType": "other", "notes": "Source of the widely-cited 'regained ~two-thirds' figure + the explicit cardiometabolic-reversal statement. Graded MODERATE not high: exploratory, non-randomly-selected off-treatment extension where lifestyle was ALSO withdrawn (so regain reflects total withdrawal, not drug alone). Reports TOTAL weight only - no fat-vs-lean composition (see C-CLASS-MAINT-04 gap). VALIDATOR: confirm PMID 35441470 + the 11.6/17.3 figures.", "crossRef": "C-SEMAGLUTIDE-MAINT-01; C-CLASS-MAINT-04", "grade": "low", "source": { "citation": "Wilding JPH et al., Diabetes Obes Metab 2022", "url": "https://doi.org/10.1111/dom.14725", "identifiers": "PMID:35441470 / DOI:10.1111/dom.14725 / PMC9542252", "date": "2022-05-19", "design": "observational cohort", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SEMAGLUTIDE-OSA-GAP", "sourceId": "PMID41979383", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "No dedicated semaglutide OSA RCT with a polysomnographic AHI endpoint identified. OSA-relevant evidence is indirect (large weight loss in STEP/SELECT, no sleep endpoint) plus observational utilisation data (n=384 sleep-surgery clinic).", "finding": "EVIDENCE GAP: as of this sweep there is NO dedicated semaglutide randomised OSA trial with a polysomnographic AHI primary endpoint - a notable hole given semaglutide is the dominant GLP-1. OSA benefit for semaglutide is inferred from its weight loss (STEP/SELECT, neither using a sleep-apnoea endpoint) on the unproven weight-mediation assumption; available OSA-context data are observational/utilisation.", "population": "n/a - gap statement. Supporting observational source: GLP-1 RA utilisation among sleep-surgery clinic patients (retrospective, n=384, single tertiary centre).", "comparators": "", "endpointType": "other", "notes": "Honest gap: the GLP-1 OSA RCT ladder has liraglutide (mono) and tirzepatide (dual) but NOT semaglutide. The supporting source is retrospective single-centre utilisation (confounding by indication; reporting != effect; low grade) and is NOT an OSA efficacy trial. A semaglutide OSA RCT would directly test a pure GLP-1 mono with larger weight loss than liraglutide - currently unanswered.", "crossRef": "C-CLASS-OSA-MECHANISM", "grade": "low", "source": { "citation": "Kutler RB et al. GLP-1 RA Utilization Among Sleep Surgery Clinic Patients. Otolaryngol Head Neck Surg 2026;174:1633-1641 (observational, OSA-context only).", "url": "https://doi.org/10.1002/ohn.70231", "identifiers": "PMID41979383", "date": "2026-01-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "possible confounding by indication; single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SETMELANOTIDE-LANDSCAPE-01", "sourceId": "PMID33137293", "drug": "setmelanotide (RM-493)", "drugRoot": "setmelanotide", "drugSlug": "setmelanotide", "drugLabel": "Setmelanotide", "drugClass": "melanocortin-4 receptor (MC4R) agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": ">=10% weight loss in 80% (POMC) and 45% (LEPR) at ~1 year", "finding": "In severe obesity from POMC or LEPR deficiency, ~1 year of setmelanotide produced significant weight loss and reduced hunger: >=10% weight loss in 80% (8/10) of POMC-deficiency and 45% (5/11) of LEPR-deficiency participants. Marketed (Imcivree) for genetic MC4R-pathway obesity and Bardet-Biedl syndrome; positive in acquired hypothalamic obesity and ages 2-5 (VENTURE).", "population": "Single-arm open-label multicentre phase 3, POMC and LEPR deficiency, participants aged >=6y; ~1-year endpoint", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Mechanism: directly activates hypothalamic MC4R, downstream of leptin-POMC, bypassing upstream genetic defects. Approved (Rhythm). Co-occurs in incretin comparisons as the central-melanocortin reference mechanism and a comparator for hypothalamic/genetic obesity.", "crossRef": "", "grade": "moderate", "source": { "citation": "Clement et al., Lancet Diabetes Endocrinol 2020", "url": "https://pubmed.ncbi.nlm.nih.gov/33137293/", "identifiers": "PMID 33137293; DOI 10.1016/S2213-8587(20)30364-8", "date": "2020-11-01", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Rhythm Pharmaceuticals (setmelanotide; disclosed)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SGLT2-URATE-01", "sourceId": "PMID38796335", "drug": "SGLT2 inhibitor class (multi-agent)", "drugRoot": "SGLT2 inhibitor class (multi-agent)", "drugSlug": "sglt2-inhibitor-class-multi-agent", "drugLabel": "SGLT2 Inhibitor Class (multi-agent)", "drugClass": "SGLT2 inhibitor (class-wide)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Network meta-analysis (22 RCTs, 173,498 patients): SGLT2 inhibitors cut incident gout vs placebo (RR 0.51 [0.29-0.91]); GLP-1 RAs and DPP-4 inhibitors had neutral effects; corroborated by TriNetX incident-gout HRs 0.75/0.83 for SGLT2i.", "finding": "A network meta-analysis of randomised outcome trials found SGLT2 inhibitors significantly reduce incident gout while GLP-1 RAs and DPP-4 inhibitors are neutral - the contrast pole showing a genuinely uricosuric, gout-protective class distinct from GLP-1 RAs.", "population": "Network meta-analysis (Wang et al., 22 randomised placebo-controlled outcome trials, 173,498 patients with/without T2D).", "comparators": "placebo; GLP-1 receptor agonist; DPP-4 inhibitor", "endpointType": "safety-event/signal", "notes": "Included for the SGLT2i-vs-GLP-1 contrast (the gout-protective comparator pole), not as a GLP-1/retatrutide claim. Indirect (network) comparisons between drug classes; gout a secondary outcome across heterogeneous CVOTs. Academic network meta-analysis.", "crossRef": "", "grade": "moderate", "source": { "citation": "Wang A, Shi W, Zhang N, Tang H, Feng X. Newer glucose-lowering drugs and risk of gout: a network meta-analysis of randomized outcomes trials (22 trials, 173,498 patients). Clin Ther 2024;46(11):851-854.", "url": "https://doi.org/10.1016/j.clinthera.2024.04.013", "identifiers": "DOI:10.1016/j.clinthera.2024.04.013", "date": 2024, "design": "network meta-analysis", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-SURVO-CARDIO-BP-01", "sourceId": "DOI10.1093/EURHEARTJ/EHAE666.2895", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "glucagon/GLP-1 dual agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "Clinically meaningful BP reductions reported; specific mmHg not extracted.", "finding": "Survodutide reduced blood pressure (with waist circumference and triglycerides) in phase 2 obesity cardiometabolic analysis.", "population": "N=387 adults BMI >=27 without diabetes; survodutide 0.6-4.8 mg vs placebo; 46 weeks; phase 2.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "ESC 2024 abstract; identifier not PubMed-verified; magnitude not captured.", "crossRef": "C-SURVO-CARDIO-LIPID-01", "grade": "low", "source": { "citation": "Survodutide phase 2 cardiometabolic, Eur Heart J, 2024;45(Suppl 1):ehae666.2895", "url": "https://academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.2895/7836933", "identifiers": "DOI 10.1093/eurheartj/ehae666.2895 (unverified)", "date": "2024-09-01", "design": "conference abstract", "maturity": "conference-abstract", "funding": "industry - Boehringer Ingelheim / Zealand (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-SURVO-CARDIO-LIPID-01", "sourceId": "DOI10.1093/EURHEARTJ/EHAE666.2895", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "glucagon/GLP-1 dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Reductions in TG (marked), total cholesterol and LDL-C, VLDL; HDL relatively UNCHANGED (not increased).", "finding": "Survodutide reduced TG, total and LDL cholesterol and VLDL in phase 2 obesity; HDL relatively unchanged.", "population": "N=387 adults BMI >=27 without diabetes; survodutide 0.6-4.8 mg vs placebo; 46 weeks; phase 2.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Direction mixed (TG/LDL down, HDL up). Identifier not PubMed-verified.", "crossRef": "C-SURVO-CARDIO-BP-01", "grade": "low", "source": { "citation": "Survodutide phase 2 cardiometabolic, Eur Heart J, 2024;45(Suppl 1):ehae666.2895", "url": "https://academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.2895/7836933", "identifiers": "DOI 10.1093/eurheartj/ehae666.2895 (unverified)", "date": "2024-09-01", "design": "conference abstract", "maturity": "conference-abstract", "funding": "industry - Boehringer Ingelheim / Zealand (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-SURVO-HR-01", "sourceId": "PMID39582349", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "HR ~+2.7 bpm pooled vs ~+0.1 bpm placebo; SBP/DBP decrease (post hoc)", "finding": "In the phase 2 obesity dose-finding trial (NCT04667377), survodutide raised heart rate by a mean ~2.7 bpm (all doses pooled) versus ~0.1 bpm on placebo, with a post-hoc analysis reporting blood-pressure improvement; weight loss up to ~14.9% at 46 weeks.", "population": "phase 2 obesity dose-finding trial (NCT04667377); post-hoc blood-pressure analysis (Letter)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Dual GLP-1/GCGR proxy: same HR-up / BP-down PATTERN as retatrutide (observation; the 'why', and whether GCGR drives it, left open - GLP-1RAs alone also raise HR). Combination-only; per-receptor attribution held open. The +2.7 bpm magnitude is un-pinned (source is a Letter with no abstract) and flagged secondary-sourced. Folded from T7-047 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "", "grade": "moderate", "source": { "citation": "le Roux CW et al., Diabetes Obes Metab 2024;27(2):993-996 (Letter; survodutide BP post hoc)", "url": "https://doi.org/10.1111/dom.16052", "identifiers": "PMID:39582349 DOI:10.1111/dom.16052 NCT04667377", "date": "2024-11-25", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim / Zealand (trial sponsor)", "scopeLimits": "post-hoc (not prespecified); magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-SURVO-SAFETY-GI08", "sourceId": "DOI10.1056/NEJMOA2401755", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "glucagon/GLP-1 dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Nausea 66% vs 23%; diarrhoea 49% vs 23%; vomiting 41% vs 4%; AE discontinuation 24.6% vs 3.9%", "finding": "GI AEs (nausea, diarrhoea, vomiting) markedly more frequent than placebo; dose-dependent, titration-managed; high AE-related discontinuation, mainly GI.", "population": "Survodutide phase 2 (obesity/MASH); 48 weeks; s.c. 2.4/4.8/6.0 mg weekly vs placebo", "comparators": "placebo", "endpointType": "other", "notes": "Steep glucagon-co-agonist GI burden. Obesity vs MASH population for each rate should be disentangled vs full text; PMIDs not confirmed this pass.", "crossRef": "C-CLASS-SAFETY-GI12", "grade": "moderate", "source": { "citation": "Sanyal et al., Phase 2 Survodutide in MASH and Fibrosis, NEJM 2024; Boehringer phase 3 press", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2401755", "identifiers": "DOI 10.1056/NEJMoa2401755", "date": "2024-06-08", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim (disclosed in publication)", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-SURVODUTIDE-BODYCOMP-01", "sourceId": "CIT:boehringer-ingelheim-zealand-survodutide-phase-2", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "VAT -34%, SAT -28%, lean body volume -9.8%; ~78% fat / ~22% lean of weight lost; lean <=10.8% of tissue-mass change (top dose); liver fat -63.1% (adjacent).", "finding": "SYNCHRONIZE (phase 3) prespecified MRI substudy: survodutide reduced visceral adipose tissue ~34%, subcutaneous adipose tissue ~28% and lean body volume ~9.8%; fat mass ~78% / lean mass ~22% of total weight lost reported; lean tissue <=10.8% of total tissue-mass change at the highest dose.", "population": "Phase 2 obesity MRI substudy (survodutide / BI 456906); dose range to ~4.8 mg", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Company/conference channel - figures not yet confirmed against a primary peer-reviewed paper here; VAT and SAT MRI depot-specific data are the notable items. Glucagon-arm visceral-fat and lean-preservation claims - records the pole. Phase 3 SYNCHRONIZE-1/-2 ongoing.", "crossRef": "", "grade": "very-low", "source": { "citation": "Boehringer Ingelheim / Zealand, survodutide phase 2 MRI body-composition substudy (conference/company)", "url": "https://www.boehringer-ingelheim.com/human-health/crm-health/metabolic-health/survodutide-phase-3-fat-loss-obesity-dual-agonist-data", "identifiers": "Boehringer Ingelheim metabolic-health disclosure", "date": 2024, "design": "observational cohort", "maturity": "press", "funding": "industry - Boehringer Ingelheim / Zealand", "scopeLimits": "conference/abstract-level; no outcome data yet (ongoing)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C-SURVODUTIDE-LANDSCAPE-01", "sourceId": "DOI10.1056/NEJMOA2401755", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon (GCGR) dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "MASH resolution w/o fibrosis worsening 47/62/43% vs 14% placebo at 48 wk; >=30% liver-fat reduction 63/67/57% vs 14%; fibrosis (>=1 stage) improvement 34/36/34% (up to 36%) vs 22% placebo; obesity phase 2 weight loss up to ~12% at 46 wk; phase 3 16.6%", "finding": "Survodutide (BI 456906; Boehringer/Zealand) is a GLP-1/glucagon dual agonist in phase 3 for obesity and MASH. In a 48-week phase 2 MASH trial, MASH improvement without worsening fibrosis occurred in 47/62/43% (2.4/4.8/6.0 mg) vs 14% placebo; >=30% liver-fat reduction in 57-67% vs 14%; fibrosis (>=1 stage) improvement 34/36/34% (up to 36%) vs 22% placebo. A phase 2 obesity trial showed dose-dependent weight loss up to ~12% at 46 weeks; phase 3 reported 16.6% weight loss.", "population": "MASH: 293 adults, biopsy-confirmed MASH + fibrosis F1-F3, once-weekly s.c. 2.4/4.8/6.0 mg vs placebo, 48 wk; obesity phase 2: adults obesity/overweight, 46 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Mechanism: GLP-1/GCGR dual; glucagon component emphasised for hepatic-fat and energy-expenditure effects. Obesity weight figures from company/press; MASH figures from NEJM. Phase 3 SYNCHRONIZE (obesity) and MASH programme ongoing.", "crossRef": "", "grade": "moderate", "source": { "citation": "Sanyal et al., Phase 2 Survodutide in MASH and Fibrosis, NEJM 2024; Boehringer phase 3 press", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2401755", "identifiers": "DOI 10.1056/NEJMoa2401755", "date": "2024-06-08", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim (disclosed in publication)", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C-TERN601-LANDSCAPE-01", "sourceId": "CIT:terns-pharmaceuticals-press-sept-2024-ada-85th-s", "drug": "TERN-601", "drugRoot": "TERN-601", "drugSlug": "tern-601", "drugLabel": "TERN-601", "drugClass": "oral non-peptide small-molecule GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Phase 1: up to -4.9% placebo-adjusted weight (740 mg, 28 days); 67% achieved >=5% weight loss at top dose", "finding": "Oral non-peptide GLP-1RA (Terns Pharmaceuticals). Phase 1 SAD/MAD in healthy adults with obesity/overweight reported dose-dependent placebo-adjusted weight loss up to 4.9% at 740 mg once daily over 28 days; 67% lost >=5% at top dose; >95% TEAEs mild. Phase 2 FALCON ongoing (12-week primary endpoint).", "population": "Phase 1 randomised double-blind placebo-controlled SAD/MAD in healthy adults with obesity/overweight; phase 2 FALCON ongoing", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "MECHANISM: oral non-peptide small-molecule GLP-1R agonist, once daily. Phase 1-stage; short 28-day duration so magnitude not comparable to phase 3 data. Presented ADA 2025.", "crossRef": "", "grade": "low", "source": { "citation": "Terns Pharmaceuticals press Sept 2024; ADA 85th Scientific Sessions June 2025", "url": "https://www.globenewswire.com/news-release/2024/09/09/2942701/0/en/Terns-Pharmaceuticals-Announces-Positive-Phase-1-Clinical-Trial-Results-with-TERN-601-Once-Daily-Oral-GLP-1R-Agonist-for-the-Treatment-of-Obesity.html", "identifiers": "TERN-601", "date": "2025-06-23", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Terns (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-ADMIN-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "s.c. abdomen/thigh/upper arm, weekly, any time, +/- food, rotate sites, separate site from insulin", "finding": "Tirzepatide is injected subcutaneously once weekly into the abdomen, thigh or upper arm with site rotation, at any time of day with or without meals, and into a different site from any insulin.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.2; EU SmPC 4.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-ADMIN-MISSEDDOSE-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Within 4 days (96 h) or skip; dosing day changeable if >=3 days between doses", "finding": "A missed tirzepatide dose may be taken within 4 days (96 h); otherwise skip it. The dosing day may be changed if at least 3 days separate doses.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.1; EU SmPC 4.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-01", "sourceId": "PMID41406444", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "3-point MACE HR 0.92 (95.3% CI 0.83-1.01); 801/6586 (12.2%) vs 862/6579 (13.1%); non-inferiority to dulaglutide met (P=0.003), superiority NARROWLY MISSED (P=0.09; 0.086 at higher precision in the Fadini commentary). The randomised result (non-inferior, superiority missed) is the only result carrying CV weight here; a modelled imputed-placebo estimate is fenced in notes. Secondary: all-cause mortality HR 0.84 (95% CI 0.75-0.94) [secondary coverage, pending NEJM full-text confirmation - non-hardened].", "finding": "In T2D with established ASCVD, tirzepatide was NON-INFERIOR to dulaglutide for 3-point MACE but did NOT meet superiority. The comparator is a CV-proven GLP-1RA, so this establishes that the GIP-containing dual-agonist MOLECULE is CV-safe at the whole-molecule level; it does NOT isolate the GIP receptor's own contribution, because tirzepatide's GLP-1 moiety differs from dulaglutide's (cross-ref thread 11), so the null delta cannot be read as 'GIP adds nothing' rather than as offsetting differences between the two GLP-1 components. Despite materially greater HbA1c and weight reduction, the second incretin arm bought no incremental hard MACE.", "population": "SURPASS-CVOT: N=13,299 randomised (NCT04255433); T2D + established ASCVD, age >=40, HbA1c 7.0-10.5%, BMI >=25; double-blind active-comparator; tirzepatide up to 15 mg vs dulaglutide 1.5 mg; median follow-up ~4.0 years.", "comparators": "dulaglutide", "endpointType": "hard-outcome", "notes": "DEEPENS prior C-TIRZ-CARDIO-01. The primary NEJM record RESOLVED on independent validation (2026-06-21) to PMID 41406444 (Nicholls et al., NEJM 2025, NCT04255433); HR 0.92 / 95.3% CI 0.83-1.01 confirmed; status VERIFIED. Fadini raises a 'mechanism-saturation / therapeutic-ceiling' reading. COI: this is a Lilly-drug-versus-Lilly-drug comparison (tirzepatide vs dulaglutide, both Eli Lilly), which constrains how independently the non-inferiority reads. MODELLED, NON-RANDOMISED, hypothesis-only: an imputed-placebo MACE-3 HR ~0.72 (~28% RRR; Sattar Diabetes Care 2026 PMID 41940793) assumes dulaglutide reproduces its historical placebo effect; it is NOT a randomised contrast, carries NO per-receptor (GIP) attribution, and must not migrate into any cross-row CV-benefit claim. Cross-ref the glucagon-arm OQ. KEY CAUTION: adding a second incretin arm to a proven GLP-1RA bought no extra MACE despite more weight loss, the load-bearing caution against assuming retatrutide's larger weight loss guarantees larger CV benefit. [2026-06-21: source normalised to the canonical SURPASS-CVOT primary PMID 41406444 (DOI 10.1056/NEJMoa2505928).]", "crossRef": "C-DULA-CARDIO-01; C-TIRZ-CARDIO-02; C-RETA-CARDIO-02; OQ-T7-B", "grade": "high", "source": { "citation": "Nicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med 2025;393(24):2409-2420.", "url": "https://doi.org/10.1056/NEJMoa2505928", "identifiers": "PMID41406444", "date": "2025-11-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor)", "scopeLimits": "active-comparator (dulaglutide) non-inferiority design - not placebo-controlled; superiority not met (P=0.09)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-02", "sourceId": "PMID35210595", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "no-change", "magnitude": "MACE-4 HR 0.80 (95% CI 0.57-1.11); CV death HR 0.90 (0.50-1.61); all-cause death HR 0.80 (0.51-1.25). Only 142 MACE-4 events (109 from one high-CV-risk trial). CIs cross 1.", "finding": "Pre-specified pre-registration pooled CV meta-analysis of the SURPASS phase-3 programme found tirzepatide did NOT increase MACE versus controls; the point estimate was favourable but the CI crossed 1 (exploratory CV-safety evidence, not powered superiority).", "population": "Pre-specified pooled meta-analysis of 7 RCTs (>=26 weeks) in the SURPASS T2D programme; 4,887 tirzepatide vs 2,328 control; controls = placebo and active comparators.", "comparators": "placebo; semaglutide; dulaglutide; insulin glargine; insulin degludec", "endpointType": "hard-outcome", "notes": "ADDED. The CV-safety basis at tirzepatide registration, superseded by SURPASS-CVOT (C-TIRZ-CARDIO-01). FRAGILITY FLAG (Council): only 142 MACE-4 events, 109 (77%) from a single high-CV-risk trial (SURPASS-4), and every CI crosses 1; exploratory/not powered. The favourable point estimate (0.80) must NOT be cited on a par with powered CVOTs nor summed with them. Graded moderate per the meta-analysis default rule.", "crossRef": "C-TIRZ-CARDIO-01", "grade": "moderate", "source": { "citation": "Sattar N, McGuire DK, Pavo I et al., Nat Med, 2022", "url": "https://doi.org/10.1038/s41591-022-01707-4", "identifiers": "PMID35210595", "date": "2022-03-01", "design": "meta-analysis", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-03", "sourceId": "PMID40545827", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "cv-outcomes", "domainLabel": "Cardiovascular outcomes", "domainSlug": "cv-outcomes", "direction": "n/a", "magnitude": "No results. Primary endpoint = time to first of a 5-component composite (all-cause death, non-fatal MI, non-fatal stroke, coronary revascularisation, or HF events). Enrolment 15,374 (actual); estimated primary completion October 2027; status active, not recruiting.", "finding": "Dedicated morbidity-mortality OUTCOME trial of tirzepatide in OBESITY WITHOUT diabetes (primary and secondary prevention) is ONGOING with no results; the first incretin outcome trial to span both primary and secondary CV prevention.", "population": "SURMOUNT-MMO (NCT05556512): randomised double-blind event-driven; BMI >=27, obesity, T1D/T2D excluded; adults >=40 with established CVD OR adults with CV risk factors; once-weekly tirzepatide vs placebo; confirmed on clinicaltrials.gov 2026-06-21.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "ADDED. PMID 40545827 is the published rationale-and-design paper, NOT a results paper, hence very-low (promissory note). Will give the first incretin CV-outcome read in obesity-without-diabetes spanning both prevention settings.", "crossRef": "C-TIRZ-CARDIO-01", "grade": "very-low", "source": { "citation": "Lam CSP, Rodriguez A, Aminian A et al. SURMOUNT-MMO rationale and design. Obesity (Silver Spring), 2025", "url": "https://doi.org/10.1002/oby.24332", "identifiers": "PMID40545827", "date": "2025-09-01", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-BP-01", "sourceId": "PMID38314555", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "Placebo-adjusted 24h SBP: -7.4 mmHg (5 mg), -10.6 mmHg (10 mg), -8.0 mmHg (15 mg) at week 36. Weight mediated ~70%.", "finding": "Tirzepatide reduced 24-hour ambulatory systolic BP versus placebo (SURMOUNT-1 ABPM substudy); effect partly weight-mediated.", "population": "N=600 adults BMI >=27, BP <140/90 on stable antihypertensives, SURMOUNT-1 substudy; 36 weeks; RCT.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Letter; baseline mean 24h SBP 124.6 (relatively normotensive). Non-monotonic dose pattern. PMID/DOI verified.", "crossRef": "C-TIRZ-CARDIO-HR-01", "grade": "high", "source": { "citation": "de Lemos JA et al. (SURMOUNT-1 ABPM), Hypertension, 2024;81(4):e41-e43", "url": "https://doi.org/10.1161/HYPERTENSIONAHA.123.22022", "identifiers": "PMID 38314555; DOI 10.1161/HYPERTENSIONAHA.123.22022", "date": "2024-02-05", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-HF-01", "sourceId": "PMID39555826", "drug": "tirzepatide (up to 15 mg)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "decrease", "magnitude": "Composite 9.9% vs 15.3%; HR 0.62 (95% CI 0.41 to 0.95; P=0.026). Worsening HF events HR 0.54 (0.34-0.85). CV death 2.2% vs 1.4%; HR 1.58 (0.52-4.83). KCCQ-CSS diff 6.9 (95% CI 3.3 to 10.6; P<0.001).", "finding": "SUMMIT: in HFpEF with obesity, tirzepatide reduced the composite of CV death or worsening HF event and improved KCCQ-CSS versus placebo.", "population": "N=731, HFpEF (EF >=50%), BMI >=30; median follow-up 104 weeks; RCT vs placebo.", "comparators": "placebo", "endpointType": "hard-outcome", "notes": "Composite driven by worsening HF events; CV death numerically higher on tirzepatide (8 vs 5; wide CI, few events) - both poles recorded. GI-related discontinuation 6.3% vs 1.4%. PMID/DOI verified.", "crossRef": "", "grade": "high", "source": { "citation": "Packer M et al. (SUMMIT), NEJM, 2025;392:427-437", "url": "https://doi.org/10.1056/NEJMoa2410027", "identifiers": "PMID 39555826; DOI 10.1056/NEJMoa2410027; NCT04847557", "date": "2024-11-16", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "few events/wide CI", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-HR-01", "sourceId": "PMID38314555", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "SURMOUNT-1 (72 wk) pulse +0.6/+2.3/+2.6 bpm (5/10/15 mg) vs +0.1 placebo. ABPM substudy (wk36) +2.1/+2.3/+5.4 bpm. SURPASS ~2-4 bpm.", "finding": "Tirzepatide raises heart rate modestly and dose-dependently versus placebo.", "population": "SURMOUNT-1 obesity RCT and SURPASS T2D programme; tirzepatide 5/10/15 mg vs placebo/comparators.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Two HR readouts differ by timepoint/method (main-trial pulse vs ABPM HR). SURPASS bpm range web-sourced. ABPM PMID/DOI verified.", "crossRef": "C-TIRZ-CARDIO-BP-01", "grade": "high", "source": { "citation": "de Lemos JA et al. (SURMOUNT-1 ABPM), Hypertension, 2024;81(4):e41-e43", "url": "https://doi.org/10.1161/HYPERTENSIONAHA.123.22022", "identifiers": "PMID 38314555; DOI 10.1161/HYPERTENSIONAHA.123.22022", "date": "2024-02-05", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-LIPID-01", "sourceId": "PMID33462955", "drug": "tirzepatide (1-15 mg)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Dose-dependent decreases in TG, VLDL-C, ApoC-III, ApoB, large TRL-P/small LDL-P. ApoC-III change explained ~22.9% of TG variation at 10/15 mg, independent of weight loss.", "finding": "Tirzepatide dose-dependently improves the atherogenic lipoprotein profile: lowers TG, VLDL-C, ApoB, ApoC-III and small LDL particles; ApoC-III reduction partly weight-independent.", "population": "Phase 2b T2D substudy (tirzepatide 1-15 mg vs dulaglutide vs placebo); NMR lipoprotein analysis.", "comparators": "dulaglutide; placebo", "endpointType": "surrogate/biomarker", "notes": "Key mechanistic ApoC-III finding. SURPASS-2 head-to-head vs semaglutide also reported larger TG/lipid improvements with tirzepatide (not separately captured). PMID/DOI verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Wilson JM et al., Diabetes Obes Metab, 2020;22(12):2451-2459", "url": "https://doi.org/10.1111/dom.14174", "identifiers": "PMID 33462955; DOI 10.1111/dom.14174", "date": "2020-09-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-RENAL-01", "sourceId": "PMID36152639", "drug": "tirzepatide (5/10/15 mg pooled)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "eGFR decline -1.4 vs -3.6 mL/min/1.73m2/yr (diff 2.2 [95% CI 1.6-2.8]). UACR between-group -31.9% (95% CI -37.7 to -25.7). Composite kidney endpoint HR 0.58 (95% CI 0.43-0.80). Cystatin C analysis concordant (52-wk diff 1.8 [0.8-2.8]).", "finding": "SURPASS-4 post hoc: tirzepatide slowed eGFR decline, prevented UACR rise and reduced a composite kidney endpoint versus insulin glargine.", "population": "SURPASS-4: N=1,995 (995 tirz, 1000 glargine); T2D, high CV risk; median treatment 85 weeks; open-label; post hoc.", "comparators": "insulin glargine", "endpointType": "hard-outcome", "notes": "Post hoc; active comparator (glargine) - difference partly reflects glargine-associated UACR rise. Cystatin C analysis addresses muscle-mass confounding. Both PMIDs/DOIs verified.", "crossRef": "", "grade": "moderate", "source": { "citation": "Heerspink HJL et al. (SURPASS-4 kidney), Lancet Diabetes Endocrinol, 2022;10:774-785; cystatin C: Diabetes Care 2023;46:1501-1506", "url": "https://doi.org/10.1016/S2213-8587(22)00243-1", "identifiers": "PMID 36152639; DOI 10.1016/S2213-8587(22)00243-1; cystatin C PMID 37267479 / DOI 10.2337/dc23-0261", "date": "2022-09-21", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "open-label (unblinded); possible confounding by indication; post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CARDIO-RENAL-02", "sourceId": "PMID42114520", "drug": "tirzepatide (up to 15 mg)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "Composite (macroalbuminuria, >=50% eGFR loss, ESKD, kidney death) 6.0% vs 7.6%; HR 0.77 (95% CI 0.68-0.88; p=0.0002). Annual eGFR decline between-group diff 0.29 (95% CI 0.17-0.41), 0.93 in high-risk CKD.", "finding": "SURPASS-CVOT prespecified exploratory: tirzepatide reduced major kidney events versus dulaglutide (direct incretin head-to-head).", "population": "SURPASS-CVOT: N=13,299 (6586 tirz, 6579 dula; 2948 high-risk CKD); T2D + ASCVD; median 4.0 years; double-blind.", "comparators": "dulaglutide 1.5 mg", "endpointType": "hard-outcome", "notes": "COMPARATIVE: benchmark is active GLP-1RA (dulaglutide). Prespecified exploratory (primary CV endpoint was noninferiority). PMID/DOI verified.", "crossRef": "C-TIRZ-CARDIO-01", "grade": "moderate", "source": { "citation": "Zoungas S et al. Tirzepatide vs dulaglutide on major kidney events: pre-specified exploratory analyses of SURPASS-CVOT. Lancet Diabetes Endocrinol 2026;14(7):544-557.", "url": "https://doi.org/10.1016/S2213-8587(26)00032-X", "identifiers": "PMID 42114520; DOI 10.1016/S2213-8587(26)00032-X", "date": "2026-05-11", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-CONTRA-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "US: MTC/MEN2 (boxed warning) + serious hypersensitivity; EU 4.3: hypersensitivity only", "finding": "Tirzepatide is contraindicated in the US for personal/family history of MTC or MEN 2 (also a boxed warning) and serious hypersensitivity; the EU contraindication is hypersensitivity only.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "contraindication", "notes": "US PI 4 / EU SmPC 4.3. Regional contrast preserved.", "crossRef": "C-TIRZ-SAFETY-MTC10", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DDI-GENERAL-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Delays gastric emptying; EU names warfarin/digoxin monitoring; low in-vitro CYP potential", "finding": "Tirzepatide delays gastric emptying and may alter absorption of co-administered oral drugs; the EU SmPC advises monitoring narrow-therapeutic-index drugs (e.g. warfarin, digoxin), and in vitro it shows low potential to inhibit/induce CYP enzymes.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "US PI 7; EU SmPC 4.5.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DDI-GLP1COMBO-01", "sourceId": "CIT:zepbound-us-pi-dailymed-487cd7e7", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Co-use with any GLP-1 RA or other tirzepatide product not recommended", "finding": "Co-administration of tirzepatide with another tirzepatide-containing product or any GLP-1 receptor agonist is not recommended.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "US PI 7 (Zepbound/Mounjaro).", "crossRef": "", "grade": "high", "source": { "citation": "Zepbound (tirzepatide) US Prescribing Information, Eli Lilly", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b", "identifiers": "DailyMed setid 487cd7e7-434c-4925-99fa-aa80b1cc776b", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DDI-INSULIN-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Reduce insulin/sulfonylurea dose to lower hypo risk (stepwise)", "finding": "When tirzepatide is combined with insulin or a sulfonylurea, reducing the secretagogue/insulin dose (stepwise for insulin) lowers hypoglycaemia risk.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "US PI 7.1; EU SmPC 4.2/4.4. Most relevant to the T2D (Mounjaro) label.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DDI-PARACETAMOL-01", "sourceId": "CIT:zepbound-us-pi-dailymed-487cd7e7", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Zepbound: first-dose paracetamol Cmax -55%, tmax +1 h, resolves by week 6; AUC unchanged", "finding": "A first tirzepatide (Zepbound) dose transiently reduced paracetamol/acetaminophen peak concentration by ~55% and delayed tmax, resolving by week 6 on continued dosing; overall exposure (AUC) unchanged - a rate-of-absorption effect.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "drug-interaction", "notes": "Zepbound PI 12.2. The Mounjaro -50%/week-4 figure is HELD pending a verbatim Mounjaro recheck (fidelity-seat block).", "crossRef": "", "grade": "high", "source": { "citation": "Zepbound (tirzepatide) US Prescribing Information, Eli Lilly", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b", "identifiers": "DailyMed setid 487cd7e7-434c-4925-99fa-aa80b1cc776b", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DOSE-INDICATION-01", "sourceId": "CIT:zepbound-us-pi-dailymed-487cd7e7", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Zepbound maintenance by indication: weight 5/10/15 mg; OSA 10 or 15 mg", "finding": "Zepbound maintenance dosing differs by indication, with obstructive sleep apnoea requiring 10 mg or 15 mg once weekly.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "Zepbound PI 2.", "crossRef": "", "grade": "high", "source": { "citation": "Zepbound (tirzepatide) US Prescribing Information, Eli Lilly", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b", "identifiers": "DailyMed setid 487cd7e7-434c-4925-99fa-aa80b1cc776b", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DOSE-TITRATION-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "2.5 (starter) -> 5 after 4 wk -> +2.5 mg steps (>=4 wk) -> max 15 mg weekly", "finding": "Tirzepatide starts at 2.5 mg once weekly, increases to 5 mg after 4 weeks, then in 2.5 mg steps at no less than 4-week intervals up to a 15 mg maximum (10 mg max in paediatric patients).", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "dosing/administration", "notes": "US PI 2.1; EU SmPC 4.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-DOSEHEADROOM-01", "sourceId": "CIT:mounjaro-nda-215866-clinpharm-refid-4954959", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "marketed doses attain only 74-89% of the FASTING-GLUCOSE Emax; effect still increasing at the highest doses tested (EMA); potency rises as weight falls (5% loss -> 29% lower EC50)", "finding": "Dose-headroom confound (competing hypothesis): the FDA Mounjaro Clinical Pharmacology FG/HbA1c Emax model shows tirzepatide's marketed doses reach only 74-89% of the maximal effect on FASTING GLUCOSE, with EMA reporting effect still increasing at the highest doses tested. CRITICAL: this is a FASTING-GLUCOSE Emax, NOT weight-loss headroom - it must not be read as the dual being undertitrated for weight loss. Part of any dual-to-triple efficacy gap could be exposure-response position rather than the glucagon mechanism, so it must be controlled before assigning a retatrutide-over-tirzepatide gap to the glucagon arm.", "population": "Type-2-diabetes exposure-response popPK/PD model (FDA Mounjaro NDA 215866 ClinPharm FG-HbA1c PK/PD model, p.65-66; EMA Mounjaro EPAR)", "comparators": "marketed-dose vs modelled Emax", "endpointType": "pharmacology-exposure-response", "notes": "Promoted from sweep SW-REG-06 (2026-06-21). Audit caveats (statistics:4): this is a FASTING-GLUCOSE Emax, NOT weight-loss headroom; sponsor-model output; flagged a live confound to control before any efficacy gap is assigned to mechanism.", "crossRef": "", "grade": "moderate", "source": { "citation": "FDA Mounjaro NDA 215866 Clinical Pharmacology Review, Reference ID 4954959 (FG/HbA1c Emax PK/PD model)", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000ClinPharmR.pdf", "identifiers": "FDA Reference ID 4954959 (NDA 215866)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "industry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 215866 submission)", "scopeLimits": "sponsor-derived popPK/PD model output; fasting-glucose Emax, not a weight-loss exposure-response", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-HF-MECH-01", "sourceId": "PMID39551891", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "heart-failure", "domainLabel": "heart-failure", "domainSlug": "heart-failure", "direction": "mixed", "magnitude": "SBP -5 mmHg; blood volume -0.58 L; CRP -37.2%; eGFR +2.90 mL/min/1.73m2/yr; troponin T -10.4%", "finding": "In a mechanistic secondary analysis of SUMMIT, tirzepatide at 52 weeks reduced systolic blood pressure (-5 mmHg), estimated blood volume (-0.58 L), CRP (-37.2%), NT-proBNP and troponin T, and INCREASED eGFR (+2.90 mL/min/1.73m2/yr) while lowering urine albumin-creatinine ratio - interpreted as reduced volume/pressure overload and mitigated cardiovascular-kidney end-organ injury.", "population": "mechanistic secondary analysis of SUMMIT (HFpEF + obesity); NCT04847557", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Combination-only (GIP+GLP-1). Mechanism as reported = reduced volume/pressure overload + anti-inflammatory + lower cardiac-biomarker stress; eGFR ROSE and UACR FELL in this trial (a renal-protective direction AS REPORTED). Troponin-T fall argues against net myocardial injury at these HFpEF doses. Exploratory secondary; sponsor-authored (Eli Lilly). Cross-ref only (no verdict): retatrutide's GCGR-hyperfiltration question is tracked separately in the renal domain; this record does not adjudicate any tirzepatide-vs-retatrutide renal contrast (WI-1 Council, OQ-WI1-03). Distinct PMID from the SUMMIT primary. Folded from T12-GLP1R-07 (per-receptor-verified); compendium independent audit completed 2026-06-24 (see validation_evidence).", "crossRef": "C-TIRZ-CARDIO-HF-01", "grade": "moderate", "source": { "citation": "Borlaug BA et al., Nat Med 2025;31(2):544-551 (SUMMIT mechanistic secondary)", "url": "https://doi.org/10.1038/s41591-024-03374-z", "identifiers": "PMID:39551891 DOI:10.1038/s41591-024-03374-z NCT04847557", "date": "2025-02-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; sponsor-authored)", "scopeLimits": "surrogate/exploratory endpoint; sponsor-authored COI (Eli Lilly)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-IMMUNO-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Mounjaro: ADA 51% (2570/5025); neutralising ~2% (GIP) / ~2% (GLP-1); no clinically significant PK/efficacy impact", "finding": "About half of Mounjaro-treated patients developed anti-tirzepatide antibodies, with low neutralising-antibody rates and no identified clinical impact.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "immunogenicity", "notes": "US PI 6.2. ADA incidence is HIGHLY ASSAY-DEPENDENT and not directly comparable across products or to semaglutide; the headline 51%-vs-sema-1-3% gap is partly an assay artefact.", "crossRef": "C-TIRZ-IMMUNO-02; C-SEMA-IMMUNO-01", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-IMMUNO-02", "sourceId": "CIT:zepbound-us-pi-dailymed-487cd7e7", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "n/a", "magnitude": "Zepbound: ADA 64.5% (weight) / 60.6% (OSA); neutralising 2.8%/2.7% (weight), NONE detected (OSA); no clinical impact", "finding": "In Zepbound trials the majority of patients developed anti-tirzepatide antibodies; neutralising antibodies were uncommon in the weight-management pool (2.7-2.8%) and none were detected in the OSA pool; no clinically significant PK/efficacy effect.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "immunogenicity", "notes": "US PI 6.2. Incidence highly assay-dependent. The OSA pool had NO neutralising antibodies - do not state a single ~2% range across both.", "crossRef": "C-TIRZ-IMMUNO-01", "grade": "high", "source": { "citation": "Zepbound (tirzepatide) US Prescribing Information, Eli Lilly", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b", "identifiers": "DailyMed setid 487cd7e7-434c-4925-99fa-aa80b1cc776b", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-IRON-ABSENCE-01", "sourceId": "PMID41549912", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual receptor agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Tirzepatide has NO established link to ELEVATED ferritin per trial data / SmPC and no known direct effect on iron metabolism; elevated ferritin in users reflects underlying metabolic/inflammatory/liver disease (acute-phase), not a drug effect.", "finding": "Tirzepatide has no established link to elevated ferritin per trial data and the SmPC, and no known direct effect on iron metabolism; elevated ferritin observed in users reflects underlying metabolic, inflammatory or liver disease (ferritin as an acute-phase reactant), not a drug effect.", "population": "Synthesised from the Urbina narrative review plus non-measurement of iron in SURPASS/SURMOUNT; tirzepatide iron metabolism not directly studied.", "comparators": "not applicable", "endpointType": "safety-event/signal", "notes": "Medium confidence; rests partly on a low-quality commercial pharmacy page plus non-measurement of iron in the SURPASS/SURMOUNT programmes. NO commercial/press source minted; anchored as a secondary finding on the Urbina review.", "crossRef": "", "grade": "low", "source": { "citation": "Urbina et al., GLP-1 receptor agonists and iron status, Clin Obes 2026;16:e70070", "url": "https://doi.org/10.1111/cob.70070", "identifiers": "PMID 41549912 / DOI 10.1111/cob.70070", "date": 2026, "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-LACTATION-EU-01", "sourceId": "CIT:mounjaro-eu-smpc-emc-15482", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "EU: could be considered for use during breast-feeding", "finding": "The EU SmPC states tirzepatide could be considered for use during breast-feeding.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/lactation", "notes": "EU Mounjaro SmPC 4.6. REGIONAL + DRUG CONTRAST: EU PERMITS tirzepatide in breastfeeding, opposite to EU semaglutide ('should not be used', C-SEMA-LACTATION-EU-01).", "crossRef": "C-TIRZ-LACTATION-US-01; C-SEMA-LACTATION-EU-01", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) EU Summary of Product Characteristics (EMA)", "url": "https://www.medicines.org.uk/emc/product/15482/smpc", "identifiers": "EMC product 15482 (EMA Annex I)", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-LACTATION-US-01", "sourceId": "CIT:zepbound-us-pi-dailymed-487cd7e7", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "Human study n=11: undetectable in 164/171 milk samples; <0.02% of maternal dose", "finding": "A human lactation study (n=11) after a single 5 mg dose found tirzepatide largely undetectable in breast milk (cumulative <0.02% of the maternal dose); US labels make no clinical-impact statement.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/lactation", "notes": "US PI 8.2. Fills the breastfeeding corpus blank (OQ-REPRO-A). EU posture differs - see C-TIRZ-LACTATION-EU-01. Human data is a single small study.", "crossRef": "C-TIRZ-LACTATION-EU-01", "grade": "high", "source": { "citation": "Zepbound (tirzepatide) US Prescribing Information, Eli Lilly", "url": "https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=487cd7e7-434c-4925-99fa-aa80b1cc776b", "identifiers": "DailyMed setid 487cd7e7-434c-4925-99fa-aa80b1cc776b", "date": "2026-06-22", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "regulatory label; reflects approved labelling, not an independent effect estimate", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-LIPID-SURMOUNT1-NONHDL-01", "sourceId": "PMID40550133", "drug": "tirzepatide (5-15 mg)", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Lipid improvements (TG, LDL-C, non-HDL-C down; HDL-C up) emerged mainly above 10% weight loss; reported directionally by weight-loss category, not as single placebo-adjusted percentages in the abstract.", "finding": "In a post-hoc analysis of the phase-3 SURMOUNT-1 obesity trial, tirzepatide-associated improvements in triglycerides, HDL-C, LDL-C and non-HDL cholesterol were primarily observed only after weight reductions greater than 10%.", "population": "Post-hoc analysis of phase-3 double-blind SURMOUNT-1 (NCT04184622); N=1605 adults with obesity or overweight-with-complications without diabetes; tirzepatide 5/10/15 mg; baseline to week 72.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NET-NEW gather (WI-4). Adds a SURMOUNT-1 (phase-3) lipid observation for tirzepatide, including non-HDL cholesterol, distinct from the existing phase-2b NMR/ApoC-III record C-TIRZ-CARDIO-LIPID-01 (PMID 33462955). Post-hoc, hypothesis-generating (authors' own caveat). Observation: lipid benefit tracks weight loss; the 'why' (weight-mediated vs direct) stays open. Industry-funded (Eli Lilly).", "crossRef": "C-TIRZ-CARDIO-LIPID-01", "grade": "moderate", "source": { "citation": "Linetzky B, Sattar N, Verma S, Krumholz HM, et al., Ann Intern Med 2025;178(8):1095-1105", "url": "https://doi.org/10.7326/ANNALS-24-02623", "identifiers": "PMID:40550133 DOI:10.7326/ANNALS-24-02623", "date": "2025-06-24", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-BIOAVAIL-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Absolute s.c. bioavailability 80%", "finding": "The absolute bioavailability of subcutaneous tirzepatide is 80%.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3; EU SmPC 5.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-EXCRETION-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Metabolites in urine + faeces; no intact tirzepatide excreted", "finding": "Tirzepatide metabolites are excreted via urine and faeces, with no intact tirzepatide observed in urine or faeces.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3. No quantitative urine/faeces split given.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-HALFLIFE-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Half-life ~5 days (Mounjaro) / 5-6 days (Zepbound, population-specific)", "finding": "Tirzepatide has an elimination half-life of about 5 days (5-6 days for Zepbound populations), the basis for once-weekly dosing.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3. Do not average to a flat 5 days.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-METABOLISM-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Proteolytic cleavage + beta-oxidation of C20 fatty diacid + amide hydrolysis", "finding": "Tirzepatide is cleared by metabolism via proteolytic cleavage of the peptide backbone, beta-oxidation of its C20 fatty diacid and amide hydrolysis.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3; EU SmPC 5.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-STEADYSTATE-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Steady state after ~4 weeks once-weekly", "finding": "Steady-state tirzepatide concentrations are reached after about 4 weeks of once-weekly dosing.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3; EU SmPC 5.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PK-VD-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Apparent Vd ~10 L; 99% albumin-bound", "finding": "Tirzepatide has a small apparent steady-state volume of distribution (~10 L) and is ~99% albumin-bound.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "pharmacokinetic", "notes": "US PI 12.3; EU SmPC 5.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-PREG-LABEL-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "increase", "magnitude": "Animal malformations + growth reduction (rat, rabbit) at sub-MRHD exposures; human data insufficient; Zepbound: discontinue when pregnancy recognised", "finding": "Animal reproduction studies show malformations and growth reductions in rat and rabbit at sub-clinical exposures; the label states human data are insufficient, and for weight management (Zepbound) to discontinue when pregnancy is recognised.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "reproductive-tox", "notes": "US PI 8.1. Animal harm positive; human conclusion is a label hedge. Mounjaro frames benefit/risk; Zepbound instructs discontinuation (indication-driven).", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-REG-GCGR-EC50-01", "sourceId": "CIT:mounjaro-nda-215866-pharmtox-refid-4953686", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "no-change", "magnitude": "human GCGR cAMP EC50 ~2350 nM - minimal-to-no glucagon-receptor agonism (EMA Mounjaro EPAR quantification; FDA Pharm/Tox states the same qualitatively)", "finding": "The EMA Mounjaro EPAR quantifies tirzepatide's potency at the human glucagon receptor (GCGR) as a cAMP functional EC50 of ~2350 nM - some three orders of magnitude weaker than its GIP/GLP-1 receptor potency - i.e. minimal-to-no glucagon-receptor agonism at therapeutic exposure. The FDA NDA 215866 Pharm/Tox review states the same qualitatively. This is the tirzepatide GCGR-silence half of the receptor-level glucagon-by-elimination argument (the semaglutide GCGR-negative half is C-SEMA-REG-GCGR-NEGATIVE-01): both characterised dual/mono comparators carry no meaningful glucagon-receptor activity, so the glucagon arm is the sole added pharmacology in retatrutide. Arm-elimination only - this establishes which receptor differs, NOT how much of any weight-loss difference is apportionable to glucagon agonism.", "population": "in-vitro human glucagon-receptor (GCGR) cAMP functional assay (EMA Mounjaro EPAR EMEA/H/C/005620; FDA NDA 215866 Pharm/Tox cross-confirm)", "comparators": "human GIP receptor; human GLP-1 receptor", "endpointType": "pharmacology-receptor", "notes": "Load-bearing for C1 glucagon-by-elimination - the tirzepatide GCGR-silence half (semaglutide half is C-SEMA-REG-GCGR-NEGATIVE-01); arm-elimination only, not weight-loss apportionment. In-vitro human-receptor assay (a human receptor in a dish is not a human cohort); grade follows the in-vitro/regulatory substrate and is non-load-bearing for any human-cohort magnitude claim.", "crossRef": "C-SEMA-REG-GCGR-NEGATIVE-01", "grade": "very-low", "source": { "citation": "FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Braithwaite); EMA Mounjaro EPAR EMEA/H/C/005620 cross-confirms", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000PharmR.pdf", "identifiers": "FDA Reference ID 4953686 (NDA 215866)", "date": "2022-05-13", "design": "preclinical (rodent)", "maturity": "regulatory-doc", "funding": "industry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-REG-RECEPTOR-ENGAGEMENT-01", "sourceId": "CIT:zepbound-nda-217806-clinpharm-refid-5258712", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "GIPR activity similar to native GIP; GLP-1R activity lower than native GLP-1; in-vitro human Ki GIPR 4.02 nM vs GLP-1R 378 nM; biased GLP-1R agonist favouring cAMP over beta-arrestin", "finding": "FDA Zepbound Clinical Pharmacology review characterises tirzepatide as having GIPR activity similar to native GIP but GLP-1R activity lower than native GLP-1, and as a biased GLP-1R agonist favouring cAMP over beta-arrestin (in-vitro human Ki GIPR 4.02 nM vs GLP-1R 378 nM). This establishes WHICH arms are engaged; it must NOT be read as a quantitative weight-loss apportionment (the sign of the GIPR contribution is itself unsettled).", "population": "In-vitro human receptor binding/signalling assays (FDA Zepbound NDA 217806 ClinPharm, Sec 3.2 General Pharmacology, Table 3)", "comparators": "native GIP; native GLP-1", "endpointType": "pharmacology-receptor", "notes": "Promoted from sweep SW-REG-03 (2026-06-21). Audit caveat: usable for qualitative arm-engagement only, explicitly NOT to apportion the weight-loss effect.", "crossRef": "", "grade": "low", "source": { "citation": "FDA Zepbound NDA 217806 Clinical Pharmacology Review, Reference ID 5258712", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217806Orig1s000ClinPharmR.pdf", "identifiers": "FDA Reference ID 5258712 (NDA 217806)", "date": "2023-11-08", "design": "in-vitro / cell-line / SAR", "maturity": "regulatory-doc", "funding": "industry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 217806 submission)", "scopeLimits": "in-vitro receptor assay; human relevance via pharmacology only", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-RENAL-SURPASS-01", "sourceId": "PMID42114520", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "renal", "domainLabel": "renal", "domainSlug": "renal", "direction": "decrease", "magnitude": "SURPASS-CVOT prespecified exploratory kidney analysis: composite major kidney events HR 0.77 (95% CI 0.68-0.88) for tirzepatide vs dulaglutide over median ~4.0 years.", "finding": "In T2D with established ASCVD, tirzepatide reduced a composite of major adverse kidney events versus dulaglutide in a prespecified exploratory analysis of SURPASS-CVOT. Note the comparator is an active CV-proven GLP-1RA (dulaglutide), NOT placebo, and the analysis is exploratory (not part of the confirmatory hierarchy).", "population": "Prespecified exploratory analysis of SURPASS-CVOT (NCT04255433): n=13,165 with T2D + established ASCVD; tirzepatide (max-tolerated up to 15 mg) vs dulaglutide 1.5 mg; median follow-up 4.0 years.", "comparators": "dulaglutide 1.5 mg", "endpointType": "hard-outcome", "notes": "GRADE moderate: prespecified but EXPLORATORY (outside the confirmatory testing hierarchy) and vs an ACTIVE comparator (dulaglutide), so it shows relative kidney benefit over another GLP-1RA, not vs placebo. This PMID (42114520) was previously mis-cited in C-COMPARE-15 as the SURPASS-CVOT PRIMARY CV paper - corrected: the primary is PMID 41406444; 42114520 is this kidney sub-analysis. Cross-ref C-TIRZ-CARDIO-01 (SURPASS-CVOT primary CV).", "crossRef": "C-TIRZ-CARDIO-01", "grade": "moderate", "source": { "citation": "Zoungas S et al. Tirzepatide vs dulaglutide on major kidney events: pre-specified exploratory analyses of SURPASS-CVOT. Lancet Diabetes Endocrinol 2026;14(7):544-557.", "url": "https://doi.org/10.1016/S2213-8587(26)00032-X", "identifiers": "PMID 42114520; DOI 10.1016/S2213-8587(26)00032-X", "date": "2026-05-11", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-RODENT-METRATE-01", "sourceId": "CIT:mounjaro-nda-215866-pharmtox-refid-4953686", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "DIO-mouse metabolic rate greater than semaglutide; at pair-fed / body-weight-matched doses still produced significantly greater glucose infusion rate and 2-deoxyglucose tissue uptake than semaglutide-treated and pair-fed controls (intake-independent)", "finding": "FDA Mounjaro Pharm/Tox review (rodent lead): in diet-induced-obese mice tirzepatide raised metabolic rate more than semaglutide and, at pair-fed/body-weight-matched doses, still produced greater glucose infusion rate and tissue glucose uptake - an intake-independent metabolic component. This is a RODENT mechanistic lead in the GIP arm, NOT the glucagon arm, and does NOT translate to a human intake-independent energy-expenditure claim (22C cold-stress EE inflation; poor mouse-GIPR translation; contradicted by human RMR/TEE).", "population": "DIO mice (FDA NDA 215866 Pharm/Tox in-vivo studies, Figs 3,4,7); standard ~22C housing; pair-fed / body-weight-matched comparisons", "comparators": "semaglutide; pair-fed control", "endpointType": "preclinical-mechanistic", "notes": "Promoted from sweep SW-REG-08 (2026-06-21). The one counter-direction signal. Audit caveats: does NOT translate to humans (cold-stress EE inflation ~35% at 22C vs thermoneutral; mouse-GIPR poor translation); this is the GIP arm, not glucagon. Quarantined as rodent mechanistic LEAD only; non-load-bearing for the human EE reading. Motivates the direct-human-EE open question.", "crossRef": "C-CLASS-RODENT-EEDEFENCE-01", "grade": "very-low", "source": { "citation": "FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Braithwaite); EMA Mounjaro EPAR EMEA/H/C/005620 cross-confirms", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000PharmR.pdf", "identifiers": "FDA Reference ID 4953686 (NDA 215866)", "date": "2022-05-13", "design": "preclinical (rodent)", "maturity": "regulatory-doc", "funding": "industry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-AKI13", "sourceId": "CIT:comparative-renal-safety-of-tirzepatide-and-sema", "drug": "tirzepatide vs semaglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual vs GLP-1 RA", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "AKI 432/92,807 (0.47%) tirzepatide vs 440/41,065 (1.07%) semaglutide; ROR tirzepatide vs semaglutide 0.44", "finding": "FAERS comparative disproportionality found acute kidney injury reported LESS frequently with tirzepatide than semaglutide.", "population": "FAERS Jan 2022-Sep 2025, 133,872 reports (92,807 tirzepatide; 41,065 semaglutide)", "comparators": "semaglutide", "endpointType": "safety-event/signal", "notes": "Reporting-frequency, not incidence; biases apply (semaglutide longer on market). Full PMID/DOI to confirm (page CAPTCHA-gated); PMCID confirmed.", "crossRef": "C-CLASS-SAFETY-AKI12", "grade": "very-low", "source": { "citation": "Comparative Renal Safety of Tirzepatide and Semaglutide: FAERS Disproportionality Study 2025", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12610529/", "identifiers": "PMID 41227073; DOI 10.3390/jcm14217678 [VERIFIED 2026-06-20]", "date": "2025-11-01", "design": "pharmacovigilance / disproportionality", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-BIL02", "sourceId": "PMID37908750", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "mixed", "magnitude": "Composite gallbladder/biliary RR 1.97 (1.14-3.42); pancreatitis RR 1.46 (0.59-3.61, NS)", "finding": "Composite gallbladder/biliary disease significantly associated with tirzepatide; pancreatitis and individual biliary endpoints NOT significantly increased.", "population": "9 RCTs, 9871 participants (T2D and obesity); meta-analysis", "comparators": "placebo; basal insulin; dulaglutide; semaglutide", "endpointType": "safety-event/signal", "notes": "Both poles: composite biliary signal present, pancreatitis null.", "crossRef": "C-CLASS-SAFETY-BIL01", "grade": "moderate", "source": { "citation": "Zeng Q et al., Front Endocrinol 2023", "url": "https://doi.org/10.3389/fendo.2023.1214334", "identifiers": "PMID:37908750 / DOI:10.3389/fendo.2023.1214334", "date": "2023-10-16", "design": "meta-analysis", "maturity": "human-primary", "funding": "academic / government - Sichuan Science and Technology Program (China); no industry funding", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-CONTRA04", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Oral-contraceptive interaction: ethinylestradiol Cmax reduced ~59% (AUC ~20%), norgestimate/norelgestromin Cmax reduced ~55-66%; greatest after the first dose, diminishing over time", "finding": "Tirzepatide may reduce ORAL hormonal contraceptive efficacy via delayed gastric emptying; US labelling advises switching to a non-oral method or adding a barrier method for 4 weeks after initiation and after each dose escalation.", "population": "Regulatory label (FDA Mounjaro/Zepbound PI; EU SmPC); PK interaction basis", "comparators": "", "endpointType": "drug-interaction", "notes": "REPAIRED (F1 Council): the previous magnitude field wrongly held the PARACETAMOL datapoint - that now lives in C-TIRZ-DDI-PARACETAMOL-01. Tirzepatide-specific (NOT labelled for injectable semaglutide; contrast C-SEMA-DDI-OC-01). EU SmPC 4.5 quantifies the same EE Cmax -59% but judges it 'not clinically relevant' while still giving the barrier advice - preserve that tension. Non-oral methods (IUD, implant, injection, patch, ring) unaffected.", "crossRef": "C-CLASS-SAFETY-PREG03; C-SEMA-DDI-OC-01; C-TIRZ-DDI-PARACETAMOL-01", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-GI02", "sourceId": "PMID35658024", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "AE discontinuation 4.3%/7.1%/6.2% (5/10/15 mg) vs 2.6% placebo. Nausea 24.6%/33.3%/31.0% vs 9.5%; diarrhoea 18.7%/21.2%/23.0% vs 7.3%; constipation 16.8%/17.1%/11.7% vs 5.8%; vomiting 8.3%/10.7%/12.2% vs 1.7%", "finding": "GI AEs most common, mostly mild-to-moderate, primarily during dose escalation; AE-related discontinuation dose-related. Per-symptom rates broadly dose-related (nausea peaks at 10 mg).", "population": "SURMOUNT-1: 2539 adults with obesity; 72 weeks (20-wk escalation); phase 3 RCT", "comparators": "placebo", "endpointType": "other", "notes": "Per-symptom rates from SURMOUNT-1 supplementary tables via secondary reporting; confirm against NEJM appendix. Discontinuation figures from abstract.", "crossRef": "C-TIRZ-SEMA-SAFETY-GI11", "grade": "high", "source": { "citation": "Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY3537021 phase 1 (2025)", "url": "https://pubmed.ncbi.nlm.nih.gov/35658024/", "identifiers": "PMID 35658024; NCT05669599; PMID 41391569", "date": "2022-06-04", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (SURMOUNT-1; disclosed)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-MH08", "sourceId": "DOI10.1002/OBY.70122", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "N=4056 (tirzepatide vs placebo); no meaningful PHQ-9 difference; SI/SB low and similar; numerically more moderate-risk SI on tirzepatide", "finding": "Post hoc pooled analysis of SURMOUNT-1/-2/-3 (RCT data): no clinically meaningful PHQ-9 difference vs placebo over 72 weeks; suicidal ideation/behaviour (C-SSRS) low and similar, though a numerically greater percentage of tirzepatide participants reported moderate-risk ideation.", "population": "Pooled SURMOUNT-1/-2/-3, obesity, no known major psychopathology; 72 weeks; placebo-controlled RCTs", "comparators": "placebo", "endpointType": "symptom/PRO", "notes": "RCT-level no-signal pole. The numerically-greater moderate-risk SI on tirzepatide recorded as the emerging caveat, neither amplified nor suppressed.", "crossRef": "C-CLASS-SAFETY-MH02", "grade": "moderate", "source": { "citation": "Wadden TA et al., 'Psychiatric Safety of Tirzepatide... Post Hoc Analysis of SURMOUNT'. Obesity 2026", "url": "https://onlinelibrary.wiley.com/doi/full/10.1002/oby.70122", "identifiers": "DOI:10.1002/oby.70122", "date": "2026-01-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-MTC10", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Dose/duration-dependent increase in rat C-cell adenomas/carcinomas (qualitative; rodent)", "finding": "FDA boxed warning: in a 2-year rat study tirzepatide caused dose- and treatment-duration-dependent thyroid C-cell tumours at clinically relevant exposures; contraindicated with personal/family history of MTC or MEN 2. Human relevance not determined.", "population": "2-year rat carcinogenicity study; regulatory label", "comparators": "vehicle control", "endpointType": "safety-event/signal", "notes": "Mirrors the semaglutide rodent C-cell boxed warning.", "crossRef": "C-SEMA-SAFETY-MTC09; C-LIRA-SAFETY-MTC08", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-MUSCLE13", "sourceId": "PMID42304171", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Fat mass MD -10.70 kg (-13.42 to -7.99); lean body mass MD -4.40 kg (-7.58 to -1.22). Liraglutide LBM -1.54 kg", "finding": "In a network meta-analysis, tirzepatide produced the greatest reduction in both fat mass and (absolute) lean body mass.", "population": "Network meta-analysis, 41 RCTs, 2906 participants, through Mar 2025", "comparators": "placebo; semaglutide; liraglutide; SGLT2i; metformin; insulin; DPP-4i", "endpointType": "safety-event/signal", "notes": "Largest LBM reduction of class, proportionate to larger total weight loss. Exercise reported to mitigate.", "crossRef": "C-CLASS-SAFETY-MUSCLE12; C-CLASS-SAFETY-MUSCLE14", "grade": "moderate", "source": { "citation": "Rakhsha SS et al., Diabetes Obes Metab 2026", "url": "https://doi.org/10.1111/dom.70957", "identifiers": "PMID:42304171 / DOI:10.1111/dom.70957", "date": "2026-06-16", "design": "network meta-analysis", "maturity": "review", "funding": "academic - Tehran University of Medical Sciences (Chronic Diseases Research Center; grant 1403-04-75722-221); no industry sponsor", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SAFETY-REGAIN15", "sourceId": "PMID38078870", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Lead-in loss 20.9%; week 36-88 change -5.5% (continued) vs +14.0% (placebo); difference -19.4% (-21.2 to -17.7). 89.5% maintained >=80% of loss on tirzepatide vs 16.6% placebo", "finding": "Withdrawing tirzepatide after a 36-week lead-in led to substantial weight REGAIN, whereas continued treatment maintained/augmented loss (randomized-withdrawal design).", "population": "SURMOUNT-4 (NCT04660643), phase 3 randomized-withdrawal, 670 adults with obesity/overweight (no diabetes), 52-wk double-blind after open-label lead-in", "comparators": "placebo (withdrawal)", "endpointType": "safety-event/signal", "notes": "Per PubMed; numbers CONFIRMED via metadata. Parallels STEP 1 extension: weight regain on stopping is a class phenomenon.", "crossRef": "C-SEMA-SAFETY-REGAIN14", "grade": "moderate", "source": { "citation": "Aronne LJ et al., JAMA 2024 (SURMOUNT-4)", "url": "https://doi.org/10.1001/jama.2023.24945", "identifiers": "PMID:38078870 / DOI:10.1001/jama.2023.24945 / PMC10714284", "date": "2024-01-02", "design": "randomised-withdrawal RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SEMA-SAFETY-GI11", "sourceId": "CIT:aronne-lj-et-al-surmount-5-n-engl-j-med-2025", "drug": "tirzepatide vs semaglutide (head-to-head)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual vs GLP-1 RA", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "mixed", "magnitude": "GI-AE discontinuation 5.6% semaglutide vs 2.7% tirzepatide; most AEs mild-to-moderate during escalation", "finding": "SURMOUNT-5 head-to-head: GI AEs most common with both; GI-AE-driven discontinuation occurred more often with semaglutide than tirzepatide.", "population": "SURMOUNT-5: 751 adults with obesity, no diabetes; 72 weeks; phase 3b open-label; max-tolerated tirzepatide 10/15 mg vs semaglutide 1.7/2.4 mg", "comparators": "semaglutide", "endpointType": "other", "notes": "GI discontinuation numerically lower for tirzepatide despite greater weight loss. Secondary/ACC reporting; PMID/DOI not confirmed this pass.", "crossRef": "C-TIRZ-SAFETY-GI02; C-SEMA-SAFETY-GI01", "grade": "moderate", "source": { "citation": "Aronne LJ et al., SURMOUNT-5, N Engl J Med 2025", "url": "https://www.acc.org/Latest-in-Cardiology/Journal-Scans/2025/07/10/09/09/SURMOUNT-5", "identifiers": "PMID 40353578; DOI 10.1056/NEJMoa2416394; NCT05822830 [VERIFIED 2026-06-20]", "date": "2025-05-11", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (disclosed in publication)", "scopeLimits": "identifier not fully verified; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SPECIALPOP-ELDERLY-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "No overall safety/efficacy difference; limited >=75 data", "finding": "No overall differences in safety or efficacy were detected in elderly patients, with limited data above 75 years.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/elderly", "notes": "US PI 8.5.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SPECIALPOP-HEPATIC-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "No dose adjustment in hepatic impairment", "finding": "US labelling specifies no dose adjustment for hepatic impairment (no PK change across degrees of impairment).", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/hepatic", "notes": "US PI 8.7.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SPECIALPOP-PAED-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "Mounjaro US established >=10 y T2D (more vomiting/abdominal pain/hypo vs adults); Zepbound not established in children; EU not <18", "finding": "Paediatric status differs by product/region: the US Mounjaro label establishes use in T2D from age 10 (with higher vomiting/abdominal pain/hypoglycaemia than adults); Zepbound is not established in children, and the EU has not established use under 18.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/paediatric", "notes": "US PI 8.4; EU SmPC 4.2.", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-SPECIALPOP-RENAL-01", "sourceId": "CIT:mounjaro-tirzepatide-us-prescribing-information-", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "n/a", "magnitude": "No dose adjustment incl. ESRD; monitor renal function if severe GI adverse reactions", "finding": "US labelling specifies no dose adjustment for renal impairment including ESRD, with advice to monitor renal function when initiating/escalating in patients with severe GI adverse reactions.", "population": "Regulatory label / SmPC (primary document)", "comparators": "", "endpointType": "special-population/renal", "notes": "US PI 8.6. Scoped to US (an EU severe-renal restriction was not section-confirmed here).", "crossRef": "", "grade": "high", "source": { "citation": "Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories", "url": "https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0", "identifiers": "FDA-label-Mounjaro (DailyMed setid d2d7da5d-ad07-4228-955f-cf7e355c8cc0)", "date": "2022-05-13", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-T1D-01", "sourceId": "PMID41264593", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "special-populations", "domainLabel": "special-populations", "domainSlug": "special-populations", "direction": "decrease", "magnitude": "Tirzepatide phase-2 T1D trial (12wk, n=24, BMI>30): weight estimated treatment difference vs placebo -8.7kg (95% CI -12.0,-5.5; P<0.0001), 8.8% loss (primary endpoint); HbA1c MD -0.4% (-0.7,0.0; P=0.05); total daily insulin -35.1% (-46.5,-21.3; P=0.0002); 'no significant adverse events in either group'.", "finding": "A single small phase-2 RCT (n=24, 12 weeks) found tirzepatide added to insulin in obese type-1 diabetes produced large weight loss (-8.7kg, 8.8%), a borderline HbA1c reduction, and a 35% cut in insulin dose, with no significant adverse events - promising but very preliminary.", "population": "Tirzepatide phase-2 double-blind placebo-controlled T1D RCT (Snaith et al., TIRTLE1, single-centre, 12wk, n=24 [22 completed], T1D + BMI>30, Garvan Institute; PMC12719702).", "comparators": "placebo (insulin background)", "endpointType": "surrogate/biomarker", "notes": "VERY PRELIMINARY: n=24, single-centre, 12wk, PRIMARY endpoint = weight (NOT glycaemic/safety-powered); authors note the trial was likely underpowered for glycaemic superiority and other secondary outcomes. The 'no significant AEs' must NOT be read as a safety clearance - too small/short to detect the ketosis/hypo signals seen in the larger liraglutide trials. Larger phase-3 confirmatory trials (SURPASS-T1D-1/2) are flagged as the needed next step (routed to OQ-T1D-A).", "crossRef": "C-LIRA-T1D-SAFETY-02", "grade": "moderate", "source": { "citation": "Snaith JR, Frampton R, Samocha-Bonet D, Greenfield JR. Tirzepatide in Adults With Type 1 Diabetes: A Phase 2 Randomized Placebo-Controlled Clinical Trial. Diabetes Care 2026;49(1):161-170.", "url": "https://doi.org/10.2337/dc25-2379", "identifiers": "DOI:10.2337/dc25-2379", "date": "2026-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "academic/charity (Garvan Institute sponsor; Breakthrough T1D/JDRF, UNSW, Australian Diabetes Society)", "scopeLimits": "small sample (N=24); single-centre; short duration (12wk); weight-primary (not glycaemic/safety-powered)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-URATE-01", "sourceId": "PMID41198460", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "SURMOUNT-1 post hoc (n=2,539): mean 72-wk change in serum uric acid -0.69 / -0.92 / -0.95 mg/dL at tirzepatide 5/10/15 mg (all P<.001) vs -0.18 mg/dL placebo; weight loss up to 20.9%; reduction held regardless of baseline urate quartile or BMI.", "finding": "In a post hoc analysis of the SURMOUNT-1 obesity RCT, tirzepatide lowered serum uric acid dose-dependently versus placebo over 72 weeks, with the effect independent of baseline uric-acid level or BMI.", "population": "Tirzepatide phase-3 obesity RCT post hoc (Sattar et al., SURMOUNT-1, NCT04184622); 2,539 adults with obesity/overweight + >=1 weight-related complication.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Post hoc (not a prespecified gout/urate endpoint); biochemical surrogate (SUA), not a clinical gout outcome. Lilly-sponsored trial. The drop is real and dose-dependent but - see C-TIRZ-URATE-02 - largely weight-mediated.", "crossRef": "", "grade": "moderate", "source": { "citation": "Sattar N et al. Tirzepatide and change in uric acid and its association with weight reduction: post hoc analyses of the SURMOUNT-1 randomised placebo-controlled trial. Ann Rheum Dis 2025;85(3):558-565.", "url": "https://doi.org/10.1016/j.ard.2025.10.009", "identifiers": "DOI:10.1016/j.ard.2025.10.009", "date": 2025, "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-URATE-02", "sourceId": "PMID41198460", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "decrease", "magnitude": "Mediation analysis: weight reduction explained 72.7% of the serum-uric-acid reduction; ~73% weight-mediated.", "finding": "A mediation analysis in the same SURMOUNT-1 post hoc found that about 73% of tirzepatide's serum-uric-acid reduction was explained by weight loss - implicating weight loss rather than a direct uricosuric drug effect.", "population": "Tirzepatide phase-3 obesity RCT post hoc (Sattar et al., SURMOUNT-1, NCT04184622); mediation analysis of weight change vs SUA change.", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "ASSOCIATIONAL mediation, NOT a designed causal endpoint - the 72.7% weight-mediated figure is a model decomposition, not a randomised mechanistic test. Confounded with all weight-loss-correlated changes. Supports the weight-mediated (not direct-uricosuric) reading of the class.", "crossRef": "C-TIRZ-URATE-01", "grade": "moderate", "source": { "citation": "Sattar N et al. Tirzepatide and change in uric acid and its association with weight reduction: post hoc analyses of the SURMOUNT-1 randomised placebo-controlled trial. Ann Rheum Dis 2025;85(3):558-565.", "url": "https://doi.org/10.1016/j.ard.2025.10.009", "identifiers": "DOI:10.1016/j.ard.2025.10.009", "date": 2025, "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-VS-SEMA-BODYCOMP-01", "sourceId": "DOI10.64898/2026.04.11.26350687V1", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Excess LBM loss with tirzepatide vs semaglutide: 1.1%, 1.5%, 1.3%, 2.0% at 3, 6, 9, 12 months. Depletive metabotype 10.3% (tirz) vs 6.7% (sema), p<0.001.", "finding": "EHR-linked body-composition digital-phenotyping study (LLM extraction) of routine-care users found tirzepatide associated with GREATER relative lean-body-mass loss than semaglutide at every timepoint; a 'Depletive GLP-1 metabotype' (>20% TBW loss with >5% LBM loss) was more frequent with tirzepatide.", "population": "670,422 first-episode GLP-1RA users (semaglutide 456,742; tirzepatide 213,680); 7,965 with paired pre/post body-composition over 12 months; retrospective real-world EHR cohort", "comparators": "semaglutide", "endpointType": "imaging/physiological surrogate", "notes": "TENSION: directionally OPPOSITE to the matched ~25% lean fraction seen for both drugs in their respective RCT DXA substudies (SURMOUNT-1, STEP). Real-world/observational, body-composition method heterogeneous (LLM-extracted from EHR notes), confounding by indication likely. Baseline musculoskeletal pain / reduced exercise tolerance were top correlates of LBM loss. [VALIDATION 2026-06-21: WebFetch of full text was blocked (403). RE-CHECK 2026-06-22: medRxiv source (10.64898/2026.04.11.26350687v1, posted 14 Apr 2026) now reachable and SUPPORTS the claim - every figure matches: n=670,422 (sema 456,742 / tirz 213,680), 7,965 paired; excess tirz LBM loss 1.1/1.5/1.3/2.0% at 3/6/9/12 mo; Depletive metabotype 10.3% vs 6.7% p<0.001; musculoskeletal pain (cervicalgia, knee pain) top correlate. Source-supports-claim CONFIRMED, but this remains a non-peer-reviewed preprint with LLM-extracted EHR body composition and likely confounding by indication, directionally OPPOSITE the matched-fraction RCT DXA data - NON-GRADUATING; cite only as a flagged tension, never as evidence.]", "crossRef": "C-TIRZEPATIDE-BODYCOMP-01", "grade": "low", "source": { "citation": "Greater lean-body-mass decline with tirzepatide than semaglutide in routine care (digital phenotyping), medRxiv/Research Square preprint, 2026", "url": "https://www.medrxiv.org/content/10.64898/2026.04.11.26350687v1", "identifiers": "medRxiv 10.64898/2026.04.11.26350687v1; Research Square rs-9407186/v1", "date": "2026-04-11", "design": "observational cohort", "maturity": "preprint", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "conference/abstract-level; possible confounding by indication", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZ-VS-SEMA-TOLGI-01", "sourceId": "DOI10.1056/NEJMOA2416394", "drug": "tirzepatide vs semaglutide (head-to-head GI tolerability)", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 vs GLP-1", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "n/a", "magnitude": "SURMOUNT-5 head-to-head (Aronne, NEJM 2025): tirzepatide -20.2% vs semaglutide -13.7% weight (tirz stronger), yet GI-driven DISCONTINUATION was lower with tirzepatide (2.7% vs 5.6%, ~half). Indirect comparisons/network meta-analyses rank tirzepatide slightly below semaglutide for nausea (both clearly elevated). Preclinical GIP-antiemetic mechanism: GIPR agonism in area-postrema/NTS GABAergic neurons blocks GLP-1-induced emesis/malaise (in shrews semaglutide caused dose-dependent vomiting; tirzepatide produced zero emetic episodes).", "finding": "FOLK-CLAIM VERDICT ('tirzepatide is gentler than semaglutide despite being stronger', attributed to GIP): MIXED, leaning TRUE - the robust HUMAN finding is LOWER GI-driven discontinuation with tirzepatide (SURMOUNT-5, 2.7% vs 5.6%); the nausea gap itself is modest and partly dose/exposure-confounded. The GIP-antiemetic mechanism is real but mostly ANIMAL-proven. So tirzepatide is MODESTLY better tolerated (clearest on vomiting/discontinuation), not dramatically 'gentle'.", "population": "SURMOUNT-5 randomised head-to-head (tirzepatide vs semaglutide, obesity) + indirect/network meta-analyses + preclinical GIP-antiemetic mechanism (shrew/rat area postrema).", "comparators": "semaglutide", "endpointType": "other", "notes": "GRADE moderate: the discontinuation difference is from a real head-to-head RCT (high-quality), but 'gentler' overall is mixed and the antiemetic mechanism is preclinical. Belief-vs-reality: 'tirz barely makes you sick' overshoots; it is modestly better tolerated, the GIP-antiemetic mechanism is real but animal-proven, and both still cause substantial GI AEs. Reta relevance: reta (GIP/GLP-1/glucagon) shares the GIP arm but is GI-dominant in tolerability and adds a heart-rate/dysesthesia profile (cross-ref). [VALIDATION: the 2.7% vs 5.6% GI-driven discontinuation figure is from the SURMOUNT-5 full text/supplement, not the abstract; the weight figures (-20.2 vs -13.7) are abstract-confirmed.]", "crossRef": "C-CLASS-TOLGI-FOLKVERDICT-01", "grade": "moderate", "source": { "citation": "Aronne LJ et al. Tirzepatide vs semaglutide for obesity (SURMOUNT-5). N Engl J Med 2025 (DOI 10.1056/NEJMoa2416394); GIP-antiemetic mechanism PMC12175907.", "url": "https://doi.org/10.1056/NEJMoa2416394", "identifiers": "DOI10.1056/NEJMoa2416394", "date": "2025-05-11", "design": "network meta-analysis", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-APP-01", "sourceId": "PMID40555748", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "Phase-1 ingestive-behaviour RCT (n=114, 6 wk; tirz vs placebo vs liraglutide): energy intake -524.6 kcal vs placebo (p<0.0001); decreased food cravings, tendency to overeat, hunger and food-cue reactivity. fMRI: reduced BOLD activation to high-fat/high-sugar food images in medial frontal/cingulate gyri, orbitofrontal cortex and hippocampus (a reward-circuit signal, but partial - no change to overall palatable-food activation). Food Craving Inventory analysis (n=55, 18 wk): overall craving -0.35 (p=0.0098), sweets -0.49 (p=0.004), carbs/starches -0.43 (p=0.007).", "finding": "Tirzepatide reduces food cravings (Food Craving Inventory) and food-cue reward-circuit reactivity (fMRI) - the strongest MECHANISTIC evidence for the lay 'food noise' claim, demonstrating a central reward component, though the fMRI effect was partial (high-fat/high-sugar regions, not overall palatable-food response).", "population": "Phase-1 ingestive-behaviour RCT (n=114, 6 wk) + a phase-1 RCT FCI secondary analysis (n=55, 18 wk); adults with obesity; tirzepatide vs placebo (+ liraglutide arm).", "comparators": "placebo; liraglutide", "endpointType": "imaging/physiological surrogate", "notes": "Best MECHANISTIC package of the three (direct craving instruments + the only reward-circuit fMRI), but note the fMRI signal is partial/qualified. Cross-ref C-CLASS-APP-FOODNOISE-01. [VALIDATION: the FCI magnitudes are from PMID 40874370 (Kennedy SF, a Letter whose abstract is not on PubMed) - on-topic and PMID-correct but the exact figures are not independently abstract-confirmed; the anchor (PMID 40555748) is fully verified.]", "crossRef": "C-CLASS-APP-FOODNOISE-01", "grade": "moderate", "source": { "citation": "Martin CK, Coskun T et al. Tirzepatide effects on ingestive behaviour and brain response to food cues. Nat Med 2025 (with Kennedy SF et al., Diabetes Obes Metab 2025, PMID 40874370, the FCI analysis).", "url": "https://doi.org/10.1038/s41591-025-03774-9", "identifiers": "PMID40555748", "date": "2025-06-20", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "conference/abstract-level; small sample (N~114)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-BODYCOMP-01", "sourceId": "PMID39996356", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Pooled tirzepatide (SURMOUNT-1 DXA, Week 72): body weight -21.3%, fat mass -33.9%, lean mass -10.9%; placebo -5.3% / -8.2% / -2.6% (p<0.001 all). ~75% fat / ~25% lean of weight lost for BOTH arms, holding across sex/age/weight-loss-tertile. Absolute lean-kg not in the abstract (percent change only; baseline mean weight 102.5 kg).", "finding": "SURMOUNT-1 DXA substudy: tirzepatide's large total loss was accompanied by a PROPORTIONALLY matched lean loss (~25% of weight lost), and crucially the same ~75/25 split held for PLACEBO too, so the lean fraction is a property of weight loss at this magnitude, not specifically of the drug. The decision-relevant corollary: a much larger absolute loss at the same proportion carries a larger ABSOLUTE lean-kg loss.", "population": "SURMOUNT-1 DXA substudy: n=160 of 2539 (pooled tirzepatide n=124, placebo n=36), adults with obesity/overweight, mean weight 102.5 kg; baseline-to-Week-72 DXA; post-hoc substudy of a phase-3 double-blind placebo-controlled RCT.", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "DEEPENED (D2): added the absolute lean/fat figures and the decision-relevant point that the ~25% lean fraction held for placebo too (it is a property of weight loss, not the drug); and that absolute lean-kg is not in the abstract. This is the GLP-1+GIP combination benchmark, thread-5 T5-010. DXA lean is not muscle (Neeland 2024). Post-hoc DXA substudy, small N -> moderate. COI (validation): SURMOUNT-1 and this substudy are Eli Lilly-sponsored with several Lilly-employee co-authors.", "crossRef": "C-CLASS-BODYCOMP-03; T5-010", "grade": "moderate", "source": { "citation": "Look M et al., Diabetes Obes Metab, 2025", "url": "https://doi.org/10.1111/dom.16275", "identifiers": "PMID 39996356; DOI 10.1111/dom.16275", "date": "2025-02-25", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "post-hoc (not prespecified); small sample (N~160)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-BODYCOMP-02", "sourceId": "PMID39566869", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "LV mass -11 g (95% CI -19 to -4) placebo-corrected (p=0.004); paracardiac adipose tissue -45 mL (95% CI -69 to -22) placebo-corrected (p<0.001).", "finding": "SUMMIT CMR substudy (obesity-related HFpEF): tirzepatide reduced LV mass and paracardiac (epicardial + pericardial) adipose tissue vs placebo at 52 weeks; the paracardiac reduction was driven by the pericardial component, with the LV-mass change paralleling weight loss.", "population": "175 obesity-related HFpEF patients underwent CMR; 106 analysable (treated 50, placebo 56); tirzepatide to max 15 mg weekly; 52 weeks; RCT (NCT04847557)", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Epicardial/pericardial depot. Coverage notes the volume drop was driven by PERICARDIAL not epicardial fat - a depot-specificity caveat worth preserving. Cross-ref heart-failure domain (SUMMIT).", "crossRef": "C-TIRZEPATIDE-BODYCOMP-01", "grade": "moderate", "source": { "citation": "Kramer CM et al., J Am Coll Cardiol, 2024", "url": "https://doi.org/10.1016/j.jacc.2024.11.001", "identifiers": "PMID 39566869; DOI 10.1016/j.jacc.2024.11.001; NCT04847557", "date": "2024-11-18", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-01", "sourceId": "NCTNCT06893211", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "BAT-positive participants 41.2% -> 64.7% (P=0.005)", "finding": "In premenopausal women with obesity, 24 weeks of tirzepatide increased the proportion of participants with cold-stimulated PET/CT-detectable brown adipose tissue (BAT) activity from 41.2% to 64.7%, with no comparable change in the placebo group; cold-stimulated BAT activity and volume also increased (absolute changes greater vs placebo). MRI assessment was consistent with FDG-PET/CT. Signs of white subcutaneous fat converting to 'beige' fat were also reported.", "population": "TABFAT trial; N=34 premenopausal women with obesity, median age 39 y, median BMI 36.9 kg/m2; randomised 1:1 tirzepatide vs placebo; 24 weeks; cold-stimulated 18F-FDG-PET/CT, MRI, infrared thermography", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "KEY TENSION (record, do not resolve): the same trial reported resting energy expenditure was SIMILAR between groups - if anything a greater decrease in the tirzepatide group, not increased (P=0.3) - and the BAT activation signal was NOT correlated with degree of weight loss. So tissue-level BAT activation co-exists with whole-body REE that is not increased. This mirrors the Ravussin/Cell Metabolism phase 1 finding (C-TIRZEPATIDE-EE-03). First human PET/CT BAT result for tirzepatide. Peer-reviewed primary publication pending; design/rationale published as protocol paper (C-TIRZEPATIDE-EE-02).", "crossRef": "C-TIRZEPATIDE-EE-02; C-TIRZEPATIDE-EE-03", "grade": "low", "source": { "citation": "Herman R et al., TABFAT trial, presented at ENDO 2026 (Endocrine Society annual meeting), Chicago, 15 June 2026; Endocrine Society press release", "url": "https://www.endocrine.org/news-and-advocacy/news-room/2026/herman-press-release-endo-2026", "identifiers": "NCT06893211", "date": "2026-06-15", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "conference-abstract", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing); small sample (N~34)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-02", "sourceId": "PMID40847412", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "n/a", "magnitude": "N=34, randomised 1:1, 24 weeks; primary outcomes BAT volume/activity and WAT browning; secondary outcomes include resting energy expenditure", "finding": "Design/rationale paper for the TABFAT trial: investigator-initiated RCT evaluating tirzepatide effects on BAT volume/activity (18F-FDG-PET/CT, MRI, infrared thermography) and WAT browning (subcutaneous adipose mRNA expression and histomorphometry) in premenopausal women with obesity, with whole-body composition and resting energy expenditure as secondary outcomes.", "population": "Protocol; 34 premenopausal women with obesity; registered ClinicalTrials.gov 2025-03-25", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Protocol/design paper (PMC12374325, open access). Per PubMed. The results were presented at ENDO 2026 (C-TIRZEPATIDE-EE-01).", "crossRef": "C-TIRZEPATIDE-EE-01", "grade": "very-low", "source": { "citation": "Herman R, Jensterle M, Horvat S, et al. Effect of tirzepatide-induced weight loss on adipose tissue in obesity: rationale and design of the TABFAT trial. Trials. 2025;26(1):300", "url": "https://doi.org/10.1186/s13063-025-09045-9", "identifiers": "PMID 40847412; DOI 10.1186/s13063-025-09045-9; NCT06893211", "date": "2025-08-22", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-03", "sourceId": "PMID40203836", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "mixed", "magnitude": "Humans: no change in sleeping/24-h EE adaptation; RER decreased (increased fat oxidation) vs placebo. Mice: attenuated EE drop; RER decreased", "finding": "Phase 1 human study with whole-room indirect calorimetry: tirzepatide did NOT attenuate weight-loss-induced metabolic adaptation (no detectable preservation of sleeping or 24-h energy expenditure) but DID increase fat oxidation (reduced respiratory exchange ratio) vs placebo, alongside reduced appetite and ad libitum calorie intake. In the paired preclinical study (calorie-restricted obese mice), tirzepatide reduced the drop in energy expenditure seen in vehicle/pair-fed mice (i.e. attenuated metabolic adaptation) and lowered RER.", "population": "Phase 1 RCT in people with obesity (NCT04081337) plus preclinical calorie-restricted obese mice with pair-fed control", "comparators": "placebo; pair-fed control (mice)", "endpointType": "imaging/physiological surrogate", "notes": "KEY TENSION (record, do not resolve): the headline human result is EE NOT increased (no protection of EE adaptation) BUT fat oxidation up - the canonical 'whole-body-EE-null vs substrate-shift' finding. Note the human vs rodent divergence WITHIN this single paper: mice showed attenuated metabolic adaptation (an EE-preserving effect) that the humans did not. Lilly-affiliated co-authors. Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-01; C-GLP1CLASS-EE-01", "grade": "low", "source": { "citation": "Ravussin E, Sanchez-Delgado G, Martin CK, et al. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation. Cell Metab. 2025;37(5):1060-1074.e4", "url": "https://doi.org/10.1016/j.cmet.2025.03.011", "identifiers": "PMID 40203836; DOI 10.1016/j.cmet.2025.03.011; NCT04081337", "date": "2025-04-08", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-04", "sourceId": "PMID41592522", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Qualitative: significant increase in BAT thermogenic activity and thermogenic/substrate-oxidation gene expression; effects present vs pair-fed control; trend toward greater visceral/subcutaneous WAT loss", "finding": "In high-fat-diet obese mice with a pair-fed control arm, tirzepatide exerted distinct effects on brown adipose tissue relative to white: significantly boosting BAT thermogenic activity and upregulating genes linked to thermogenesis and substrate oxidation, while white adipose tissue was primarily affected in lipid metabolism. These BAT effects were specific to tirzepatide and NOT attributable to reduced food intake (pair-fed mice did not show them).", "population": "HFD-induced obese mice; tirzepatide vs pair-fed control (matched body-weight loss)", "comparators": "pair-fed control", "endpointType": "imaging/physiological surrogate", "notes": "Part of the 2026 mechanistic wave ('brown fat as a key target'). Pair-feeding establishes food-intake-INDEPENDENT BAT activation in rodents - a rodent counterpoint to the human whole-body-EE-null findings (C-TIRZEPATIDE-EE-01, -03). Villarroya group. Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-05; C-TIRZEPATIDE-EE-06; C-TIRZEPATIDE-EE-07", "grade": "very-low", "source": { "citation": "Mestres-Arenas A, Quesada-Lopez T, Blasco-Roset A, Giralt M, Villarroya F, Planavila A, Peyrou M. Differential effects of the anti-obesity drug tirzepatide on adipose tissues: Brown fat as a key target. Biomed Pharmacother. 2026;195:119057", "url": "https://doi.org/10.1016/j.biopha.2026.119057", "identifiers": "PMID 41592522; DOI 10.1016/j.biopha.2026.119057", "date": "2026-01-26", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-05", "sourceId": "PMID41506434", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Reduced body weight and perirenal/inguinal WAT mass; upregulated PGC-1alpha and UCP1; effect attenuated by SQ22536 in vitro", "finding": "In HFD-obese mice and in 3T3-L1 adipocytes, tirzepatide promoted browning of white adipose tissue via the cAMP-PGC-1alpha-UCP1 signalling axis, reducing intracellular lipid droplet accumulation. Increased browning markers (PGC-1alpha, UCP1) were confirmed in vivo; in vitro the adenylyl cyclase inhibitor SQ22536 attenuated the effect, implicating cAMP-dependent signalling. Described as a direct, adipocyte-intrinsic mechanism beyond central appetite regulation.", "population": "HFD-induced obese mice (in vivo, RNA-seq) and differentiated 3T3-L1 adipocytes (in vitro, +/- SQ22536)", "comparators": "vehicle; SQ22536 (cAMP inhibitor, in vitro)", "endpointType": "imaging/physiological surrogate", "notes": "2026 mechanistic wave (tirzepatide browning of white fat via cAMP). Combines rodent in-vivo and in-vitro (3T3-L1). Mechanistic counterpart to the human PET/CT beige-fat signal in TABFAT (C-TIRZEPATIDE-EE-01). Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-04; C-TIRZEPATIDE-EE-06", "grade": "very-low", "source": { "citation": "Sun Y, Xia Y, Ge W, Li Q. Tirzepatide reduces intracellular lipid content by promoting the browning of white fat via the cAMP signaling pathway. Eur J Pharmacol. 2026;1014:178523", "url": "https://doi.org/10.1016/j.ejphar.2026.178523", "identifiers": "PMID 41506434; DOI 10.1016/j.ejphar.2026.178523", "date": "2026-01-06", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-06", "sourceId": "PMID40000395", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Decreased RER / increased fat utilisation; weight and fat reduction vs pair-fed control (food-intake-independent)", "finding": "In male mice, intracerebroventricular (i.c.v.) tirzepatide reduced body weight and fat content vs pair-fed controls by increasing white adipose lipolysis and enhancing thermogenesis in brown and beige adipose tissue, lowering respiratory exchange ratio (increased lipid utilisation). Effects were mediated by sympathetic nervous system innervation of adipose tissue, associated with neuronal activity changes in the dorsomedial hypothalamus and nucleus of the solitary tract.", "population": "Chow- or HFD-fed male mice; single/long-term i.c.v. tirzepatide vs vehicle, with pair-fed control; metabolic cages (RER)", "comparators": "vehicle; pair-fed control", "endpointType": "imaging/physiological surrogate", "notes": "Central (i.c.v.) route; positions BAT/beige thermogenesis as CNS-sympathetic-driven and food-intake-independent in rodents. Substrate shift (lower RER) echoes the human fat-oxidation finding (C-TIRZEPATIDE-EE-03). Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-03; C-TIRZEPATIDE-EE-04", "grade": "very-low", "source": { "citation": "Zhang A, Liu Q, Xiong Y, et al. Tirzepatide reduces body weight by increasing fat utilization via the central nervous system-adipose tissue axis in male mice. Diabetes Obes Metab. 2025;27(5):2844-2856", "url": "https://doi.org/10.1111/dom.16294", "identifiers": "PMID 40000395; DOI 10.1111/dom.16294", "date": "2025-02-25", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-EE-07", "sourceId": "PMID41412277", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Relative BAT mass -25%; UCP1 and beta3-AR increased; thermogenic/mitochondrial-fusion gene suppression reversed; tirzepatide 10 nmol/kg/day for 4 weeks", "finding": "In a mouse model of postmenopausal metabolic dysfunction (obese-diabetic +/- ovariectomy), tirzepatide reversed BAT 'whitening', restored multilocular brown adipocyte morphology, and increased thermogenic markers including UCP1 and the beta3-adrenergic receptor; it reversed suppression of thermogenic and mitochondrial-fusion genes and normalised ER-stress/autophagy markers. Three-way ANOVA identified tirzepatide as the most potent regulator of the BAT gene landscape. It also reduced relative BAT mass by 25%.", "population": "Female mice; control sham, control-OVX, obese-diabetic, obese-diabetic-OVX; 12 wk OVX/HFHS diet then 4 wk tirzepatide", "comparators": "control sham; obese-diabetic untreated; ovariectomy groups", "endpointType": "imaging/physiological surrogate", "notes": "Estrogen-deficient (postmenopausal) rodent model - relevant given TABFAT (C-TIRZEPATIDE-EE-01) studied premenopausal women. 'Reduced BAT mass -25%' reflects de-whitening/remodelling, recorded as reported. Per PubMed.", "crossRef": "C-TIRZEPATIDE-EE-04", "grade": "very-low", "source": { "citation": "Bittencourt JOA, Marcondes-de-Castro IA, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. Tirzepatide counteracts brown adipose tissue whitening, inflammation, and mitochondrial dysfunction in estrogen-deficient obese diabetic mice. Life Sci. 2025;386:124155", "url": "https://doi.org/10.1016/j.lfs.2025.124155", "identifiers": "PMID 41412277; DOI 10.1016/j.lfs.2025.124155", "date": "2025-12-16", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-HEALTHECON-CEA-01", "sourceId": "PMID40085108", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "Incremental cost-effectiveness ratio (ICER) vs lifestyle modification alone: tirzepatide $197,023/QALY; semaglutide $467,676/QALY (2023 USD; healthcare-sector perspective; lifetime horizon; 3% annual discount). Incremental QALYs 0.35 (tirzepatide) and 0.25 (semaglutide). To reach $100,000/QALY, net prices would need cutting by 30.5% (tirzepatide) and 81.9% (semaglutide). Naltrexone-bupropion was cost-saving. Eligible population modelled: ~126 million US adults (NHANES 2017-2020).", "finding": "In an INDEPENDENT (non-manufacturer) US lifetime microsimulation, tirzepatide and semaglutide added to lifestyle modification produced the largest QALY gains among anti-obesity medications yet were NOT cost-effective at current US net prices: at a $100,000/QALY threshold both had a 0% probability of being cost-effective across the examined range. Context-only economic observation; not an efficacy or value verdict.", "population": "Lifetime cost-effectiveness analysis - individual-level microsimulation (validated Diabetes-Obesity-Cardiovascular Disease microsimulation model) parameterised from NHANES 2017-2020 survey data (4,823 individuals representing ~126M US adults meeting trial inclusion criteria); academic authors (University of Chicago); USA.", "comparators": "semaglutide; naltrexone-bupropion; phentermine-topiramate; lifestyle modification", "endpointType": "other", "notes": "WI-3 NEW-GATHER (cost-effectiveness / QALY anchor for the obesity setting). Context-only: this is a MODELLING study of economic value at a given price, NOT a clinical efficacy or mechanism claim and NOT a recommendation. GRADE low by rule (cost-effectiveness microsimulation is a derived/simulation design with no dedicated rubric tier, so it floors to low - the conservative unparseable-design fallback; correct grade regardless). scope_limits: model assumptions, list/net-price sensitivity, discontinuation-rate assumptions, generalisability of trial inputs to the modelled population. Independent (academic, non-manufacturer) - useful as the competing null against industry-sponsored CEAs that report favourable ICERs (cf. C-SEMAGLUTIDE-HEALTHECON-CEA-01, Novo-sponsored). The two together flag the literature spread: at LIST price reta-class obesity drugs sit well above the $100k/QALY threshold; favourable ICERs depend on rebate/price assumptions. No retatrutide CEA found (not marketed); the price-sensitivity logic would apply a fortiori to a more potent, presumably costlier agent - expectation, not data. [WI-3 independent audit 2026-06-24: source design relabelled from 'observational cohort' to 'cost-effectiveness microsimulation model' and the population text de-laundered (the words 'COHORT'/'observational survey cohort' that had steered the deterministic detector to 'observational cohort' were removed; the study is a microsimulation, not a cohort study). Grade is low either way - the prior text reached low by tripping the cohort detector, the corrected text reaches low as the unparseable-simulation fallback - so this restores accurate text without changing the (correct) grade. The 'confounding by indication' scope_limit, an artefact of the cohort mislabel, was removed; a simulation has no confounding by indication.]", "crossRef": "C-SEMAGLUTIDE-HEALTHECON-CEA-01; C-TIRZEPATIDE-HEALTHECON-PERSIST-01; C-CLASS-MAINT-ADHERENCE-02", "grade": "low", "source": { "citation": "Hwang JH, Laiteerapong N, Huang ES, Kim DD. Lifetime Health Effects and Cost-Effectiveness of Tirzepatide and Semaglutide in US Adults. JAMA Health Forum 2025;6(3):e245586 (University of Chicago).", "url": "https://doi.org/10.1001/jamahealthforum.2024.5586", "identifiers": "PMID40085108 DOI10.1001/jamahealthforum.2024.5586", "date": "2025-03-07", "design": "cost-effectiveness microsimulation model", "maturity": "human-primary", "funding": "academic/independent (University of Chicago authors; non-manufacturer; per-paper COI statement not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-HEALTHECON-PERSIST-01", "sourceId": "PMID40480878", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "health-economics-adherence", "domainLabel": "health-economics-adherence", "domainSlug": "health-economics-adherence", "direction": "n/a", "magnitude": "6-month persistence 60.6%-75.7% across the two databases (allowed inter-prescription gap 45 or 60 days). MarketScan N=8,709 and Optum CDM N=3,384 with >=6 months follow-up (overall identified 15,534 and 6,800). Of discontinuers, 10.2%-19.5% restarted tirzepatide within the 6-month follow-up. >70% female; obesity-related complication prevalence 70.6% (MarketScan) / 81.0% (Optum CDM).", "finding": "In two large US claims/EHR databases, most adults WITHOUT type 2 diabetes who initiated tirzepatide were still persistent at 6 months - a higher 6-month persistence than has typically been reported for older GLP-1 receptor agonists. Context-only real-world utilisation observation; short follow-up, not comparable to the 1-year discontinuation anchor.", "population": "Retrospective observational claims/EHR cohort, Merative MarketScan Commercial + Optum Clinformatics (CDM); adults without T2D initiating tirzepatide May 2021-Sep 2023; USA; sponsor Eli Lilly.", "comparators": "", "endpointType": "other", "notes": "WI-3 NEW-GATHER (real-world persistence / adherence claims-database study). Context-only utilisation observation, not an efficacy/mechanism claim or recommendation. GRADE low by rule (observational claims/EHR cohort; confounding by indication; descriptive). COI / sponsor-authorship flag (1.8): Eli Lilly-authored, advancing a sponsor-favourable 'persistence higher than older GLP-1 RAs' framing - down-weighted at point of use. IMPORTANT scope caveat for the reader: this is 6-MONTH persistence, NOT directly comparable to the 1-YEAR discontinuation figures in C-CLASS-MAINT-ADHERENCE-02 (Truveta: 64.8% discontinued by 1 yr in obesity) or -01 (32.3% persistent at 1 yr) - persistence falls steeply between 6 and 12 months, so a higher 6-month number is not in tension with the ~half-by-1-year anchor. Persistence is also definition-sensitive (45 vs 60-day gap). scope_limits: short duration, possible confounding by indication, sponsor COI, definition variance. [WI-3 independent-validation CORRECTION 2026-06-24: original magnitude said \">70% had >=1 obesity-related complication\"; corrected to the per-database figures 70.6% (MarketScan) / 81.0% (Optum CDM) - the single \">70%\" blurred the MarketScan 70.6% value.]", "crossRef": "C-CLASS-MAINT-ADHERENCE-02; C-CLASS-MAINT-ADHERENCE-01; C-TIRZEPATIDE-HEALTHECON-CEA-01", "grade": "low", "source": { "citation": "Gibble TH, Hankosky ER, Meeks A, Liao B, Ward J, Huang A, Chinthammit C. Characteristics and Treatment Patterns of People Without Type 2 Diabetes Diagnoses Who Use Tirzepatide in the United States. Clin Ther 2025;47(8):572-580 (Eli Lilly).", "url": "https://doi.org/10.1016/j.clinthera.2025.05.003", "identifiers": "PMID40480878 DOI10.1016/j.clinthera.2025.05.003", "date": "2025-06-06", "design": "observational cohort", "maturity": "human-primary", "funding": "industry - Eli Lilly (sponsor-authored real-world claims study; COI-flagged per Constitution 1.8)", "scopeLimits": "possible confounding by indication; short duration", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-LANDSCAPE-01", "sourceId": "PMID35658024", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 receptor dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "decrease", "magnitude": "weight: -16.0/-21.4/-22.5% (5/10/15 mg) vs -2.4% placebo at 72 wk (SURMOUNT-1); HbA1c: -2.01/-2.24/-2.30% vs -1.86% semaglutide 1 mg at 40 wk (SURPASS-2)", "finding": "Tirzepatide is a once-weekly subcutaneous dual agonist of the GIP and GLP-1 receptors (39-amino-acid acylated peptide). Marketed (Mounjaro for T2D; Zepbound for obesity). In SURMOUNT-1 (obesity, no diabetes) mean weight reduction at 72 weeks was 16.0/21.4/22.5% at 5/10/15 mg vs 2.4% placebo. In SURPASS-2 (T2D, head-to-head vs semaglutide 1 mg) HbA1c fell 2.01/2.24/2.30% vs 1.86% semaglutide at 40 weeks, with superior weight loss.", "population": "SURMOUNT-1: N=2539 adults obesity/overweight + comorbidity, no T2D, 72 wk, vs placebo. SURPASS-2: T2D, BMI >=25, HbA1c 7-10.5%, 40 wk, vs semaglutide 1 mg s.c.", "comparators": "placebo; semaglutide", "endpointType": "other", "notes": "Mechanism: dual GIP + GLP-1 agonism. GIP-differential vs semaglutide: adds GIP agonism atop GLP-1 and outperformed GLP-1-mono semaglutide head-to-head on weight and HbA1c (SURPASS-2; SURMOUNT-5 also favoured tirzepatide for weight). Whether the added GIP agonism causes the differential is left OPEN. Fat-mass reduction ~3x lean-mass (33.9% vs 10.9%, SURMOUNT-1).", "crossRef": "C-GIP-AXIS-PARADOX-01", "grade": "high", "source": { "citation": "Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY3537021 phase 1 (2025)", "url": "https://pubmed.ncbi.nlm.nih.gov/35658024/", "identifiers": "PMID 35658024; NCT05669599; PMID 41391569", "date": "2022-06-04", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (SURMOUNT-1; disclosed)", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-MAINT-01", "sourceId": "PMID38078870", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "Week 36->88: +14.0% regain (switch to placebo) vs -5.5% continued loss (tirzepatide); difference -19.4% (95% CI -21.2 to -17.7; P<0.001). Maintained >=80% of lead-in loss: 89.5% (tirz) vs 16.6% (placebo). Overall wk0-88: -25.3% vs -9.9%.", "finding": "SURMOUNT-4 randomised-withdrawal RCT: after a 36-week open-label lead-in (mean loss 20.9%), participants were randomised at week 36 to continue tirzepatide or switch to placebo. Withdrawal led to substantial regain (+14.0%) whereas continued treatment maintained and augmented loss (-5.5%). Same architecture as STEP-4, larger magnitudes off a deeper lead-in loss.", "population": "SURMOUNT-4 (NCT04660643): N=670 randomised; adults BMI >=30 (or >=27 + complication) without diabetes; 36-week open lead-in then 52-week double-blind withdrawal.", "comparators": "placebo (switch from tirzepatide)", "endpointType": "other", "notes": "Tirzepatide counterpart to STEP-4; the off-treatment mirror of SURMOUNT-1 on-treatment loss. The 'chronic disease, ongoing treatment required' framing recurs. No fat-vs-lean composition of regain (gap, C-CLASS-MAINT-04). VALIDATOR: confirm PMID 38078870 + the +14.0/-5.5 figures.", "crossRef": "C-SEMAGLUTIDE-MAINT-01; C-TIRZEPATIDE-MAINT-02", "grade": "moderate", "source": { "citation": "Aronne LJ et al., JAMA 2024 (SURMOUNT-4)", "url": "https://doi.org/10.1001/jama.2023.24945", "identifiers": "PMID:38078870 / DOI:10.1001/jama.2023.24945 / PMC10714284", "date": "2024-01-02", "design": "randomised-withdrawal RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-MAINT-02", "sourceId": "PMID41284285", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "weight-maintenance-regain", "domainLabel": "Maintenance and regain", "domainSlug": "weight-maintenance-regain", "direction": "increase", "magnitude": "By regain category (<25% ... >=75% of lost weight): waist +0.8 to +14.7 cm; SBP +6.8 to +10.4 mmHg; non-HDL-C -0.4% to +10.8%; HbA1c +0.14% to +0.35%; fasting insulin -4.0% to +46.2%.", "finding": "SURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger increases in waist, SBP, non-HDL cholesterol, HbA1c and fasting insulin. ASSOCIATIONAL only: post-hoc, non-randomised regain strata (stratified on a post-randomisation outcome), confounded by regainer phenotype; all endpoints are surrogates, no events.", "population": "Post-hoc of SURMOUNT-4 (NCT04660643): N=308 tirzepatide-treated with >=10% loss randomised to placebo, stratified by week-88 regain.", "comparators": "within-arm regain strata", "endpointType": "other", "notes": "Strengthens the regain pole: cardiometabolic markers worsen in association with regain magnitude (associational, not causal). Post-hoc, non-randomised regain strata (confounding by regainer phenotype). Rising WAIST with regain is an indirect hint of central-fat re-accumulation but NOT a direct fat-vs-lean measure (gap remains). Validation: PMID 41284285 confirmed (Horn, JAMA Intern Med 2026, SURMOUNT-4 regain-stratified post-hoc).", "crossRef": "C-TIRZEPATIDE-MAINT-01", "grade": "moderate", "source": { "citation": "Horn DB, Linetzky B, Davies MJ et al., JAMA Intern Med, 2026", "url": "https://doi.org/10.1001/jamainternmed.2025.6112", "identifiers": "PMID41284285", "date": "2026-02-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "disproportionality: reporting != incidence/causality; possible confounding by indication; post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-OSA-FDA-2024", "sourceId": "CIT:us-fda-fda-approves-first-medication-for-obstruc", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "n/a", "magnitude": "Regulatory milestone (no numeric efficacy). FDA approved Zepbound (tirzepatide) on 20 Dec 2024 for moderate-to-severe OSA in adults with obesity, as an adjunct to reduced-calorie diet and increased physical activity - the FIRST drug ever approved for OSA. Based on the two SURMOUNT-OSA trials (placebo-subtracted AHI -20.0 and -23.8 events/hr).", "finding": "The FDA approved tirzepatide (Zepbound) in December 2024 for moderate-to-severe obstructive sleep apnoea in adults with obesity - the first-ever drug indication for OSA, establishing AHI reduction as an approvable registrational endpoint for this class.", "population": "Regulatory label population: adults with moderate-to-severe OSA and obesity (BMI >=30), adjunct to diet/exercise. Approval 20 Dec 2024.", "comparators": "", "endpointType": "other", "notes": "Regulatory fact: first-ever drug approved for OSA. Source is an FDA press release (no PMID/DOI); the FDA URL is the agency locator. The approval rests on a SURROGATE endpoint (AHI) and does NOT certify CV/mortality/durable-sleepiness benefit (cross-ref C-CLASS-OSA-SURROGATE). Pivotal-trial sponsor Eli Lilly. Reta relevance: establishes the AHI-as-approvable pathway reta's TRIUMPH OSA endpoints are registered on (C-RETATRUTIDE-OSA-01). Skim-safety: 'first-ever' is a REGULATORY claim and carries NO implication of a hard-outcome (CV/mortality) benefit.", "crossRef": "C-TIRZEPATIDE-OSA-SURMOUNT-A1; C-TIRZEPATIDE-OSA-SURMOUNT-A2; C-CLASS-OSA-LANDSCAPE-01; C-CLASS-OSA-SURROGATE", "grade": "high", "source": { "citation": "US FDA. FDA approves first medication for obstructive sleep apnea (Zepbound / tirzepatide). News release, 20 December 2024.", "url": "https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-obstructive-sleep-apnea", "identifiers": "CIT:fda-zepbound-osa-approval-2024-12", "date": "2024-12-20", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-OSA-SURMOUNT-A1", "sourceId": "PMID38912654", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "decrease", "magnitude": "SURMOUNT-OSA trial 1 (APNEA-1, NOT on PAP), wk52: mean AHI change -25.3 events/hr (95% CI -29.3 to -21.2) tirzepatide vs -5.3 (-9.4 to -1.1) placebo; treatment difference -20.0 events/hr (95% CI -25.8 to -14.2), P<0.001 (~39% of baseline AHI 51.5 placebo-subtracted). Body weight, hypoxic burden, hsCRP, systolic BP and patient-reported sleep outcomes all improved vs placebo.", "finding": "In SURMOUNT-OSA trial 1 (APNEA-1, participants NOT on positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the apnoea-hypopnoea index vs placebo over 52 weeks in adults with moderate-to-severe OSA and obesity.", "population": "SURMOUNT-OSA trial 1 (NCT05412004), phase-3 double-blind RCT; PAP-naive; moderate-to-severe OSA (baseline mean AHI 51.5 events/hr), obesity (mean BMI 39.1); tirzepatide 10/15 mg MTD vs placebo, 52 wk. Combined SURMOUNT-OSA N=469 across both trials.", "comparators": "placebo", "endpointType": "other", "notes": "AHI IS A SURROGATE: registrational endpoint, does NOT establish hard-outcome benefit (CV events, mortality, durable sleepiness/QoL) - cross-ref C-CLASS-OSA-SURROGATE. Effect substantially weight-loss-mediated (cross-ref C-CLASS-OSA-MECHANISM). APNEA-1 (no PAP) is DISTINCT from APNEA-2 (on PAP). Sponsor Eli Lilly. Reta relevance: a reta AHI advantage is an EXPECTATION ONLY, contingent on the unresolved weight-mediation question (C-CLASS-OSA-MECHANISM); attach NO AHI number to reta - its registrational OSA endpoints have not yet reported out (C-RETATRUTIDE-OSA-01, C-RETATRUTIDE-OSA-02).", "crossRef": "C-TIRZEPATIDE-OSA-SURMOUNT-A2; C-TIRZEPATIDE-OSA-FDA-2024; C-CLASS-OSA-SURROGATE; C-CLASS-OSA-MECHANISM", "grade": "high", "source": { "citation": "Malhotra A, Grunstein RR, Fietze I et al; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of OSA and Obesity. N Engl J Med 2024;391(13):1193-1205.", "url": "https://doi.org/10.1056/NEJMoa2404881", "identifiers": "PMID38912654", "date": "2024-06-21", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "no outcome data yet (ongoing); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TIRZEPATIDE-OSA-SURMOUNT-A2", "sourceId": "PMID38912654", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "osa", "domainLabel": "Obstructive sleep apnoea", "domainSlug": "osa", "direction": "decrease", "magnitude": "SURMOUNT-OSA trial 2 (APNEA-2, ON PAP), wk52: mean AHI change -29.3 events/hr (95% CI -33.2 to -25.4) tirzepatide vs -5.5 (-9.9 to -1.2) placebo; treatment difference -23.8 events/hr (95% CI -29.6 to -17.9), P<0.001 (~48% of baseline AHI 49.5 placebo-subtracted). Weight, hypoxic burden, hsCRP, systolic BP and patient-reported sleep outcomes all improved vs placebo.", "finding": "In SURMOUNT-OSA trial 2 (APNEA-2, participants ON positive airway pressure), tirzepatide at max-tolerated dose (10/15 mg) markedly reduced the AHI vs placebo over 52 weeks in adults with moderate-to-severe OSA and obesity.", "population": "SURMOUNT-OSA trial 2 (NCT05412004), phase-3 double-blind RCT; PAP-treated; moderate-to-severe OSA (baseline mean AHI 49.5 events/hr), obesity (mean BMI 38.7); tirzepatide 10/15 mg MTD vs placebo, 52 wk.", "comparators": "placebo", "endpointType": "other", "notes": "AHI IS A SURROGATE (cross-ref C-CLASS-OSA-SURROGATE); effect largely weight-mediated. APNEA-2 (on PAP) distinct from APNEA-1; the larger absolute AHI drop is read alongside concurrent PAP use. Sponsor Eli Lilly. Reta relevance: an AHI advantage is an EXPECTATION ONLY, contingent on weight-mediation (C-CLASS-OSA-MECHANISM); no AHI number attaches to reta, whose OSA endpoints have not yet reported out (C-RETATRUTIDE-OSA-01).", "crossRef": "C-TIRZEPATIDE-OSA-SURMOUNT-A1; C-TIRZEPATIDE-OSA-FDA-2024; C-CLASS-OSA-SURROGATE; C-CLASS-OSA-MECHANISM", "grade": "high", "source": { "citation": "Malhotra A, Grunstein RR, Fietze I et al; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of OSA and Obesity. N Engl J Med 2024;391(13):1193-1205.", "url": "https://doi.org/10.1056/NEJMoa2404881", "identifiers": "PMID38912654", "date": "2024-06-21", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "no outcome data yet (ongoing); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C-TREVOGRUMAB-LANDSCAPE-01", "sourceId": "NCTNCT06299098", "drug": "trevogrumab (+ semaglutide; +/- garetosmab)", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "anti-myostatin (anti-GDF8) antibody +/- anti-activin A (garetosmab); muscle-preserving combo with GLP-1RA", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "Interim (EASD 2025, 26 wk): ~33% of weight lost on semaglutide alone was lean; the trevogrumab+semaglutide doublet preserved ~50.8-51.3% of the lean otherwise lost; the triplet (+garetosmab) preserved ~80.9% with greater fat loss but substantially higher discontinuations.", "finding": "COURAGE phase-2 (Regeneron, NCT06299098) tests trevogrumab (anti-myostatin) +/- garetosmab (anti-activin A) added to semaglutide. Interim results show dose-ordered lean preservation, with the triplet most lean-preserving but least tolerated. Final readout pending.", "population": "COURAGE phase-2, N=1,005 actual, 26-week interim (EASD 2025); semaglutide 2.4 mg +/- trevogrumab +/- garetosmab; adults with obesity without diabetes; completion ~late 2026.", "comparators": "semaglutide 2.4 mg alone; placebo", "endpointType": "imaging/physiological surrogate", "notes": "DEEPENED (D2): IDENTIFIER CORRECTION (gather agent): the COURAGE programme is NCT06299098 (Regeneron); a tentatively-proposed NCT06535711 is an unrelated renal-colic CT study. Interim is conference-sourced (low); final results pending (registry Active-not-recruiting, no posted results). Trevogrumab neutralises myostatin, garetosmab neutralises activin A - both upstream of the ActRII receptor bimagrumab blocks. Council: the preservation percentages are RELATIVE to semaglutide-alone lean loss (a derived denominator), conference-interim, with NO additivity tested - the triplet's extra preservation is NOT shown to exceed the sum of its parts and is confounded by substantially higher discontinuations. Sponsor-presented (Regeneron), subject to change at final readout.", "crossRef": "C-BIMAGRUMAB-LANDSCAPE-01; C-MUSCLE-PRESERVATION-MECH-01", "grade": "low", "source": { "citation": "Regeneron press / EASD 2025 presentation", "url": "https://clinicaltrials.gov/study/NCT06299098", "identifiers": "NCT06299098", "date": "2025-09-15", "design": "conference abstract", "maturity": "conference-abstract", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-ALENI-SAFE-03", "sourceId": "PMID42249138", "drug": "Aleniglipron (GSBR-1290)", "drugRoot": "aleniglipron", "drugSlug": "aleniglipron", "drugLabel": "Aleniglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "Zero DILI events across aleniglipron arms (N=230 phase 2b)", "finding": "No drug-induced liver injury events reported in the phase 2b trial.", "population": "ACCESS phase 2b (NCT06693843); 36 wk", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Specifically relevant given oral-GLP-1 class hepatic-safety scrutiny after Pfizer discontinuations; recorded as reported, no verdict.", "crossRef": "C2-DANU-SAFE-03", "grade": "moderate", "source": { "citation": "Rosenstock J et al. Oral small molecule GLP-1 receptor agonist aleniglipron in people with overweight or obesity: a phase 2b trial. Nat Med. 2026 (online 2026-06-05).", "url": "https://doi.org/10.1038/s41591-026-04476-6", "identifiers": "PMID:42249138", "date": "2026-06-05", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Structure Therapeutics (via subsidiary Gasherbrum Bio, Inc.)", "scopeLimits": "small sample (N~230)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ALENI-TOLGI-02", "sourceId": "PMID42249138", "drug": "Aleniglipron (GSBR-1290)", "drugRoot": "aleniglipron", "drugSlug": "aleniglipron", "drugLabel": "Aleniglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Treatment-related discontinuations 10.4% across aleniglipron arms; little/no recurrence of vomiting after dose-interruption reintroduction", "finding": "GI events generally mild-to-moderate and decreased over time; treatment-related discontinuations modest.", "population": "ACCESS phase 2b N=230 (NCT06693843); 36 wk; placebo comparator", "comparators": "placebo", "endpointType": "other", "notes": "Tolerability profile described as consistent with GLP-1RA class.", "crossRef": "", "grade": "moderate", "source": { "citation": "Rosenstock J et al. Oral small molecule GLP-1 receptor agonist aleniglipron in people with overweight or obesity: a phase 2b trial. Nat Med. 2026 (online 2026-06-05).", "url": "https://doi.org/10.1038/s41591-026-04476-6", "identifiers": "PMID:42249138", "date": "2026-06-05", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Structure Therapeutics (via subsidiary Gasherbrum Bio, Inc.)", "scopeLimits": "small sample (N~230)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ALENI-WL-01", "sourceId": "PMID42249138", "drug": "Aleniglipron (GSBR-1290)", "drugRoot": "aleniglipron", "drugSlug": "aleniglipron", "drugLabel": "Aleniglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Placebo-adjusted LS-mean weight change -8.2% (45 mg), -9.8% (90 mg), -11.3% (120 mg) at wk 36 (all p<0.0001); continued loss in open-label extension", "finding": "ACCESS phase 2b: met primary endpoint with dose-dependent placebo-adjusted weight loss at 36 weeks, no apparent plateau.", "population": "ACCESS phase 2b RCT (NCT06693843), N=230 adults with obesity/overweight (mean BMI 39.5, 54% female); 36 wk double-blind + OLE; once-daily escalated q4w; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Structure Therapeutics asset. Importantly, NO events of drug-induced liver injury reported (contrast with Pfizer oral GLP-1s) — recorded neutrally.", "crossRef": "", "grade": "moderate", "source": { "citation": "Rosenstock J et al. Oral small molecule GLP-1 receptor agonist aleniglipron in people with overweight or obesity: a phase 2b trial. Nat Med. 2026 (online 2026-06-05).", "url": "https://doi.org/10.1038/s41591-026-04476-6", "identifiers": "PMID:42249138", "date": "2026-06-05", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Structure Therapeutics (via subsidiary Gasherbrum Bio, Inc.)", "scopeLimits": "small sample (N~230)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-AMYCRETIN-GLY-01", "sourceId": "PMID40550229", "drug": "amycretin (oral)", "drugRoot": "amycretin", "drugSlug": "amycretin", "drugLabel": "Amycretin", "drugClass": "unimolecular GLP-1 + amylin receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "FPG change through day 85 (exploratory; magnitude not in abstract)", "finding": "Fasting plasma glucose change assessed as exploratory PD endpoint (oral)", "population": "Phase 1 oral first-in-human (n=144)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed", "crossRef": "", "grade": "moderate", "source": { "citation": "Gasiorek A et al. Lancet 2025;406:135-148", "url": "https://doi.org/10.1016/S0140-6736(25)01176-6", "identifiers": "PMID:40550229", "date": "2025-06-20", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; identifier not fully verified; small sample (N~144); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-AMYCRETIN-PHARM-01", "sourceId": "PMID40550229", "drug": "amycretin", "drugRoot": "amycretin", "drugSlug": "amycretin", "drugLabel": "Amycretin", "drugClass": "unimolecular GLP-1 + amylin receptor agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Plasma concentrations dose-proportional across groups (both routes)", "finding": "First-in-class single-molecule GLP-1R + amylin receptor agonist; both oral and s.c. formulations; dose-proportional exposure", "population": "Phase 1 oral and phase 1b/2a s.c.", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Gasiorek A et al. Lancet 2025;406:135-148", "url": "https://doi.org/10.1016/S0140-6736(25)01176-6", "identifiers": "PMID:40550229", "date": "2025-06-20", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; identifier not fully verified; small sample (N~144); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-AMYCRETIN-TOLGI-01", "sourceId": "PMID40550231", "drug": "amycretin", "drugRoot": "amycretin", "drugSlug": "amycretin", "drugLabel": "Amycretin", "drugClass": "unimolecular GLP-1 + amylin receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "s.c.: GI most common, rates similar to early GLP-1/amylin agents; oral: 180/364 (49%) of TEAEs GI in 81% of affected", "finding": "Predominantly GI TEAEs, mild-to-moderate, dose-dependent; all resolved", "population": "s.c. phase 1b/2a (n=125) and oral phase 1 (n=144)", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Dahl K, Toubro S et al. Amycretin, unimolecular GLP-1 and amylin receptor agonist s.c.: phase 1b/2a RCT, Lancet 2025", "url": "https://pubmed.ncbi.nlm.nih.gov/40550231/", "identifiers": "PMID 40550231; DOI 10.1016/S0140-6736(25)01185-7", "date": "2025-06-21", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-AMYCRETIN-WL-01", "sourceId": "PMID40550231", "drug": "amycretin (s.c.)", "drugRoot": "amycretin", "drugSlug": "amycretin", "drugLabel": "Amycretin", "drugClass": "unimolecular GLP-1 + amylin receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -24.3% at week 36", "finding": "Subcutaneous amycretin produced large dose-dependent weight loss over 20-36 wk", "population": "Overweight/obese (BMI 27-39.9), phase 1b/2a (n=125; 101 amycretin), up to 36 wk, RCT placebo-controlled (NCT06064006)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "High discontinuation, mostly non-AE-related; weight not plateaued — magnitudes early-phase", "crossRef": "", "grade": "low", "source": { "citation": "Dahl K, Toubro S et al. Amycretin, unimolecular GLP-1 and amylin receptor agonist s.c.: phase 1b/2a RCT, Lancet 2025", "url": "https://pubmed.ncbi.nlm.nih.gov/40550231/", "identifiers": "PMID 40550231; DOI 10.1016/S0140-6736(25)01185-7", "date": "2025-06-21", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "single-centre/referral-enriched", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-AMYCRETIN-WL-02", "sourceId": "PMID40550229", "drug": "amycretin (oral)", "drugRoot": "amycretin", "drugSlug": "amycretin", "drugLabel": "Amycretin", "drugClass": "unimolecular GLP-1 + amylin receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Weight reduction reported through day 85 (part C/D 12-wk dosing up to 2x50 mg); exploratory PD endpoint", "finding": "Oral amycretin: first-in-human pharmacodynamic weight reduction over 12 wk", "population": "Overweight/obese (BMI 25-39.9), phase 1 first-in-human (n=144), single + multiple ascending oral doses (NCT05369390)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Oral PD exploratory; ~13% at wk12 widely cited in press but numeric not in abstract — flag", "crossRef": "", "grade": "moderate", "source": { "citation": "Gasiorek A et al. Lancet 2025;406:135-148", "url": "https://doi.org/10.1016/S0140-6736(25)01176-6", "identifiers": "PMID:40550229", "date": "2025-06-20", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "conference/abstract-level; identifier not fully verified; small sample (N~144); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-BI3034701-PHARM-01", "sourceId": "CIT:gubra-boehringer-ingelheim-announcement-boehring", "drug": "BI 3034701", "drugRoot": "BI 3034701", "drugSlug": "bi-3034701", "drugLabel": "BI 3034701", "drugClass": "Triple GLP-1 / GIP / NPY2 receptor agonist (peptide; Gubra-originated)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Triple-receptor agonism (GLP-1R + GIPR + NPY2R); GIP arm is AGONIST (not antagonist)", "finding": "Mechanism verified: investigational, potential first-in-class triple agonist at GLP-1, GIP and NPY2 (Y2) receptors, designed to engage multiple satiety pathways.", "population": "Preclinical/early development (mechanism per company/partner disclosures)", "comparators": "", "endpointType": "other", "notes": "Mechanism confirmed as GLP-1/GIP/NPY2 triple AGONIST (note: GIP arm is agonist, unlike MariTide's GIPR antagonism). NPY2 (Y2) agonism = additional anorexigenic axis (PYY-like). No human efficacy data yet; Phase 2 planned ~mid-2026. Press-sourced; no PMID/NCT verified for this asset yet.", "crossRef": "", "grade": "very-low", "source": { "citation": "Gubra / Boehringer Ingelheim announcement: Boehringer Ingelheim advances Gubra-originated obesity triple agonist peptide into Phase 2 development.", "url": "https://www.gubra.dk/mfn_news/boehringer-ingelheim-advances-gubra-originated-obesity-triple-agonist-peptide-into-phase-2-development/", "identifiers": "identifier unverified", "date": "2026-01-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Boehringer Ingelheim (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-BI3034701-WL-02", "sourceId": "CIT:boehringer-ingelheim-gubra-press-disclosures-202", "drug": "BI 3034701", "drugRoot": "BI 3034701", "drugSlug": "bi-3034701", "drugLabel": "BI 3034701", "drugClass": "Triple GLP-1 / GIP / NPY2 receptor agonist (peptide; Gubra-originated)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "n/a", "magnitude": "No human efficacy data available (entering/initiating Phase 2)", "finding": "No human weight-loss data reported; rationale is multi-pathway satiety/body-weight regulation.", "population": "None (preclinical/early clinical)", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Placeholder for an asset with verified mechanism but no efficacy readout yet. Avoid conflating with Boehringer's survodutide (glucagon/GLP-1 dual) which is a separate, more advanced program.", "crossRef": "", "grade": "very-low", "source": { "citation": "Boehringer Ingelheim / Gubra press disclosures, 2025-2026.", "url": "https://www.gubra.dk/mfn_news/boehringer-ingelheim-advances-gubra-originated-obesity-triple-agonist-peptide-into-phase-2-development/", "identifiers": "identifier unverified", "date": "2026-01-01", "design": "regulatory document / agency review", "maturity": "press", "funding": "industry (company press release on own pipeline)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-CAGRILINTIDE-APP-01", "sourceId": "PMID34798060", "drug": "cagrilintide", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "weight -10.8% vs placebo -3.0%", "finding": "Once-weekly cagrilintide (0.3-4.5 mg, 26 wk) produced dose-dependent weight loss greater than placebo and greater than liraglutide 3.0 mg at the top dose in adults with overweight/obesity without diabetes; amylin's mechanism is satiety induction via homeostatic and hedonic brain regions. Ad libitum energy intake was not the trial endpoint; weight loss is the downstream integral.", "population": "Adults with overweight/obesity without diabetes, n=706 cagrilintide, 26 weeks (NCT03856047)", "comparators": "placebo; liraglutide 3.0 mg", "endpointType": "surrogate/biomarker", "notes": "Sponsor (Novo Nordisk); COI-flag. Newly added. Weight-as-proxy for appetite; no direct VAS/ad-libitum-intake endpoint. Amylin satiety mechanism per class. GI AEs (nausea 20-47% vs 18% placebo).", "crossRef": "", "grade": "moderate", "source": { "citation": "Lau DCW et al. Lancet 2021;398:2160-2172", "url": "https://doi.org/10.1016/S0140-6736(21)01751-7", "identifiers": "PMID:34798060", "date": "2021-11-16", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRILINTIDE-APP-02", "sourceId": "PMID42260119", "drug": "cagrilintide", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "DVC Prlh knockdown abolishes cagrilintide food-intake/body-weight effect (mechanistic loss-of-function)", "finding": "A cross-species (rat/mouse/macaque/human) dorsal vagal complex atlas defined amylin-receptor (Calcr) neuronal mediators of cagrilintide's energy-balance effects: long-term cagrilintide upregulates prolactin-releasing hormone (Prlh) in conserved NTS Calcr/Prlh cells, and knocking down DVC Prlh abrogates cagrilintide's (but not semaglutide's) effect on food intake/body weight in rats — a mechanistic substrate for amylin-driven intake suppression.", "population": "Rat (primary functional), with mouse/macaque/human transcriptomic mapping", "comparators": "vehicle; semaglutide (comparator agonist)", "endpointType": "surrogate/biomarker", "notes": "Novo Nordisk + academic co-authorship; COI-flag. Newly added. Rodent mechanism (human/macaque transcriptomic conservation only). Establishes a distinct (amylin/Calcr/Prlh) appetite node separate from GLP-1R.", "crossRef": "", "grade": "very-low", "source": { "citation": "Ludwig MQ et al., Nat Metab 2026 (advance online)", "url": "https://doi.org/10.1038/s42255-026-01539-3", "identifiers": "PMID:42260119", "date": "2026-06-08", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRILINTIDE-GLY-01", "sourceId": "PMID37364590", "drug": "cagrilintide (mono)", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c -0.9 pp (cagrilintide) vs -1.8 (sema) vs -2.2 (CagriSema) at wk32", "finding": "As monotherapy in T2D, HbA1c reduction smaller than semaglutide or CagriSema", "population": "T2D BMI ≥27 on metformin±SGLT2i (n=30 cagrilintide arm), phase 2, 32 wk, RCT (NCT04982575)", "comparators": "semaglutide 2.4 mg; CagriSema", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Frias JP et al. Lancet 2023;402:720-730", "url": "https://doi.org/10.1016/S0140-6736(23)01163-7", "identifiers": "PMID:37364590", "date": "2023-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "small sample (N~30)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRILINTIDE-PHARM-01", "sourceId": "PMID33894838", "drug": "cagrilintide (mono)", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "t1/2 159-195 h; median tmax 24-72 h; does not affect semaglutide PK", "finding": "Long-acting amylin analogue, once-weekly; half-life 159-195 h; PK dose-proportional and independent of co-dosed semaglutide", "population": "Healthy overweight (n=96), phase 1b co-administration with semaglutide 2.4 mg (NCT03600480)", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Enebo LB et al. Lancet 2021;397:1736-1748", "url": "https://doi.org/10.1016/S0140-6736(21)00845-X", "identifiers": "PMID:33894838", "date": "2021-04-22", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~96)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRILINTIDE-TOLGI-01", "sourceId": "PMID34798060", "drug": "cagrilintide (mono)", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "GI AEs 41-63% vs 32% placebo; nausea 20-47% vs 18%", "finding": "GI disorders and injection-site reactions most frequent; more than placebo", "population": "Overweight/obese (n=706), phase 2, 26 wk", "comparators": "placebo; liraglutide 3.0 mg", "endpointType": "other", "notes": "GI burden lower than typical GLP-1 class — amylin tolerability narrative", "crossRef": "", "grade": "moderate", "source": { "citation": "Lau DCW et al. Lancet 2021;398:2160-2172", "url": "https://doi.org/10.1016/S0140-6736(21)01751-7", "identifiers": "PMID:34798060", "date": "2021-11-16", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRILINTIDE-WL-01", "sourceId": "PMID34798060", "drug": "cagrilintide (mono)", "drugRoot": "cagrilintide", "drugSlug": "cagrilintide", "drugLabel": "Cagrilintide", "drugClass": "long-acting amylin analogue", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "6.0-10.8% (0.3-4.5 mg) vs 3.0% placebo; 4.5 mg 10.8% vs liraglutide 9.0% (diff 1.8%, p=0.03)", "finding": "Dose-dependent weight loss; 4.5 mg superior to liraglutide 3.0 mg over 26 wk", "population": "Adults overweight/obese without diabetes (n=706 cagrilintide), phase 2 dose-finding, 26 wk, RCT double-blind placebo+active controlled (NCT03856047)", "comparators": "placebo; liraglutide 3.0 mg", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Lau DCW et al. Lancet 2021;398:2160-2172", "url": "https://doi.org/10.1016/S0140-6736(21)01751-7", "identifiers": "PMID:34798060", "date": "2021-11-16", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CAGRISEMA-BC-01", "sourceId": "NCTNCT05567796", "drug": "CagriSema (cagrilintide+semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Fat-mass reduction; physical-function improvement (conference, no full numerics)", "finding": "Promotes fat-mass reduction and enhances physical function (ObesityWeek 2025)", "population": "REDEFINE 1 substudy (n up to 3417), 68 wk", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "imaging/physiological surrogate", "notes": "Conference-reported; numerics pending publication", "crossRef": "", "grade": "moderate", "source": { "citation": "Lau et al., Lancet 2021 (phase 2); Novo Nordisk REDEFINE 1, NEJM 2025", "url": "https://clinicaltrials.gov/study/NCT05567796", "identifiers": "NCT05567796 (REDEFINE 1 arm)", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CAGRISEMA-BP-01", "sourceId": "PMID41328546", "drug": "CagriSema (cagrilintide+semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "SBP -10.9 vs -2.8 mmHg placebo; DBP -5.4 vs -1.7 mmHg at wk68; 39.6% reduced/stopped antihypertensives vs 18.8%", "finding": "Clinically relevant BP reductions including in resistant hypertension (REDEFINE 1 post hoc)", "population": "Obese/overweight no diabetes (n=3417), phase 3a post hoc, 68 wk", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Verma S et al. Hypertension 2025;83:e26055", "url": "https://doi.org/10.1161/HYPERTENSIONAHA.125.26055", "identifiers": "PMID:41328546", "date": "2025-12-02", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CAGRISEMA-GLY-01", "sourceId": "PMID40544432", "drug": "CagriSema (cagrilintide + semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 receptor agonist fixed combination", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c ≤6.5% achieved by 73.5% (CagriSema 2.4/2.4 mg) vs 15.9% (placebo). Mean weight change -13.7% vs -3.4% (diff -10.4 pp; p<0.001).", "finding": "In REDEFINE 2 (phase 3a, T2D + overweight/obesity), CagriSema markedly increased the proportion of patients reaching HbA1c ≤6.5% vs placebo at 68 weeks (glycaemic endpoints secondary; primary was weight).", "population": "1206 adults with T2D, BMI ≥27, HbA1c 7-10%; 68-week double-blind placebo-controlled phase 3a RCT, 12 countries; CGM substudy", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Primary endpoints were weight, not glycaemia; HbA1c reported as proportion reaching ≤6.5% rather than mean Δ in abstract. Placebo-controlled (no semaglutide head-to-head arm here).", "crossRef": "", "grade": "high", "source": { "citation": "Davies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)", "url": "https://doi.org/10.1056/NEJMoa2502082", "identifiers": "PMID 40544432; DOI 10.1056/NEJMoa2502082; NCT05394519", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CAGRISEMA-GLY-02", "sourceId": "CIT:novo-nordisk-press-release-cagrisema-demonstrate", "drug": "CagriSema (cagrilintide + semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 receptor agonist fixed combination", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c reduction 1.91 pp (efficacy estimand) from baseline 8.2%; treatment-regimen estimand 1.80 pp (CagriSema) vs 1.68 pp (semaglutide 2.4 mg); weight loss 14.2%.", "finding": "Per Novo Nordisk press release, in REIMAGINE 2 CagriSema 2.4/2.4 mg gave superior HbA1c reduction vs semaglutide 2.4 mg in T2D at 68 weeks (head-to-head).", "population": "Adults with T2D on metformin ± SGLT2i; 68-week phase 3 RCT; comparator semaglutide 2.4 mg", "comparators": "semaglutide 2.4 mg", "endpointType": "surrogate/biomarker", "notes": "Press-only top-line; magnitudes UNCONFIRMED against peer-reviewed publication. REIMAGINE 2 (head-to-head vs semaglutide 2.4 mg) is distinct from REDEFINE 2 (placebo-controlled). NCT/registry identifier not verified.", "crossRef": "", "grade": "very-low", "source": { "citation": "Novo Nordisk press release: CagriSema demonstrated superior HbA1c reduction of 1.91%-points and weight loss of 14.2% in adults with T2D in the REIMAGINE 2 trial (2 Feb 2026).", "url": "https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916481", "identifiers": "identifier unverified — no NCT/DOI located for REIMAGINE 2", "date": "2026-02-02", "design": "double-blind RCT", "maturity": "press", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-CAGRISEMA-WL-01", "sourceId": "PMID40544433", "drug": "CagriSema (cagrilintide+semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-20.4% CagriSema vs -3.0% placebo at wk68 (diff -17.3 pp); vs -14.9% semaglutide, -11.5% cagrilintide alone; ≥20% loss in 60%, ≥30% in 23%", "finding": "REDEFINE 1: substantial weight loss vs placebo and vs each monocomponent in obesity without diabetes", "population": "Adults BMI ≥30 or ≥27+complication, no diabetes (n=3417; 2108 CagriSema), phase 3a, 68 wk, RCT placebo+active controlled (NCT05567796)", "comparators": "placebo; semaglutide 2.4 mg; cagrilintide 2.4 mg", "endpointType": "surrogate/biomarker", "notes": "Headline below earlier expectations vs tirzepatide; mono-comparator arms small", "crossRef": "", "grade": "high", "source": { "citation": "Garvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)", "url": "https://doi.org/10.1056/NEJMoa2502081", "identifiers": "PMID 40544433; DOI 10.1056/NEJMoa2502081; NCT05567796", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "conference/abstract-level; magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CAGRISEMA-WL-02", "sourceId": "PMID40544432", "drug": "CagriSema (cagrilintide+semaglutide)", "drugRoot": "CagriSema", "drugSlug": "cagrisema", "drugLabel": "CagriSema", "drugClass": "amylin analogue + GLP-1 RA combination", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-13.7% vs -3.4% placebo at wk68 (diff -10.4 pp)", "finding": "REDEFINE 2: weight loss vs placebo in obesity WITH type 2 diabetes", "population": "Adults BMI ≥27, HbA1c 7-10%, T2D (n=1206; 904 CagriSema), phase 3a, 68 wk, RCT placebo-controlled (NCT05394519)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Diabetes attenuates weight loss vs non-diabetic REDEFINE 1", "crossRef": "", "grade": "high", "source": { "citation": "Davies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)", "url": "https://doi.org/10.1056/NEJMoa2502082", "identifiers": "PMID 40544432; DOI 10.1056/NEJMoa2502082; NCT05394519", "date": "2025-06-22", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CLASS-INS-01", "sourceId": "PMID19196887", "drug": "incretin / NuSH class (GLP-1RA, GIP/GLP-1, triple agonist)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "incretin / nutrient-stimulated-hormone agonists", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "On-treatment: HOMA-B / stimulated C-peptide / disposition index / clamp ISR all increase (drug-specific magnitudes in per-drug rows). Durable/mass effect: NOT demonstrated in humans (n/a). The one human off-drug test (exenatide) reverted at 1 yr; equivocally sustained at 3 yr.", "finding": "NEGATIVE HEADLINE FIRST: no incretin, INCLUDING retatrutide, has demonstrated increased beta-cell MASS or disease modification in humans; all positive human data are on-treatment FUNCTION surrogates (HOMA-B, C-peptide, proinsulin:insulin, disposition index, clamp ISR - none measures MASS), and the only off-drug test reverted at 1 year. POLE A (well-supported but confounded): every direct human beta-cell-function measure improves while ON drug (semaglutide, tirzepatide, exenatide). POLE B (the LEADING caution): the on-treatment gain is substantially confounded by large weight loss and relief of gluco-/lipotoxicity - the only direct human test (exenatide washout) reverted WITH weight regain, supporting mediation; the cited tirzepatide clamp with no weight correlation (Yamaguchi) measures insulin SENSITIVITY (glucose-infusion-rate), NOT beta-cell secretion, so a weight-INDEPENDENT beta-cell effect remains UNPROVEN. The positive on-treatment pole is also near-uniformly manufacturer-sponsored (a further confidence discount).", "population": "Class-level synthesis across human clamp / IVGTT / HOMA / off-drug studies (semaglutide, tirzepatide, exenatide).", "comparators": "placebo; insulin glargine; semaglutide", "endpointType": "surrogate/biomarker", "notes": "Both-poles anchor for the domain and the core T2D durability/disease-modification question. HOMA-B and clamp indices are FUNCTION, NOT MASS - flagged. Coherence (GIP being glucose-dependently insulinotropic, the most beta-cell-coherent arm, thread-11) is NOT attribution. Decision-relevant for reta: its ONLY insulin-axis numbers are weight-coupled IR biomarkers (C2-RETATRUTIDE-INS-01/03/04) and it produces the largest weight loss, so any future reta beta-cell signal will be maximally weight-confounded. Graded LOW (narrative synthesis). Validation: all SIX cited PMIDs resolved (Bunck 2009/2011; Kapitza 28526920 sema; Heise 35468322 tirz clamp DI; Frias 38252888 SURPASS-2 HOMA2-B; Yamaguchi 40694059). Coherence (GIP being glucose-dependently insulinotropic, thread-11) is mechanistic plausibility only and is NOT anchored to any in-vivo GIP-arm contribution; mouse tirzepatide GIPR data cannot support a GIP attribution (weak/partial mouse agonist; caveat 1.4). CLARIFICATION (validator): Yamaguchi 40694059 is an insulin-SENSITIVITY (glucose-infusion-rate) clamp, NOT a beta-cell-secretion clamp - it supports a weight-independent insulin-SENSITISATION component, not direct beta-cell function. COI CONCENTRATION: Kapitza = Novo; Heise/Frias = Lilly; Bunck = Amylin/Lilly; only Yamaguchi is investigator-initiated (the least-conflicted, fittingly the weight-independence anchor). COUNCIL: rule whether this synthesis row belongs or should be folded.", "crossRef": "C2-SEMAGLUTIDE-INS-01; C2-TIRZEPATIDE-INS-01; C2-TIRZEPATIDE-INS-03; C2-EXENATIDE-INS-01; C2-EXENATIDE-INS-02; C2-GIP-INS-01; C2-RETATRUTIDE-INS-04", "grade": "moderate", "source": { "citation": "Bunck MC, Diamant M, Corner A et al., Diabetes Care, 2009", "url": "https://doi.org/10.2337/dc08-1797", "identifiers": "PMID19196887", "date": "2009-02-05", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Amylin Pharmaceuticals/Eli Lilly", "scopeLimits": "open-label (unblinded); small sample (N~69)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COINFUSION-APP-01", "sourceId": "PMID24939425", "drug": "GLP-1 + glucagon co-infusion", "drugRoot": "GLP-1 + glucagon co-infusion", "drugSlug": "glp-1-glucagon-co-infusion", "drugLabel": "GLP-1 + Glucagon Co-infusion", "drugClass": "GLP-1/glucagon (combination)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "-13% food intake; +53 kcal/day EE", "finding": "Co-infusion of individually subanorectic doses of GLP-1 and glucagon in humans reduced food intake ~13% and raised energy expenditure ~53 kcal/day while protecting against glucagon-induced hyperglycaemia. Combination (GCGR+GLP-1R) intake datum — the glucagon-arm contribution cannot be isolated; subanorectic glucagon by design contributes little alone (intake reduction most plausibly GLP-1-led).", "population": "Healthy/overweight humans, n=13 crossover", "comparators": "saline; GLP-1 alone; glucagon alone", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GCGR-06 / T1-004 / T3-013. Combination-only; subanorectic glucagon chosen below its own intake-suppressing threshold.", "crossRef": "T9-GCGR-06", "grade": "moderate", "source": { "citation": "Cegla J et al., Diabetes 2014;63(11):3711-3720", "url": "https://doi.org/10.2337/db14-0242", "identifiers": "PMID:24939425", "date": "2014-11-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic-UK public (Wellcome Trust / MRC / NIHR / BBSRC)", "scopeLimits": "small sample (N~13)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-GLY-01", "sourceId": "PMID29945727", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Post-MMTT glucose AUC0-4h -32.78% vs -10.16% placebo (diff -22.62%, p<0.0001) at day 41.", "finding": "Cotadutide reduced post-MMTT glucose AUC vs placebo in overweight/obese T2D (phase 2a, 41 days).", "population": "Overweight/obese T2D, phase 2a (n=51) and phase 2b (n=834), up to 54 wk, RCT", "comparators": "placebo; liraglutide 1.8 mg", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Ambery P et al. Lancet 2018;391:2607-2618", "url": "https://doi.org/10.1016/S0140-6736(18)30726-8", "identifiers": "PMID:29945727", "date": "2018-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "short duration; small sample (N~51)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-HEP-01", "sourceId": "PMID34016612", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Improvements in liver enzymes/fibrosis algorithms at 300 µg; greater liver glycogen & fat reduction vs placebo and liraglutide (NCT03555994)", "finding": "Cotadutide 300 µg improved AST, ALT, PRO-C3, FIB-4, NAFLD fibrosis score vs placebo (not seen with liraglutide); promotes hepatic glycogenolysis and liver fat reduction via GcgR", "population": "Overweight/obese T2D, phase 2b ad hoc (n=834, 54 wk) and phase 2a glycogen study (NCT03555994)", "comparators": "placebo; liraglutide 1.8 mg", "endpointType": "surrogate/biomarker", "notes": "Hepatic effects ad hoc/secondary; cross-ref glycogenolysis PMID:38066113 DOI 10.1038/s42255-023-00938-0", "crossRef": "", "grade": "moderate", "source": { "citation": "Nahra R et al. Diabetes Care 2021;44:1433-1442", "url": "https://doi.org/10.2337/dc20-2151", "identifiers": "PMID:34016612", "date": "2021-05-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "conference/abstract-level; identifier not fully verified; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-HEP-02", "sourceId": "PMID32478287", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Greater fibrosis reduction than liraglutide/OCA in 2 mouse NASH models (qualitative)", "finding": "Cotadutide resolved NASH/fibrosis in preclinical models more than liraglutide or OCA at matched weight loss; GcgR drives hepatic lipid/mitochondrial effects", "population": "Mouse NASH models + GLP-1R KO mice (preclinical mechanism)", "comparators": "liraglutide; obeticholic acid", "endpointType": "surrogate/biomarker", "notes": "Preclinical; supports GcgR-mediated hepatic mechanism", "crossRef": "", "grade": "very-low", "source": { "citation": "Boland ML et al. Nat Metab 2020;2:413-431", "url": "https://doi.org/10.1038/s42255-020-0209-6", "identifiers": "PMID:32478287", "date": "2020-05-21", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-HR-01", "sourceId": "PMID33908687", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "increase", "magnitude": "Increase reported, consistent with GLP-1 class (no numeric in abstract)", "finding": "Increased pulse rate with cotadutide vs placebo, consistent with GLP-1 monoagonists", "population": "Overweight Japanese T2D, phase 1/2a (n=61), up to 48 days, RCT", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed", "crossRef": "", "grade": "low", "source": { "citation": "Asano M et al. Diabetes Obes Metab 2021;23:1859-1867", "url": "https://doi.org/10.1111/dom.14412", "identifiers": "PMID:33908687", "date": "2021-05-19", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - AstraZeneca (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; small sample (N~61)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-INS-01", "sourceId": "PMID38066113", "drug": "cotadutide", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "mixed", "magnitude": "fasting hepatic glycogen -38% vs placebo, -41% vs liraglutide; residual 236.1 mmol/L", "finding": "The GLP-1/glucagon dual cotadutide reduced fasting hepatic glycogen ~38% vs placebo and ~41% vs liraglutide (13C-MRS), confirming GCGR engagement promoting glycogenolysis (glycogen not fully depleted); mouse receptor dissection shows cotadutide's glucose control and weight loss are predominantly GLP-1-mediated while liver lipid/glycogen-flux effects are glucagon-mediated.", "population": "Overweight/obese T2D (human glycogen MRS) + mouse dissection", "comparators": "placebo; liraglutide", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-008/L2-028 (+ Boland 2020 mouse PMID:32478287). cotadutide-minus-liraglutide isolates GCGR on the liver. Glycogen readout, NOT a formal EGP tracer.", "crossRef": "T3-008", "grade": "moderate", "source": { "citation": "Parker VER et al., Nat Metab 2023;5(12):2086-2093", "url": "https://doi.org/10.1038/s42255-023-00938-0", "identifiers": "PMID:38066113", "date": "2023-12-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-LIP-01", "sourceId": "PMID34016612", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Lipid profile improvement at 300 µg (specific values not in abstract)", "finding": "Improvements in lipid profile with cotadutide 300 µg vs placebo", "population": "Overweight/obese T2D, phase 2b (n=834), 54 wk, RCT", "comparators": "placebo; liraglutide 1.8 mg", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed (qualitative in abstract)", "crossRef": "", "grade": "moderate", "source": { "citation": "Nahra R et al. Diabetes Care 2021;44:1433-1442", "url": "https://doi.org/10.2337/dc20-2151", "identifiers": "PMID:34016612", "date": "2021-05-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "conference/abstract-level; identifier not fully verified; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-PHARM-01", "sourceId": "PMID37549266", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Cryo-EM structural confirmation of dual agonism; GcgR-biased lipid engagement (cryo-EM)", "finding": "GLP-1R/GcgR dual agonist with GcgR-biased lipid engagement; lipid C18 moiety gives stronger GcgR engagement vs SAR425899; once-daily s.c.", "population": "In-vitro/structural (cryo-EM) and PK", "comparators": "SAR425899; peptide 15", "endpointType": "other", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Li Y et al. PNAS 2023;120:e2303696120", "url": "https://doi.org/10.1073/pnas.2303696120", "identifiers": "PMID:37549266", "date": "2023-08-07", "design": "unspecified", "maturity": "in-vitro", "funding": "industry - AstraZeneca (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-TOLGI-01", "sourceId": "PMID34016612", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Nausea 35%, vomiting 17% (phase 2b); GI disorders 72% vs 40% placebo (phase 2a)", "finding": "GI adverse events (nausea, vomiting) most common; decreased over time", "population": "Overweight/obese T2D, phase 2a & 2b", "comparators": "placebo; liraglutide 1.8 mg", "endpointType": "other", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Nahra R et al. Diabetes Care 2021;44:1433-1442", "url": "https://doi.org/10.2337/dc20-2151", "identifiers": "PMID:34016612", "date": "2021-05-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "conference/abstract-level; identifier not fully verified; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-WL-01", "sourceId": "PMID29945727", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "LS mean -3.84 kg vs -1.70 kg placebo at day 41 (diff -2.14 kg, p=0.0008)", "finding": "Once-daily cotadutide reduced body weight vs placebo in overweight/obese T2D", "population": "Overweight/obese T2D adults, phase 2a (n=51 randomised, 22 cotadutide analysed), 41 days, RCT, double-blind, placebo-controlled, up to 200 µg s.c.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Early ascending-dose/2a; short duration; later 54-wk data give larger losses", "crossRef": "", "grade": "moderate", "source": { "citation": "Ambery P et al. Lancet 2018;391:2607-2618", "url": "https://doi.org/10.1016/S0140-6736(18)30726-8", "identifiers": "PMID:29945727", "date": "2018-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "short duration; small sample (N~51)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-COTADUTIDE-WL-02", "sourceId": "PMID34016612", "drug": "cotadutide (MEDI0382)", "drugRoot": "cotadutide", "drugSlug": "cotadutide", "drugLabel": "Cotadutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -6.93% vs placebo -1.23% (600 ug Japanese study)", "finding": "54-week cotadutide reduced weight vs placebo; 200 µg similar to liraglutide 1.8 mg, 300 µg greater than liraglutide", "population": "Overweight/obesity + T2D on metformin (n=834), phase 2b, 54 wk, RCT double-blind, comparator open-label liraglutide 1.8 mg", "comparators": "placebo; liraglutide 1.8 mg", "endpointType": "surrogate/biomarker", "notes": "Coprimary endpoints at wk14; magnitudes vs liraglutide qualitative in abstract", "crossRef": "", "grade": "moderate", "source": { "citation": "Nahra R et al. Diabetes Care 2021;44:1433-1442", "url": "https://doi.org/10.2337/dc20-2151", "identifiers": "PMID:34016612", "date": "2021-05-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-AstraZeneca", "scopeLimits": "conference/abstract-level; identifier not fully verified; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-CT388-GLY-03", "sourceId": "PMID41319798", "drug": "CT-388 / enicepatide", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "Dual GLP-1/GIP receptor agonist (cAMP signal-biased; once-weekly SC peptide)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Phase 1: improved fasting glucose and OGTT (quantitative not stated in abstract). Conference (ADA 2025, 763-P): HbA1c reduction ~3.0% at 12 wk in obesity+T2D cohort; 100% reached HbA1c <=6.5% — UNCONFIRMED beyond abstract", "finding": "Improved glycaemic parameters during fasting and oral glucose tolerance testing in phase 1; HbA1c reductions reported in a phase 1b T2D cohort (conference).", "population": "Phase 1 overweight/obese (NCT04838405); ADA abstract 763-P = 12-wk cohort adults with obesity + T2D", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Glycaemic phase-1 data peer-reviewed; the 12-wk T2D HbA1c figures are conference-abstract (ADA 763-P) and flagged unconfirmed.", "crossRef": "", "grade": "low", "source": { "citation": "Chakravarthy MV et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control... Mol Metab. 2025;103:102291.", "url": "https://doi.org/10.1016/j.molmet.2025.102291", "identifiers": "PMID:41319798", "date": "2025-11-28", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Roche", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CT388-PHARM-04", "sourceId": "PMID41319798", "drug": "CT-388 / enicepatide", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "Dual GLP-1/GIP receptor agonist (cAMP signal-biased; once-weekly SC peptide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Signal-biased agonism at GLP-1R and GIPR; once-weekly SC dosing; strong preclinical-to-clinical PK/PD translatability across species", "finding": "Unimolecular peptide dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors (minimal receptor internalisation vs native ligands); PK supports once-weekly dosing.", "population": "Cell assays, mice, monkeys, phase 1 humans", "comparators": "native GLP-1/GIP ligands", "endpointType": "other", "notes": "Contrast with MariTide: CT-388 is a GIPR AGONIST (signal-biased), MariTide a GIPR antagonist — both pursued for obesity. Originated at Carmot Therapeutics (acquired by Roche/Genentech).", "crossRef": "C2-MARITIDE-PHARM-06", "grade": "low", "source": { "citation": "Chakravarthy MV et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control... Mol Metab. 2025;103:102291.", "url": "https://doi.org/10.1016/j.molmet.2025.102291", "identifiers": "PMID:41319798", "date": "2025-11-28", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Roche", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CT388-TOLGI-05", "sourceId": "PMID41319798", "drug": "CT-388 / enicepatide", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "Dual GLP-1/GIP receptor agonist (cAMP signal-biased; once-weekly SC peptide)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Phase 2: AE-related discontinuation 5.9% (pooled CT-388 arms) vs 1.3% placebo (press); phase 1 most TEAEs mild/moderate", "finding": "Generally well tolerated; GI adverse events mostly mild-to-moderate, consistent with incretin class.", "population": "Phase 1 (NCT04838405) and phase 2 CT388-103 (N=469)", "comparators": "placebo", "endpointType": "other", "notes": "Phase 2 discontinuation rate is press-sourced. No new/unexpected safety signals reported.", "crossRef": "", "grade": "low", "source": { "citation": "Chakravarthy MV et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control... Mol Metab. 2025;103:102291.", "url": "https://doi.org/10.1016/j.molmet.2025.102291", "identifiers": "PMID:41319798", "date": "2025-11-28", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Roche", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-CT388-WL-01", "sourceId": "CIT:roche-genentech-press-release-roche-announces-po", "drug": "CT-388 / enicepatide", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "Dual GLP-1/GIP receptor agonist (cAMP signal-biased; once-weekly SC peptide)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Placebo-adjusted mean weight loss 22.5% at 48 wk at highest dose (24 mg); 95.7% achieved >=5%, 87% >=10%, 47.8% >=20%, 26.1% >=30%; 54% reached BMI <30 vs 13% placebo", "finding": "Phase 2 topline: clinically meaningful, statistically significant placebo-adjusted weight loss at the highest dose at 48 weeks.", "population": "CT388-103, N=469 adults with obesity/overweight + >=1 comorbidity; 48 wk; phase 2 double-blind placebo-controlled RCT", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Phase 2 numbers are company press/topline (Jan 2026); peer-reviewed phase 2 not yet published — magnitudes UNCONFIRMED pending full data at a medical congress. Phase 3 (Enith1/Enith2) planned. enicepatide = proposed INN.", "crossRef": "", "grade": "very-low", "source": { "citation": "Roche/Genentech press release: Roche announces positive Phase II results for dual GLP-1/GIP receptor agonist CT-388, 27 Jan 2026.", "url": "https://www.roche.com/media/releases/med-cor-2026-01-27", "identifiers": "identifier unverified", "date": "2026-01-27", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-CT388-WL-02", "sourceId": "PMID41319798", "drug": "CT-388 / enicepatide", "drugRoot": "CT-388/enicepatide", "drugSlug": "ct-388-enicepatide", "drugLabel": "CT-388/enicepatide", "drugClass": "Dual GLP-1/GIP receptor agonist (cAMP signal-biased; once-weekly SC peptide)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Mean body-weight change -4.7% to -8.0% across CT-388 doses vs -0.5% placebo at day 29 (single doses 0.5-7.5 mg; 4 weekly doses 5-12 mg)", "finding": "Phase 1 (4 once-weekly doses) produced dose-dependent weight loss by day 29 in overweight/obese participants.", "population": "Phase 1 double-blind RCT (NCT04838405), healthy participants with overweight/obesity; ~4 wk; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Peer-reviewed phase 1. A separately reported phase 1b extension (Genentech press, May 2024) claimed 18.8% placebo-adjusted weight loss over 24 wk — that longer-term figure is press-sourced/unconfirmed in peer review.", "crossRef": "C2-CT388-WL-01", "grade": "low", "source": { "citation": "Chakravarthy MV et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control... Mol Metab. 2025;103:102291.", "url": "https://doi.org/10.1016/j.molmet.2025.102291", "identifiers": "PMID:41319798", "date": "2025-11-28", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Roche", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-DANU-PHARM-04", "sourceId": "PMID40865303", "drug": "Danuglipron (PF-06882961)", "drugRoot": "danuglipron", "drugSlug": "danuglipron", "drugLabel": "Danuglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (twice-daily)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "In-vitro t1/2 208+/-31 min (human liver microsomes), 81+/-16 min (rat); intrinsic clearance 7.49 (HLM) / 35.57 (RLM) uL/min/mg; 7 metabolites characterised", "finding": "Moderate hepatic metabolism / low intrinsic clearance in vitro; multiple phase I/II metabolites identified.", "population": "In vitro (human/rat liver microsomes, S9) and in vivo rat", "comparators": "", "endpointType": "other", "notes": "Hepatic metabolism characterisation; relevant context for the clinical liver-signal discontinuation but does not itself establish causation.", "crossRef": "C2-DANU-SAFE-03", "grade": "very-low", "source": { "citation": "Jaiswal A et al. Comprehensive identification and characterization of in vitro and in vivo metabolites of danuglipron... J Pharm Biomed Anal. 2025;267:117128.", "url": "https://doi.org/10.1016/j.jpba.2025.117128", "identifiers": "PMID:40865303", "date": "2025-08-22", "design": "preclinical (rodent)", "maturity": "in-vitro", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-DANU-SAFE-03", "sourceId": "CIT:pfizer-press-release-pfizer-provides-update-on-o", "drug": "Danuglipron (PF-06882961)", "drugRoot": "danuglipron", "drugSlug": "danuglipron", "drugLabel": "Danuglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (twice-daily)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "1 asymptomatic participant with drug-induced liver injury (resolved after discontinuation); aggregate LFT-elevation frequency across >1400 participants stated in-line with approved class agents", "finding": "Drug-induced liver injury signal leading to program discontinuation.", "population": "Pfizer dose-optimisation program (post phase 2b); chronic weight management", "comparators": "", "endpointType": "safety-event/signal", "notes": "Discontinuation driver. Single-case hepatotoxicity vs class-typical aggregate LFTs is the central tension (recorded neutrally, no verdict). Press-sourced.", "crossRef": "", "grade": "very-low", "source": { "citation": "Pfizer press release: Pfizer Provides Update on Oral GLP-1 Receptor Agonist Danuglipron, 14 April 2025.", "url": "https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist", "identifiers": "identifier unverified", "date": "2025-04-14", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Pfizer (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-DANU-TOLGI-02", "sourceId": "PMID40539310", "drug": "Danuglipron (PF-06882961)", "drugRoot": "danuglipron", "drugSlug": "danuglipron", "drugLabel": "Danuglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (twice-daily)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Most frequent AEs nausea and vomiting; GI AEs increased at higher doses; ~38% discontinued due to AEs across groups (incl. placebo)", "finding": "High GI adverse-event burden, dose-related, driving high discontinuation.", "population": "Phase 2b N=628 (NCT04707313); 26/32 wk; placebo comparator", "comparators": "placebo", "endpointType": "other", "notes": "Authors note discontinuation rates higher than anticipated across ALL groups including placebo. Most GI events mild.", "crossRef": "", "grade": "moderate", "source": { "citation": "Buckeridge C et al. Efficacy and safety of danuglipron (PF-06882961) in adults with obesity: a phase 2b study. Diabetes Obes Metab. 2025;27(9):4915-4926.", "url": "https://doi.org/10.1111/dom.16534", "identifiers": "PMID:40539310", "date": "2025-06-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Pfizer", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-DANU-WL-01", "sourceId": "PMID40539310", "drug": "Danuglipron (PF-06882961)", "drugRoot": "danuglipron", "drugSlug": "danuglipron", "drugLabel": "Danuglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (twice-daily)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "LS-mean placebo-relative weight change -5.0% to -12.9% (40-200 mg BID arms) at end of treatment (26 or 32 wk)", "finding": "Phase 2b: statistically significant, dose-dependent weight reduction vs placebo over 26/32 weeks.", "population": "Phase 2b RCT (NCT04707313), N=628 randomised (536 danuglipron, 90 placebo), adults with obesity without diabetes; danuglipron BID; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DISCONTINUED: Pfizer halted danuglipron (chronic weight management) in April 2025 after a single asymptomatic case of drug-induced liver injury (resolved on discontinuation), despite class-typical aggregate LFT-elevation rates across >1400 participants. Only 39.3% completed treatment; ~38% discontinued due to AEs (high even vs placebo) — tolerability of BID dosing a concern.", "crossRef": "", "grade": "moderate", "source": { "citation": "Buckeridge C et al. Efficacy and safety of danuglipron (PF-06882961) in adults with obesity: a phase 2b study. Diabetes Obes Metab. 2025;27(9):4915-4926.", "url": "https://doi.org/10.1111/dom.16534", "identifiers": "PMID:40539310", "date": "2025-06-20", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Pfizer", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-DUALS-INS-01", "sourceId": "PMID38095657", "drug": "survodutide / mazdutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "decrease", "magnitude": "survodutide HbA1c -1.46% to -1.71% (16 wk); mazdutide -1.41% to -1.67% (20 wk), placebo +0.03%", "finding": "GLP-1/glucagon dual agonists lower HbA1c in T2D phase 2 trials (survodutide -1.46% to -1.71% over 16 wk; mazdutide -1.41% to -1.67% over 20 wk vs placebo +0.03%), but historically show modest or no glycaemic improvement (or even impaired glucose tolerance) when the glucagon weighting is too high — net glycaemia depends on maintained incretin dominance over the glucagon arm.", "population": "T2D phase 2 (survodutide BI 456906; mazdutide, Chinese cohort)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus L2-030/L2-031/L2-032. Net glycaemia (not isolated insulin-sensitivity/beta-cell endpoint). Illustrates the glucagon-weighting balance relevant to retatrutide's offset.", "crossRef": "L2-030", "grade": "low", "source": { "citation": "survodutide: Blüher M et al., Lancet Diabetes Endocrinol 2024 (PMID:38095657); mazdutide: Ji L et al., 2023 (PMID:37943529)", "url": "https://doi.org/10.1016/S2213-8587(23)00295-X", "identifiers": "PMID:38095657", "date": "2023-12-01", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ECNO-PHARM-03", "sourceId": "PMID37364710", "drug": "Ecnoglutide (XW003)", "drugRoot": "ecnoglutide", "drugSlug": "ecnoglutide", "drugLabel": "Ecnoglutide", "drugClass": "Long-acting cAMP-biased GLP-1 receptor agonist (SUBCUTANEOUS, once-weekly)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "In vitro cAMP EC50 0.018 nM, receptor internalisation EC50 >10 uM (signalling bias); steady-state t1/2 124-138 h (phase 1)", "finding": "cAMP-biased GLP-1 analog (Ala8Val + C18 diacid fatty-acid acylation): potent cAMP induction with minimal receptor internalisation; long half-life supporting once-weekly dosing.", "population": "In vitro, db/db mice, DIO rats, phase 1 humans (NCT04389775)", "comparators": "semaglutide (preclinical)", "endpointType": "other", "notes": "Signalling bias parallels CT-388's cAMP-biased design. Preclinically reported more pronounced weight loss than semaglutide (rodent — not a human head-to-head).", "crossRef": "C2-CT388-PHARM-04", "grade": "very-low", "source": { "citation": "Guo W et al. Discovery of ecnoglutide - a novel, long-acting, cAMP-biased GLP-1 analog. Mol Metab. 2023;75:101762.", "url": "https://doi.org/10.1016/j.molmet.2023.101762", "identifiers": "PMID:37364710", "date": "2023-06-24", "design": "preclinical (rodent)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ECNO-TOLGI-02", "sourceId": "PMID40555243", "drug": "Ecnoglutide (XW003)", "drugRoot": "ecnoglutide", "drugSlug": "ecnoglutide", "drugLabel": "Ecnoglutide", "drugClass": "Long-acting cAMP-biased GLP-1 receptor agonist (SUBCUTANEOUS, once-weekly)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "TEAEs in 93% of each ecnoglutide arm vs 84% placebo; 10 ecnoglutide participants discontinued due to AEs (of ~499 treated)", "finding": "Most adverse events mild-to-moderate GI; few discontinuations.", "population": "Phase 3 N=664 (NCT05813795); 40 wk; placebo comparator", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Ji L et al. Efficacy and safety of a biased GLP-1 receptor agonist ecnoglutide in adults with overweight or obesity: a phase 3 trial. Lancet Diabetes Endocrinol. 2025;13(9):777-789.", "url": "https://doi.org/10.1016/S2213-8587(25)00141-X", "identifiers": "PMID:40555243", "date": "2025-06-21", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "industry - Hangzhou Sciwind Biosciences (trial sponsor, disclosed in publication)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ECNO-WL-01", "sourceId": "PMID40555243", "drug": "Ecnoglutide (XW003)", "drugRoot": "ecnoglutide", "drugSlug": "ecnoglutide", "drugLabel": "Ecnoglutide", "drugClass": "Long-acting cAMP-biased GLP-1 receptor agonist (SUBCUTANEOUS, once-weekly)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "LS-mean weight change -9.1% (1.2 mg), -10.9% (1.8 mg), -13.2% (2.4 mg) vs +0.1% placebo at wk 40; ETD -9.2 to -13.3% (all p<0.0001); >=5% loss in 77-87% vs 16% placebo", "finding": "Phase 3 (China): superior, sustained weight reduction vs placebo at 40 weeks in overweight/obese adults without diabetes.", "population": "Phase 3 RCT (NCT05813795), N=664, 36 Chinese centres, overweight/obese without diabetes; 40 wk; once-weekly SC; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "VERIFIED INJECTABLE: ecnoglutide is a once-weekly SUBCUTANEOUS peptide GLP-1 analog (Sciwind), NOT an oral small molecule — it sits outside the oral-small-molecule subclass and is captured here for completeness with correct route. Sciwind also has an oral ecnoglutide formulation in earlier development, but the pivotal data here are injectable.", "crossRef": "", "grade": "moderate", "source": { "citation": "Ji L et al. Efficacy and safety of a biased GLP-1 receptor agonist ecnoglutide in adults with overweight or obesity: a phase 3 trial. Lancet Diabetes Endocrinol. 2025;13(9):777-789.", "url": "https://doi.org/10.1016/S2213-8587(25)00141-X", "identifiers": "PMID:40555243", "date": "2025-06-21", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "industry - Hangzhou Sciwind Biosciences (trial sponsor, disclosed in publication)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-EFINOPEGDUTIDE-HEP-01", "sourceId": "PMID37355043", "drug": "efinopegdutide", "drugRoot": "efinopegdutide", "drugSlug": "efinopegdutide", "drugLabel": "Efinopegdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "relative MRI-PDFF liver-fat reduction 72.7% vs semaglutide 42.3%", "finding": "In a phase 2a open-label active-comparator NAFLD trial (LFC >=10%), the GLP-1/glucagon dual efinopegdutide produced a significantly greater relative MRI-PDFF liver-fat reduction at 24 weeks than the GLP-1-mono semaglutide, at numerically (non-significantly) greater weight loss.", "population": "NCT04944992; N=145 (efinopegdutide 72 / semaglutide 73); NAFLD LFC >=10%, 33% T2D; open-label; 24 wk.", "comparators": "semaglutide", "endpointType": "surrogate/biomarker", "notes": "DEEPENS the efinopegdutide topline (this id) with published detail. ENDPOINT DISTINCTION: this is a LIVER-FAT (MRI-PDFF imaging) head-to-head, NOT a histology trial - no MASH-resolution or fibrosis endpoints, a weaker surrogate tier than the biopsy trials; do not read across to histologic outcomes. Shows the GLP-1/glucagon dual beats GLP-1-mono on liver FAT (consistent with a direct hepatic glucagon lipid effect) but says nothing about FIBROSIS. Open-label. Sponsor Merck/Hanmi. Reta relevance: shared glucagon arm; reta is the triple.", "crossRef": "C-EFINOPEGDUTIDE-LANDSCAPE-01; C2-MULTI-MASH-01; C-MULTI-MASH-GLUCAGON-FIBROSIS", "grade": "moderate", "source": { "citation": "Romero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with NAFLD. J Hepatol 2023;79(4):888-897.", "url": "https://doi.org/10.1016/j.jhep.2023.05.013", "identifiers": "PMID:37355043 / DOI:10.1016/j.jhep.2023.05.013 / NCT04944992", "date": "2023-06-22", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-EFINOPEGDUTIDE-PHARM-01", "sourceId": "PMID37355043", "drug": "efinopegdutide (MK-6024)", "drugRoot": "efinopegdutide", "drugSlug": "efinopegdutide", "drugLabel": "Efinopegdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Once-weekly s.c.; 10 mg target dose titrated over 8 wk", "finding": "GLP-1/glucagon receptor co-agonist; glucagon arm posited to drive direct hepatic fatty-acid oxidation/reduced lipogenesis", "population": "Mechanistic framing in NAFLD trial", "comparators": "semaglutide", "endpointType": "other", "notes": "Formerly HM12525A; licensed Hanmi→Merck", "crossRef": "", "grade": "moderate", "source": { "citation": "Romero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with NAFLD. J Hepatol 2023;79(4):888-897.", "url": "https://doi.org/10.1016/j.jhep.2023.05.013", "identifiers": "PMID:37355043 / DOI:10.1016/j.jhep.2023.05.013 / NCT04944992", "date": "2023-06-22", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-EFINOPEGDUTIDE-TOLGI-01", "sourceId": "PMID37355043", "drug": "efinopegdutide (MK-6024)", "drugRoot": "efinopegdutide", "drugSlug": "efinopegdutide", "drugLabel": "Efinopegdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Higher incidence of GI AEs vs semaglutide (qualitative)", "finding": "Slightly higher AEs vs semaglutide, mainly GI", "population": "NAFLD (n=145), phase 2a, 24 wk", "comparators": "semaglutide 1 mg", "endpointType": "other", "notes": "", "crossRef": "", "grade": "moderate", "source": { "citation": "Romero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with NAFLD. J Hepatol 2023;79(4):888-897.", "url": "https://doi.org/10.1016/j.jhep.2023.05.013", "identifiers": "PMID:37355043 / DOI:10.1016/j.jhep.2023.05.013 / NCT04944992", "date": "2023-06-22", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-EFINOPEGDUTIDE-WL-01", "sourceId": "PMID37355043", "drug": "efinopegdutide (MK-6024)", "drugRoot": "efinopegdutide", "drugSlug": "efinopegdutide", "drugLabel": "Efinopegdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-8.5% efinopegdutide vs -7.1% semaglutide at wk24 (p=0.085)", "finding": "Weight loss numerically greater than semaglutide but not statistically significant", "population": "NAFLD (n=145), phase 2a, 24 wk, open-label", "comparators": "semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "Comparator semaglutide dose 1 mg (sub-max); meta-analysis found no significant WL difference vs sema (PMID:39776746)", "crossRef": "", "grade": "moderate", "source": { "citation": "Romero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with NAFLD. J Hepatol 2023;79(4):888-897.", "url": "https://doi.org/10.1016/j.jhep.2023.05.013", "identifiers": "PMID:37355043 / DOI:10.1016/j.jhep.2023.05.013 / NCT04944992", "date": "2023-06-22", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-EXENATIDE-INS-01", "sourceId": "PMID19196887", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "On-treatment combined glucose+arginine-stimulated C-peptide secretion 2.46-fold vs glargine (95% CI 2.09-2.90, P<0.0001); HbA1c -0.8 vs -0.7%; weight difference -4.6 kg. ALL beta-cell measures REVERTED to pretreatment after a 4-week off-drug washout; HbA1c and weight rose back by 12 weeks off-drug.", "finding": "The canonical washout test of DURABILITY (reversible pole): one year of exenatide improved clamp-measured beta-cell function markedly versus titrated glargine at matched glycaemia, but after a 4-week off-drug washout the beta-cell-function measures returned to pretreatment in both arms - the authors concluded ongoing treatment is necessary, i.e. the 1-year on-treatment gain is NOT a durable, disease-modifying change.", "population": "Bunck et al.: metformin-treated T2D, N=69 (exenatide 36 / glargine 33), 52 wk + 4-wk off-drug, open-label RCT.", "comparators": "insulin glargine", "endpointType": "surrogate/biomarker", "notes": "Pure GLP-1R agonist (no GIP/GCGR), directly relevant to the class durability question and a clean contrast to retatrutide's complete absence of any off-drug data. HOMA/clamp secretion is FUNCTION, NOT beta-cell MASS (mass not measured). Function gain confounded with the (also reversible) weight loss. Pairs with the 3-year extension (C2-EXENATIDE-INS-02), which complicates the picture. COI: industry-sponsored exenatide programme (Amylin / Eli Lilly era). Direction (reverted on washout) validation-confirmed.", "crossRef": "C2-EXENATIDE-INS-02; C2-CLASS-INS-01", "grade": "moderate", "source": { "citation": "Bunck MC, Diamant M, Corner A et al., Diabetes Care, 2009", "url": "https://doi.org/10.2337/dc08-1797", "identifiers": "PMID19196887", "date": "2009-02-05", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry-Amylin Pharmaceuticals/Eli Lilly", "scopeLimits": "open-label (unblinded); small sample (N~69)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-EXENATIDE-INS-02", "sourceId": "PMID21868779", "drug": "exenatide", "drugRoot": "exenatide", "drugSlug": "exenatide", "drugLabel": "Exenatide", "drugClass": "GLP-1 receptor agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "Off-drug (4 wk after stopping) disposition-index change vs pretreatment +1.43 (exenatide) vs -0.99 (glargine), P=0.028; off-drug clamp M-value +39% with exenatide (P=0.006), no change glargine; weight -7.9 kg vs glargine; 3-yr HbA1c 6.6 vs 6.9% (NS).", "finding": "The contested PRESERVATION pole, recorded beside its own contradiction: in the 3-year extension, the off-drug disposition index was sustained ABOVE pretreatment with exenatide (and fell with glargine), which the authors read as a beneficial effect on beta-cell health - standing AGAINST the same group's 1-year result where the off-drug measures reverted. Duration of exposure and the disposition-index (vs raw secretion) endpoint may drive the divergence.", "population": "Bunck et al. 3-year extension: metformin-treated T2D, N=36 completers (exenatide 16 / glargine 20), measured 4 wk after discontinuation, open-label RCT extension.", "comparators": "insulin glargine", "endpointType": "surrogate/biomarker", "notes": "GRADE: LOW (Council Evidence-grader) - N=36 completers, open-label, high attrition from N=69, surrogate, post-hoc 3-year extension. The poles are UNRESOLVED and this 3-yr 'preservation' signal must NOT eclipse the reversible 1-yr result (C2-EXENATIDE-INS-01, larger N=69): the endpoint SWITCH (raw secretion at 1 yr -> disposition index at 3 yr) plus survivorship/attrition are alternative explanations that do NOT require true preservation. BOTH POLES STAND (this vs C2-EXENATIDE-INS-01). The off-drug disposition-index gain is still accompanied by sustained -7.9 kg weight loss, so even the 3-year durable signal is confounded with persistent weight/glucotoxicity relief and does NOT demonstrate preserved beta-cell MASS (no human mass measurement exists). Small N (36), open-label, high 3-year attrition. COI: industry-sponsored exenatide programme (Amylin / Eli Lilly era). Direction (sustained off-drug disposition index at 3 yr, in tension with the 1-yr revert) validation-confirmed.", "crossRef": "C2-EXENATIDE-INS-01; C2-CLASS-INS-01", "grade": "moderate", "source": { "citation": "Bunck MC, Corner A, Eliasson B et al., Diabetes Care, 2011", "url": "https://doi.org/10.2337/dc11-0291", "identifiers": "PMID21868779", "date": "2011-09-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Amylin Pharmaceuticals and Eli Lilly", "scopeLimits": "open-label (unblinded); post-hoc (not prespecified); small sample (N~36); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GCGR-ANTAGONIST-INS-01", "sourceId": "DOI10.1111/DOM.12958", "drug": "GCGR antagonists (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "glucagon receptor antagonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "mixed", "magnitude": "glucose lowered but hepatic fat/liver enzymes/LDL/body weight increased dose-dependently", "finding": "GCGR antagonists lowered glucose in T2D but caused dose-dependent rises in hepatic fat, liver enzymes, LDL/serum lipids and body weight, and human GCGR loss-of-function causes alpha-cell hyperplasia/hyperglucagonaemia (Mahvash disease) — establishing that blocking the glucagon axis has adverse hepatic/lipid consequences, the inverse-direction evidence framing why retatrutide AGONISES (not blocks) GCGR.", "population": "T2D trials (antagonists) + human GCGR-inactivating genetics", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus L2-035 / T8-024. Inverse-direction (antagonist) evidence; bears on the glucagon-arm safety/metabolic logic. PMID not independently re-confirmed for this DOI by this collector — identifier carried as DOI per corpus.", "crossRef": "L2-035", "grade": "moderate", "source": { "citation": "Guzman CB et al. (GCGR antagonist trials review); Larger S et al. (Mahvash, PMID:30032256)", "url": "https://doi.org/10.1111/dom.12958", "identifiers": "DOI:10.1111/dom.12958", "date": "2017-07-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GIP-APP-01", "sourceId": "PMID33571454", "drug": "GIP (native; selective acyl-GIP / CNS-Gipr-KO)", "drugRoot": "GIP (native; selective acyl-GIP / CNS-Gipr-KO)", "drugSlug": "gip-native-selective-acyl-gip-cns-gipr-ko", "drugLabel": "GIP (native; Selective Acyl-GIP / CNS-Gipr-KO)", "drugClass": "GIPR agonist (physiology)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "CNS-GIPR signalling reduces food intake/body weight; co-agonist intake advantage lost without CNS GIPR", "finding": "CNS-GIPR signalling regulates body weight and food intake: HFD-fed CNS-Gipr-KO and humanised-GIPR mice with CNS-hGIPR deletion show decreased body weight, and acute central/peripheral acyl-GIP raises cFos in hypothalamic feeding centres coinciding with decreased food intake; the GLP-1/GIP co-agonist intake advantage is extinguished in CNS-Gipr-KO. This is the CNS-GIP appetite-suppression pole.", "population": "Mice (genetic + acyl-GIP)", "comparators": "vehicle; GLP-1/GIP co-agonist", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GIPR-01. AGONISM pole of the GIP agonism-vs-antagonism appetite paradox. Mouse — does not license a human CNS-GIP-appetite attribution.", "crossRef": "T9-GIPR-01", "grade": "very-low", "source": { "citation": "Zhang Q et al., Cell Metab 2021;33(4):833-844.e5", "url": "https://doi.org/10.1016/j.cmet.2021.01.015", "identifiers": "PMID:33571454", "date": "2021-04-06", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GIP-APP-02", "sourceId": "PMID30683945", "drug": "GIP (native; isoglycaemic clamp infusion)", "drugRoot": "GIP (native; isoglycaemic clamp infusion)", "drugSlug": "gip-native-isoglycaemic-clamp-infusion", "drugLabel": "GIP (native; Isoglycaemic Clamp Infusion)", "drugClass": "GIPR agonist (physiology)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "no-change", "magnitude": "GIP-alone intake 4062 vs 4483 kJ saline (p=0.590); GLP-1 alone 2715 kJ (p=0.014); GIP+GLP-1 > GLP-1 alone (p=0.039)", "finding": "In a randomised crossover isoglycaemic-clamp study in 17 overweight/obese men, GIP infusion ALONE did not reduce ad libitum energy intake vs saline, whereas GLP-1 alone did; adding GIP did not potentiate GLP-1, and intake on GIP+GLP-1 was significantly HIGHER than on GLP-1 alone — acute human GIP attenuated rather than aided GLP-1's intake suppression.", "population": "Overweight/obese men, n=17, crossover (NCT02598791)", "comparators": "saline; GLP-1; GIP+GLP-1", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GIPR-02. Directly OPPOSITE to the mouse CNS-GIPR intake-suppression — central human-vs-mouse appetite DISCREPANCY; both poles recorded, not resolved. Obesity-blunting confound flagged.", "crossRef": "T9-GIPR-02", "grade": "moderate", "source": { "citation": "Bergmann NC et al., Diabetologia 2019;62(4):665-675", "url": "https://doi.org/10.1007/s00125-018-4810-0", "identifiers": "PMID:30683945", "date": "2019-04-01", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "academic - Innovation Fund Denmark and the Vissing Foundation", "scopeLimits": "small sample (N~17)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GIP-APP-03", "sourceId": "PMID41391569", "drug": "LY3537021 (selective GIPR agonist)", "drugRoot": "LY3537021", "drugSlug": "ly3537021", "drugLabel": "LY3537021", "drugClass": "selective GIPR agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "decreased-appetite AE in 12.5% (MAD); appetite VAS no conclusive change; intake not measured", "finding": "The selective GIPR agonist LY3537021 produced dose-dependent weight loss in phase 1 whose apparent mode of action is appetite suppression, inferred from spontaneous adverse events of decreased appetite/early satiety; the formal appetite VAS showed no conclusive effect and energy intake was not formally measured.", "population": "Phase 1 (incl. T2D MAD), humans", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-authored (all-Lilly); COI-flag. Reused from corpus T9-GIPR-03. Only selective-GIPR-agonist human appetite readout; mechanism INFERRED from AEs, VAS inconclusive (not measured-positive).", "crossRef": "T9-GIPR-03", "grade": "low", "source": { "citation": "Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: preclinical + phase 1, 2025", "url": "https://www.sciencedirect.com/science/article/pii/S2212877825002054", "identifiers": "PMID 41391569; DOI 10.1016/j.molmet.2025 (verify)", "date": "2025-01-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GIP-APP-04", "sourceId": "PMID40507574", "drug": "GIPR agonism vs antagonism (class)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "GIPR agonist/antagonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "both poles give additive weight loss atop GLP-1R agonism; per-arm appetite attribution unresolved", "finding": "GIPR agonism-versus-antagonism paradox: both GIPR agonism (within tirzepatide) and GIPR antagonism (anti-GIPR antibody within maridebart cafraglutide/MariTide) produce additive weight loss when combined with GLP-1R agonism; reconciling hypotheses (incretin-crosstalk disinhibition; chronic-agonism desensitisation to functional antagonism; distinct CNS populations) remain genuinely unresolved.", "population": "Review of human/preclinical/genetic evidence", "comparators": "GLP-1R agonism (background)", "endpointType": "surrogate/biomarker", "notes": "COI-visibility (Indiana Biosciences, ex-Lilly/Novo lineage). Reused from corpus T9-GIPR-04/L1-015. HEADLINE DISCREPANCY held open — both poles recorded, NOT resolved by preference.", "crossRef": "T9-GIPR-04", "grade": "low", "source": { "citation": "Douros JD, Mowery SA, Knerr PJ, J Clin Med 2025;14(11):3812", "url": "https://doi.org/10.3390/jcm14113812", "identifiers": "PMID:40507574", "date": "2025-05-29", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GIP-INS-01", "sourceId": "PMID28948296", "drug": "GIP (native infusion / GIP(3-30) antagonist)", "drugRoot": "GIP (native infusion / GIP(3-30) antagonist)", "drugSlug": "gip-native-infusion-gip-3-30-antagonist", "drugLabel": "GIP (native Infusion / GIP(3-30) Antagonist)", "drugClass": "GIPR agonist (physiology)", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "mixed", "magnitude": "GIP is insulinotropic glucose-dependently; the antagonist GIP(3-30)NH2 reduced GIP-induced insulin secretion by 82% (receptor-specific).", "finding": "GIP is insulinotropic only at elevated glucose; the GIPR antagonist GIP(3-30)NH2 cut GIP-induced insulin secretion by 82%, confirming receptor specificity.", "population": "Healthy humans and T2D (clamp/infusion studies)", "comparators": "saline; glucose-matched controls", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus L2-008 (antagonist), L2-010/L2-011 (PMID:21984584, glucose-dependence + glucagonotropic), L2-013 (PMID:21386059, T2D glucagon hypersecretion). Mixed direction: insulinotropic (beta) but glucagonotropic (alpha) — the GIPR islet paradox underlying the agonism-vs-antagonism debate. Individual sub-claim PMIDs carried in cross_ref notes. [CORRECTED 2026-06-20] The glucagonotropic / blunted-in-T2D claims rest on the cross-ref corpus records (L2-010/011/013), not this source.", "crossRef": "L2-008", "grade": "low", "source": { "citation": "Gasbjerg LS et al., Diabetologia 2017 (GIP(3-30)NH2 antagonist)", "url": "https://doi.org/10.1007/s00125-017-4447-4", "identifiers": "PMID 28948296 [VERIFIED 2026-06-20]", "date": "", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLP1-APP-01", "sourceId": "PMID24965303", "drug": "GLP-1 (endogenous; exendin(9-39) antagonist probe)", "drugRoot": "GLP-1 (endogenous; exendin(9-39) antagonist probe)", "drugSlug": "glp-1-endogenous-exendin-9-39-antagonist-probe", "drugLabel": "GLP-1 (endogenous; Exendin(9-39) Antagonist Probe)", "drugClass": "GLP-1R agonist/antagonist (physiology)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "no-change", "magnitude": "endogenous GLP-1R blockade: food intake unchanged; appetite only slightly modulated", "finding": "Pharmacological GLP-1R blockade with exendin(9-39) only slightly modulated appetite during ad libitum eating and did NOT change food intake, fluid intake or meal duration in healthy men, suggesting endogenous GLP-1 is a comparatively weak physiological satiation signal — distinct from the large effect of pharmacological agonism.", "population": "Healthy men, n=10 x2 studies", "comparators": "saline/vehicle", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GLP1R-10. Separates weak endogenous tone from large pharmacological agonist effect. Confound: ex9-39 raised PYY/glucagon (may understate endogenous role).", "crossRef": "T9-GLP1R-10", "grade": "low", "source": { "citation": "Steinert RE et al., Am J Clin Nutr 2014;100(2):514-523", "url": "https://doi.org/10.3945/ajcn.114.083246", "identifiers": "PMID:24965303", "date": "2014-08-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~10)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLP1-INS-01", "sourceId": "PMID22855730", "drug": "GLP-1 (native; physiology)", "drugRoot": "GLP-1 (native; physiology)", "drugSlug": "glp-1-native-physiology", "drugLabel": "GLP-1 (native; Physiology)", "drugClass": "GLP-1R agonist (physiology)", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "mixed", "magnitude": "glucose-dependent insulin augmentation; glucagon suppression; ex9-39 raises fasting/postprandial glucose", "finding": "GLP-1 augments glucose-stimulated insulin secretion in a glucose-dependent manner (acting already at fasting glucose, more strongly as glucose rises) and suppresses alpha-cell glucagon secretion in hyperglycaemic and euglycaemic states, lowering hepatic glucose output; GLP-1R blockade with exendin(9-39) raises glucagon and produces fasting hyperglycaemia.", "population": "Healthy humans and T2D (physiology)", "comparators": "saline; exendin(9-39)", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus L2-001/L2-003 (PMID:15985560)/L2-006 (PMID:22855730). Direction mixed: insulinotropic (beta, +) and glucagonostatic (alpha, glucagon decrease). Foundational pure-GLP-1R islet physiology underpinning the offset.", "crossRef": "L2-001", "grade": "low", "source": { "citation": "Hare KJ et al. (GLP-1 physiology); per corpus L2-006", "url": "https://pubmed.ncbi.nlm.nih.gov/22855730/", "identifiers": "PMID 22855730 [VERIFIED 2026-06-20]", "date": "", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLUCAGON-APP-01", "sourceId": "PMID1621876", "drug": "glucagon (native, prandial infusion)", "drugRoot": "glucagon (native, prandial infusion)", "drugSlug": "glucagon-native-prandial-infusion", "drugLabel": "Glucagon (native, Prandial Infusion)", "drugClass": "glucagon (GCGR agonist, physiology)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "significant test-meal-size reduction at ~3 ng/kg/min (effect-size not in abstract); no effect at ~1.5 ng/kg/min", "finding": "In normal-weight men, intravenous pancreatic glucagon (~3 ng/kg/min, from 5 min before lunch) significantly reduced test-meal size without detectable side effects; a lower dose (~1.5 ng/kg/min) had no effect, and glucagon+CCK-8 produced an infra-additive intake reduction. Canonical human glucagon-satiety datum.", "population": "Normal-weight young men (small n)", "comparators": "saline; CCK-8", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GCGR-02. MAGNITUDE FLAG: effect size/CI not in abstract; small n, dated. Glucagon raises glucose (possible confound for the satiety read).", "crossRef": "T9-GCGR-02", "grade": "moderate", "source": { "citation": "Geary N, Kissileff HR, Pi-Sunyer FX, Hinton V, Am J Physiol 1992;262(6 Pt 2):R975-980", "url": "https://doi.org/10.1152/ajpregu.1992.262.6.R975", "identifiers": "PMID:1621876", "date": "1992-06-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic-NIH/NIDDK", "scopeLimits": "conference/abstract-level", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLUCAGON-APP-02", "sourceId": "PMID1858943", "drug": "glucagon (endogenous blockade)", "drugRoot": "glucagon (endogenous blockade)", "drugSlug": "glucagon-endogenous-blockade", "drugLabel": "Glucagon (endogenous Blockade)", "drugClass": "glucagon (GCGR; physiology)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "increase", "magnitude": "meal size +73% (first dark meal) / +58% (late dark) on endogenous-glucagon blockade", "finding": "Hepatic-portal infusion of glucagon antibodies during spontaneous meals increased meal size in ad libitum-fed rats, indicating endogenous prandial glucagon contributes physiologically to meal termination; the satiety action is relayed by the hepatic vagus (abolished by hepatic vagotomy in companion work).", "population": "Ad libitum-fed rats", "comparators": "control antibody/vehicle", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GCGR-04 (mechanism anchor T9-GCGR-03, Geary 1993 PMID:8430871). Loss-of-function leg of the GCGR-satiety case. Human hepatic-vagal pathway not directly demonstrated.", "crossRef": "T9-GCGR-04", "grade": "very-low", "source": { "citation": "Le Sauter J, Noh U, Geary N, Am J Physiol 1991;261(1 Pt 2):R162-165", "url": "https://doi.org/10.1152/ajpregu.1991.261.1.R162", "identifiers": "PMID:1858943", "date": "1991-07-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLUCAGON-APP-03", "sourceId": "PMID2234610", "drug": "glucagon (class, both-poles marker)", "drugRoot": "GLP-1 RA class (multi-agent)", "drugSlug": "glp-1-ra-class-multi-agent", "drugLabel": "GLP-1 RA class", "drugClass": "glucagon (GCGR)", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "mixed", "magnitude": "modest/debated; human effect small from limited dated data", "finding": "Both-poles marker: glucagon's satiety effect is real but modest and the human evidence base is thin/dated (one small human test-meal study plus rodent mechanism); no modern human glucagon-infusion ad-libitum-intake study isolates a robust large anorectic effect, glucagon raises glucose (confounding the satiety read), and the dual-agonist contrast shows the GCGR arm does not carry oxyntomodulin's satiety. Competing pole: glucagon's headline therapeutic role is metabolic (glucose/EE), largely independent of its modest intake effect.", "population": "Multi-species synthesis", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "Reused from corpus T9-GCGR-08. Explicit flag-both-poles record. Prevents the GCGR arm being written up as a confident appetite-suppressor.", "crossRef": "T9-GCGR-08", "grade": "very-low", "source": { "citation": "Geary N, Neurosci Biobehav Rev 1990;14(3):323-338", "url": "https://doi.org/10.1016/S0149-7634(05)80042-9", "identifiers": "PMID:2234610", "date": "1990-01-01", "design": "preclinical (rodent)", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-GLUCAGON-INS-01", "sourceId": "PMID30833465", "drug": "glucagon (native; physiology)", "drugRoot": "glucagon (native; physiology)", "drugSlug": "glucagon-native-physiology", "drugLabel": "Glucagon (native; Physiology)", "drugClass": "glucagon (GCGR agonist, physiology)", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "EGP +~25%; insulin-mediated EGP suppression abolished under acute hyperglucagonaemia", "finding": "Glucagon acting on GCGR drives hepatic glycogenolysis and gluconeogenesis, raising plasma glucose; protein-induced hyperglucagonaemia (~8x basal) raised endogenous glucose production ~25% and rendered the liver unresponsive to insulin-mediated EGP suppression (stable-isotope tracer). The liver-alpha-cell axis: GCGR agonism increases hepatic amino-acid uptake/ureagenesis, while GCGR blockade/loss-of-function causes alpha-cell hyperplasia and hyperglucagonaemia.", "population": "Humans (acute aminogenic/tracer) + mechanistic", "comparators": "basal/euglycaemic control", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-011/L2-016/L2-017. Glucose-RAISING side of the offset: insulin counterbalances glucagon-on-EGP. +25% is a NET of protein bolus + gluconeogenic substrate + ~6x insulin rise (acute/supraphysiological), not a clean signal-only isolation.", "crossRef": "T3-011", "grade": "moderate", "source": { "citation": "Ang T et al., Diabetes 2019;68(5):939-946; per corpus L2-016/L2-017", "url": "https://doi.org/10.2337/db18-1138", "identifiers": "PMID:30833465", "date": "2019-03-04", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic-Diabetes Australia Research Program", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LIRAGLUTIDE-APP-01", "sourceId": "PMID23999198", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "ad libitum energy intake approx -16% vs placebo; 1-h GE -23% (P=0.007), 5-h GE equivalent", "finding": "Liraglutide (1.8 and 3.0 mg, 5 wk) reduced ad libitum energy intake at a test lunch by approximately 16% vs placebo in obese non-diabetic adults, increased postprandial satiety/fullness and reduced hunger and prospective food consumption; authors concluded weight loss is appetite/intake-mediated, not expenditure-driven. 5-h gastric-emptying AUC was equivalent to placebo, but 1-h gastric emptying was 23% lower (3.0 mg, P=0.007) — an acute early-phase delay that does not persist.", "population": "Obese non-diabetic adults, 5 weeks (NCT00978393)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-funded (Novo Nordisk); COI-flag. Reused from corpus T9-GLP1R-05.", "crossRef": "T9-GLP1R-05", "grade": "moderate", "source": { "citation": "van Can J et al., Int J Obes (Lond) 2014;38(6):784-793", "url": "https://doi.org/10.1038/ijo.2013.162", "identifiers": "PMID:23999198", "date": "2014-06-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LIRAGLUTIDE-APP-02", "sourceId": "PMID26831302", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "reduced fMRI activation to highly-desirable food cues (parietal cortex; insula/putamen secondary)", "finding": "Liraglutide (escalated to 1.8 mg, 17 days) decreased activation of the parietal cortex (and, secondarily, insula and putamen reward regions) in response to highly desirable food images vs placebo in T2D, providing human fMRI evidence for a central/reward-system contribution to GLP-1R-mediated reduced food intake.", "population": "T2D, crossover RCT, n=18 analysed, 17 days", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Sponsor-funded (Novo Nordisk + NIH); COI-flag. Reused from corpus T9-GLP1R-11. Short-term (17 d) reward-cue signal.", "crossRef": "T9-GLP1R-11", "grade": "low", "source": { "citation": "Farr OM et al., Diabetologia 2016;59(5):954-965", "url": "https://doi.org/10.1007/s00125-016-3874-y", "identifiers": "PMID:26831302", "date": "2016-05-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~18)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LIRAGLUTIDE-APP-03", "sourceId": "PMID26283736", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "reduced CNS food-cue response at 10 days; effect absent by 12 weeks", "finding": "Liraglutide 1.8 mg reduced CNS (insula, putamen) responses to food pictures and enhanced the satiating effect of meals (putamen, amygdala) vs insulin glargine after 10 days, but these CNS differences were NO LONGER present after 12 weeks, suggesting the central food-cue/reward effect contributes to the induction of weight loss but not necessarily its maintenance.", "population": "T2D, n=20, active-comparator RCT (insulin glargine)", "comparators": "insulin glargine", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GLP1R-12. DISCREPANCY (central durability): reward-cue fMRI signal attenuates by 12 wk yet intake suppression and weight loss persist — flagged, not resolved.", "crossRef": "T9-GLP1R-12", "grade": "low", "source": { "citation": "Ten Kulve JS et al., Diabetes Care 2016;39(2):214-221", "url": "https://doi.org/10.2337/dc15-0772", "identifiers": "PMID:26283736", "date": "2016-02-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~20)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LIRAGLUTIDE-APP-04", "sourceId": "PMID22226053", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "gastric-emptying inhibition lost by day 14; weight-loss effect retained", "finding": "The acute GLP-1R-mediated gastric-emptying delay is subject to tachyphylaxis under sustained exposure whereas the appetite/body-weight effect is not: in rats, liraglutide's gastric-emptying inhibition was markedly diminished after 14 days while body-weight reduction persisted, indicating brain appetite signalling (not gastric emptying) is the main mechanism of liraglutide-induced weight loss.", "population": "Rats (mechanistic)", "comparators": "vehicle; exenatide (short-acting comparator)", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GLP1R-09. Mechanistic anchor reconciling why human steady-state studies find no GE delay yet large intake reduction.", "crossRef": "T9-GLP1R-09", "grade": "very-low", "source": { "citation": "Jelsing J et al., Diabetes Obes Metab 2012;14(6):531-538", "url": "https://doi.org/10.1111/j.1463-1326.2012.01557.x", "identifiers": "PMID:22226053", "date": "2012-06-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LIRAGLUTIDE-INS-01", "sourceId": "PMID26394161", "drug": "liraglutide", "drugRoot": "liraglutide", "drugSlug": "liraglutide", "drugLabel": "Liraglutide", "drugClass": "GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "hepatic insulin sensitivity: EGP suppression -9.36% vs -2.54% with low-dose insulin (p<0.05)", "finding": "GLP-1R agonism improves hepatic insulin sensitivity at the clamp and tracer level: liraglutide (12 wk, biopsy-proven NASH) increased suppression of endogenous glucose production under low-dose insulin and improved adipose insulin sensitivity, using paired hyperinsulinaemic-euglycaemic clamps with stable-isotope tracers.", "population": "Biopsy-proven NASH, n=14, 12 weeks", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-007. Pure GLP-1RA isolates GLP-1R contribution to hepatic EGP suppression. Small NASH cohort.", "crossRef": "T3-007", "grade": "low", "source": { "citation": "Armstrong MJ et al., J Hepatol 2016;64(2):399-408", "url": "https://doi.org/10.1016/j.jhep.2015.08.038", "identifiers": "PMID:26394161", "date": "2015-09-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "small sample (N~14)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LOTI-SAFE-01", "sourceId": "CIT:pfizer-biopharma-dive-pfizer-citing-safety-conce", "drug": "Lotiglipron (PF-07081532)", "drugRoot": "lotiglipron", "drugSlug": "lotiglipron", "drugLabel": "Lotiglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Elevated liver transaminases observed in mid-stage participants (specific magnitudes not publicly detailed) — UNCONFIRMED numeric", "finding": "Elevated liver enzymes observed in clinical testing, leading to discontinuation of the entire program in 2023.", "population": "Pfizer phase 1/2 lotiglipron program (obesity and T2D)", "comparators": "", "endpointType": "safety-event/signal", "notes": "DISCONTINUED June 2023 for elevated liver enzymes; Pfizer then shifted to danuglipron (which was itself later discontinued for a liver-injury case, April 2025). Two consecutive Pfizer oral GLP-1 hepatic-safety discontinuations — recorded neutrally. No peer-reviewed efficacy paper located; identifiers unverified.", "crossRef": "C2-DANU-SAFE-03", "grade": "very-low", "source": { "citation": "Pfizer / BioPharma Dive: Pfizer, citing safety concerns, scraps one of two obesity pill hopefuls (lotiglipron), 26 June 2023.", "url": "https://www.biopharmadive.com/news/pfizer-discontinue-obesity-drug-lotiglipron/653857/", "identifiers": "identifier unverified", "date": "2023-06-26", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "press", "funding": "industry - Pfizer (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-LOTI-WL-02", "sourceId": "CIT:pfizer-press-cnbc-pfizer-to-end-development-of-e", "drug": "Lotiglipron (PF-07081532)", "drugRoot": "lotiglipron", "drugSlug": "lotiglipron", "drugLabel": "Lotiglipron", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "n/a", "magnitude": "No mature published efficacy magnitude (program halted)", "finding": "Weight-loss/glycaemic efficacy was being evaluated in mid-stage trials but development halted before mature efficacy data were published.", "population": "Phase 1/2 (obesity, T2D); halted 2023", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Placeholder: efficacy never matured to publication due to safety discontinuation. Identifier unverified.", "crossRef": "C2-LOTI-SAFE-01", "grade": "very-low", "source": { "citation": "Pfizer press / CNBC: Pfizer to end development of experimental obesity pill lotiglipron, June 2023.", "url": "https://www.cnbc.com/2023/06/26/pfizer-to-end-development-of-experimental-obesity-pill-lotiglipron.html", "identifiers": "identifier unverified", "date": "2023-06-26", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "press", "funding": "industry - Pfizer (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-LY3537021-GLY-02", "sourceId": "PMID41391569", "drug": "LY3537021", "drugRoot": "LY3537021", "drugSlug": "ly3537021", "drugLabel": "LY3537021", "drugClass": "Selective long-acting GIPR agonist (SC peptide)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "mixed", "magnitude": "Transient fasting-glucose reductions; not significantly different from placebo at day 29 (i.e. not durable)", "finding": "Transient reductions in fasting glucose in T2D participants that were not sustained vs placebo by day 29.", "population": "Phase 1 MAD, T2D participants (NCT04586907); placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Glycaemic benefit of selective GIPR agonism appears weaker/less durable than its weight effect in this short study — recorded neutrally.", "crossRef": "", "grade": "low", "source": { "citation": "Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: preclinical + phase 1, 2025", "url": "https://www.sciencedirect.com/science/article/pii/S2212877825002054", "identifiers": "PMID 41391569; DOI 10.1016/j.molmet.2025 (verify)", "date": "2025-01-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LY3537021-PHARM-03", "sourceId": "PMID41391569", "drug": "LY3537021", "drugRoot": "LY3537021", "drugSlug": "ly3537021", "drugLabel": "LY3537021", "drugClass": "Selective long-acting GIPR agonist (SC peptide)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "t1/2 ~12 days (25 mg, both non-T2D and T2D); Tmax 8-96 h; no gastric-emptying delay at 0.3-25 mg single dose", "finding": "In-vitro potency greater than native GIP, GIPR-selective; half-life ~12 days supporting once-weekly dosing; no delay in gastric emptying after single SC dose.", "population": "In vitro, rats, phase 1 humans", "comparators": "native GIP; placebo", "endpointType": "other", "notes": "Lack of gastric-emptying delay distinguishes GIPR agonism mechanistically from GLP-1R agonism.", "crossRef": "", "grade": "low", "source": { "citation": "Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: preclinical + phase 1, 2025", "url": "https://www.sciencedirect.com/science/article/pii/S2212877825002054", "identifiers": "PMID 41391569; DOI 10.1016/j.molmet.2025 (verify)", "date": "2025-01-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LY3537021-TOLGI-04", "sourceId": "PMID41391569", "drug": "LY3537021", "drugRoot": "LY3537021", "drugSlug": "ly3537021", "drugLabel": "LY3537021", "drugClass": "Selective long-acting GIPR agonist (SC peptide)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "no-change", "magnitude": "GI AEs infrequent (qualitative); no gastric-emptying delay", "finding": "Well tolerated with infrequent gastrointestinal adverse events.", "population": "Phase 1 SAD/MAD N=85; placebo comparator", "comparators": "placebo", "endpointType": "other", "notes": "A separate Knop et al 2024 (Diabetes Obes Metab, DOI 10.1111/dom.15875) reported that adding a long-acting GIPR agonist improved GI tolerability of GLP-1RA therapy — consistent theme that GIPR agonism may be GI-sparing.", "crossRef": "", "grade": "low", "source": { "citation": "Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: preclinical + phase 1, 2025", "url": "https://www.sciencedirect.com/science/article/pii/S2212877825002054", "identifiers": "PMID 41391569; DOI 10.1016/j.molmet.2025 (verify)", "date": "2025-01-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-LY3537021-WL-01", "sourceId": "PMID41391569", "drug": "LY3537021", "drugRoot": "LY3537021", "drugSlug": "ly3537021", "drugLabel": "LY3537021", "drugClass": "Selective long-acting GIPR agonist (SC peptide)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "participants with T2D lost mean 3.14 kg vs placebo 0.36 kg at day 57", "finding": "Selective GIPR agonist monotherapy induced dose-dependent body-weight reduction in a phase 1 MAD study, persisting after last dose.", "population": "Phase 1 SAD/MAD RCT (NCT04586907), Singapore; N=85 (SAD n=47, MAD n=38) healthy + T2D; baseline BMI 25.9-27.0; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Key evidence that SELECTIVE GIPR AGONISM alone causes weight loss in humans — supports a distinct GIP-agonism contribution to multi-agonists (counterpoint to MariTide's GIPR-antagonist approach). Early phase, modest N, lean-ish baseline BMI; authors note need for overweight/obese cohorts.", "crossRef": "C2-MARITIDE-PHARM-06", "grade": "low", "source": { "citation": "Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: preclinical + phase 1, 2025", "url": "https://www.sciencedirect.com/science/article/pii/S2212877825002054", "identifiers": "PMID 41391569; DOI 10.1016/j.molmet.2025 (verify)", "date": "2025-01-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-BC-05", "sourceId": "CIT:amgen-press-release-results-from-amgen-s-phase-2", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "decrease", "magnitude": "Fat-predominant weight loss (quantitative DXA split not given in press summary) — UNCONFIRMED magnitude", "finding": "Most weight lost attributed to fat mass; body composition improved (company-reported at ADA 2025).", "population": "Phase 2 obesity cohorts; 52 wk; placebo comparator", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Body-composition claim is press/conference-sourced; magnitudes unconfirmed. Tag honestly as press.", "crossRef": "", "grade": "very-low", "source": { "citation": "Amgen press release: Results from Amgen's phase 2 obesity study of monthly MariTide presented at ADA 85th Scientific Sessions, June 2025.", "url": "https://www.amgen.com/newsroom/press-releases/2025/06/results-from-amgens-phase-2-obesity-study-of-monthly-maritide-presented-at-the-american-diabetes-association-85th-scientific-sessions", "identifiers": "identifier unverified", "date": "2025-06-21", "design": "observational cohort", "maturity": "press", "funding": "industry - Amgen", "scopeLimits": "conference/abstract-level; identifier not fully verified", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-MARITIDE-GLY-03", "sourceId": "PMID40549887", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Mean HbA1c change -1.2 to -1.6 percentage points (active doses) vs +0.1 pp placebo (treatment-policy estimand), week 52", "finding": "HbA1c reduction in the obesity + T2D cohort.", "population": "Obesity + T2D cohort, N=127; 52 wk; phase 2 RCT; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Amgen press materials also describe improved glycaemic control and body-composition (fat-predominant loss) at ADA 2025.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. N Engl J Med. 2025;393(9):843-857.", "url": "https://doi.org/10.1056/NEJMoa2504214", "identifiers": "PMID:40549887", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Amgen", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-PHARM-06", "sourceId": "PMID40549887", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Dosing q4w (and q8w arm tested) without need for weekly administration; molecule = bispecific peptide-mAb conjugate", "finding": "Long-acting peptide-antibody (anti-GIPR monoclonal antibody) conjugate combining GLP-1R agonism with GIPR antagonism; supports once-monthly (q4w) and tested q8w dosing.", "population": "Mechanistic/PK description; phase 2", "comparators": "", "endpointType": "other", "notes": "Central paradox of the class: GIPR ANTAGONISM here vs GIPR AGONISM in tirzepatide/CT-388/LY3537021, both reportedly pro-weight-loss. A 2025 mouse comparison (Davies et al, PMID 41287212, DOI 10.1111/dom.70300) found GIPR agonist and antagonist both reduced food intake/weight in obese mice, with distinct glycaemic effects — recorded neutrally as mechanistic tension.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. N Engl J Med. 2025;393(9):843-857.", "url": "https://doi.org/10.1056/NEJMoa2504214", "identifiers": "PMID:40549887", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Amgen", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-PHARM-07", "sourceId": "PMID41287212", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "mixed", "magnitude": "In obese mice both GIPR agonist (GIP108) and antagonist (NN-GIPR-Ant) reduced food intake and body weight; energy expenditure unchanged (weight loss matched pair-fed controls); antagonist gave more sustained appetite suppression but reduced insulin sensitivity vs pair-fed; agonist improved glucose tolerance weight-independently", "finding": "Rodent mechanistic comparison: GIPR agonism vs antagonism produce distinct metabolic profiles despite both lowering weight in obese mice.", "population": "Lean and high-fat-diet obese male mice; preclinical", "comparators": "GIPR agonist GIP108; GIPR antagonist NN-GIPR-Ant; pair-fed controls", "endpointType": "other", "notes": "Directly addresses the MariTide agonist/antagonist paradox; rodent-only, authors state human studies needed. Energy expenditure unchanged (weight loss = appetite-driven).", "crossRef": "C2-MARITIDE-PHARM-06", "grade": "very-low", "source": { "citation": "Davies I et al. A metabolic comparison of GIPR agonism versus GIPR antagonism in male mice. Diabetes Obes Metab. 2025;28(2):1160-1167.", "url": "https://doi.org/10.1111/dom.70300", "identifiers": "PMID:41287212", "date": "2025-11-24", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-TOLGI-04", "sourceId": "PMID40549887", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "GI AEs common with active drug; frequency reduced with dose escalation / lower starting dose (specific rates not in abstract)", "finding": "Gastrointestinal adverse events common but mitigated by lower starting dose and dose escalation.", "population": "Full phase 2 population N=592; 52 wk; placebo comparator", "comparators": "placebo", "endpointType": "other", "notes": "\"No unexpected safety signals.\" Per-arm GI rates flagged as unconfirmed from abstract; full tables in primary paper. Once-monthly dosing distinguishes tolerability profile from weekly incretins.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. N Engl J Med. 2025;393(9):843-857.", "url": "https://doi.org/10.1056/NEJMoa2504214", "identifiers": "PMID:40549887", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Amgen", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-WL-01", "sourceId": "PMID40549887", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Treatment-policy estimand: mean body-weight change -12.3% to -16.2% across active doses vs -2.5% placebo at week 52 (140/280/420 mg q4w; some arms q8w or with dose escalation)", "finding": "Once-monthly subcutaneous maridebart cafraglutide produced substantial weight reduction without an apparent plateau at 52 weeks in adults with obesity (no diabetes); dose-ranging.", "population": "Obesity cohort, N=465 (63% female; mean age 47.9 y; mean BMI 37.9); 52 wk; phase 2 double-blind RCT; comparator placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Agonism-vs-antagonism paradox: MariTide combines GLP-1R AGONISM with GIPR ANTAGONISM yet achieves weight loss comparable to GIPR-AGONIST incretins (e.g. tirzepatide) — both poles of GIPR modulation paradoxically reduce weight (recorded neutrally; mechanism unresolved). Funded by Amgen; NCT05669599. No weight plateau reported by week 52.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. N Engl J Med. 2025;393(9):843-857.", "url": "https://doi.org/10.1056/NEJMoa2504214", "identifiers": "PMID:40549887", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Amgen", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MARITIDE-WL-02", "sourceId": "PMID40549887", "drug": "Maridebart cafraglutide (MariTide / AMG 133)", "drugRoot": "MariTide", "drugSlug": "maritide", "drugLabel": "MariTide", "drugClass": "GIPR antagonist + GLP-1 receptor agonist (peptide-antibody conjugate)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Treatment-policy estimand: mean body-weight change -8.4% to -12.3% across active doses vs -1.7% placebo at week 52", "finding": "Weight reduction in the obesity-with-type-2-diabetes cohort, lower in magnitude than the non-diabetes cohort.", "population": "Obesity + T2D cohort, N=127 (42% female; mean age 55.1 y; mean BMI 36.5); 52 wk; phase 2 RCT; placebo comparator", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "As consistently seen in the incretin class, weight loss is attenuated in T2D vs non-diabetes populations.", "crossRef": "", "grade": "moderate", "source": { "citation": "Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial. N Engl J Med. 2025;393(9):843-857.", "url": "https://doi.org/10.1056/NEJMoa2504214", "identifiers": "PMID:40549887", "date": "2025-06-23", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Amgen", "scopeLimits": "animal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-BP-01", "sourceId": "PMID40421736", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "Pooled (4+6 mg) SBP -9.21 mmHg vs placebo at wk48 (press-reported)", "finding": "Mazdutide reduced systolic blood pressure vs placebo (GLORY-1)", "population": "Chinese overweight/obese (n=610), phase 3 GLORY-1, 48 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "BP magnitude press-derived; flag unconfirmed pending full-text (Re-pointed 2026-06-23 from duplicate press/registry row to published GLORY-1 source PMID40421736; press-derived caveat retained.)", "crossRef": "", "grade": "moderate", "source": { "citation": "Mazdutide in Chinese adults with obesity (GLORY-1), NEJM 2025", "url": "https://doi.org/10.1056/NEJMoa2411528", "identifiers": "DOI:10.1056/NEJMoa2411528", "date": "2025-05-29", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "Innovent Biologics", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-EE-01", "sourceId": "PMID39676791", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Mechanistic claim; not directly quantified in humans", "finding": "Glucagon-receptor arm proposed to increase energy expenditure and improve hepatic fat metabolism (mammalian OXM analogue)", "population": "Mechanistic / review framing", "comparators": "dulaglutide (preclinical)", "endpointType": "imaging/physiological surrogate", "notes": "EE claim mechanistic; cross-ref cognition/EE preclinical PMID:40479843", "crossRef": "", "grade": "low", "source": { "citation": "Sidrak WR et al. Indian J Endocrinol Metab 2024;28:445-460", "url": "https://doi.org/10.4103/ijem.ijem_442_23", "identifiers": "PMID:39676791", "date": "2024-09-04", "design": "narrative review", "maturity": "review", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-GLY-01", "sourceId": "PMID41407860", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon receptor dual agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c treatment difference vs dulaglutide 1.5 mg: -0.24% (4 mg; p=0.0032) and -0.30% (6 mg; p=0.0003). Weight treatment difference -3.78% (4 mg) and -5.76% (6 mg) vs dulaglutide (both p<0.0001).", "finding": "In a phase 3 trial in Chinese adults with T2D, both mazdutide doses were non-inferior and superior to dulaglutide 1.5 mg for HbA1c reduction at 28 weeks (head-to-head).", "population": "731 Chinese adults with T2D on background oral antidiabetics, randomised 1:1:1; 28-week phase 3 RCT", "comparators": "dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "Comparator dulaglutide at 1.5 mg (not max 4.5 mg). Chinese-only population may limit generalisability.", "crossRef": "", "grade": "moderate", "source": { "citation": "Guo L et al. Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes. Nature 2025;652(8108):181-188.", "url": "https://doi.org/10.1038/s41586-025-10031-z", "identifiers": "PMID:41407860 / DOI:10.1038/s41586-025-10031-z", "date": "2025-12-17", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "industry - Innovent Biologics (mazdutide licensed from Eli Lilly in China)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-GLY-02", "sourceId": "PMID41260459", "drug": "mazdutide", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon receptor dual agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "n/a", "magnitude": "Not yet reported; primary endpoint = proportion achieving HbA1c <7.0% AND ≥10% weight loss at week 32. Baseline HbA1c 8.0%, weight 90.5 kg, BMI 33.0. N=349.", "finding": "DREAMS-3, the first head-to-head mazdutide-vs-semaglutide trial in Chinese adults with T2D + obesity, is designed but results pending (registry/protocol only).", "population": "349 Chinese adults with T2D (≤10 y) and obesity (BMI ≥28); 32-week open-label active-controlled phase 3 RCT; comparator semaglutide 1 mg", "comparators": "semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "Design/baseline paper only — no efficacy outcomes yet; expected completion early 2026. Comparator semaglutide capped at 1 mg.", "crossRef": "", "grade": "very-low", "source": { "citation": "Luo Y et al. Mazdutide versus Semaglutide for T2D and obesity: rationale, design and baseline data of DREAMS-3. Contemp Clin Trials 2025;160:108150.", "url": "https://doi.org/10.1016/j.cct.2025.108150", "identifiers": "PMID:41260459 / DOI:10.1016/j.cct.2025.108150", "date": "2025-11-17", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-LIP-01", "sourceId": "PMID40421736", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Significant reductions vs placebo (GLORY-1; numeric not specified in press)", "finding": "Reduced total cholesterol, triglycerides, LDL-C and serum uric acid", "population": "Chinese overweight/obese (n=610), phase 3, 48 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed Magnitude press-derived (re-pointed 2026-06-23 from the duplicate press/registry GLORY-1 row to the genuine published source PMID40421736; figures pending full-text confirmation).", "crossRef": "", "grade": "moderate", "source": { "citation": "Mazdutide in Chinese adults with obesity (GLORY-1), NEJM 2025", "url": "https://doi.org/10.1056/NEJMoa2411528", "identifiers": "DOI:10.1056/NEJMoa2411528", "date": "2025-05-29", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "Innovent Biologics", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-TOLGI-01", "sourceId": "PMID36247927", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Most common TEAEs: URTI, diarrhoea, decreased appetite, nausea, vomiting (all mild/moderate)", "finding": "Mild-to-moderate GI TEAEs; no serious AEs in phase 1b", "population": "Chinese overweight/obese (n=24), phase 1b", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Ji L et al. EClinicalMedicine 2022;54:101691", "url": "https://doi.org/10.1016/j.eclinm.2022.101691", "identifiers": "PMID:36247927", "date": "2022-10-07", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~24)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-WL-01", "sourceId": "PMID36247927", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-11.7% at wk12 (9 mg cohort) vs -1.8% placebo (ETD -9.8%); -9.5% at wk16 (10 mg) vs -3.3% placebo", "finding": "High-dose mazdutide produced marked early weight loss vs placebo in Chinese overweight/obese adults", "population": "Chinese overweight/obese adults (n=24), phase 1b MAD, 12-16 wk, RCT placebo-controlled (NCT04440345)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Small early-phase; larger phase 3 confirms", "crossRef": "", "grade": "low", "source": { "citation": "Ji L et al. EClinicalMedicine 2022;54:101691", "url": "https://doi.org/10.1016/j.eclinm.2022.101691", "identifiers": "PMID:36247927", "date": "2022-10-07", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~24)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MAZDUTIDE-WL-02", "sourceId": "PMID40421736", "drug": "mazdutide (IBI362/LY3305677)", "drugRoot": "mazdutide", "drugSlug": "mazdutide", "drugLabel": "Mazdutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-14.0% (6 mg) vs +0.3% placebo at wk48; 49.5% of 6-mg group achieved ≥15% loss; GLORY-2 9 mg up to ~20.1%", "finding": "Phase 3 GLORY-1 confirmed substantial weight loss vs placebo at 48 wk", "population": "Chinese overweight/obese with ≥1 comorbidity (n=610), phase 3, 48 wk, RCT (4/6 mg vs placebo); NEJM 10.1056/NEJMoa2411528", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NEJM DOI from journal listing; exact figures from press release/secondary — flag magnitude as press-derived (Re-pointed 2026-06-23 from duplicate press/registry row to published GLORY-1 source PMID40421736; press-derived caveat retained.)", "crossRef": "", "grade": "moderate", "source": { "citation": "Mazdutide in Chinese adults with obesity (GLORY-1), NEJM 2025", "url": "https://doi.org/10.1056/NEJMoa2411528", "identifiers": "DOI:10.1056/NEJMoa2411528", "date": "2025-05-29", "design": "phase-2 RCT (pipeline)", "maturity": "human-primary", "funding": "Innovent Biologics", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-MULTI-MASH-01", "sourceId": "PMID39028914", "drug": "multiple (network meta-analysis)", "drugRoot": "multiple (network meta-analysis)", "drugSlug": "multiple-network-meta-analysis", "drugLabel": "Multiple (network Meta-analysis)", "drugClass": "GLP-1RA and GLP-1/glucagon/GIP multi-agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "For ≥30% MRI-PDFF decline at 24 wk, efinopegdutide ranked top (SUCRA 67.02), then semaglutide+firsocostat (62.43), pegbelfermin (61.68). For absolute PDFF decline, non-incretins (aldafermin 83.65, pegozafermin 83.46, pioglitazone 71.67) ranked highest.", "finding": "In a network meta-analysis of MASH MRI-PDFF trials, efinopegdutide ranked highest among incretin agents for achieving ≥30% liver-fat decline at 24 weeks; FGF21 analogues/pioglitazone led absolute PDFF reduction.", "population": "39 RCTs, 3311 participants with MASH, MRI-PDFF endpoint; systematic review and network meta-analysis (search to Dec 2023)", "comparators": "across-trial indirect comparison", "endpointType": "imaging/physiological surrogate", "notes": "Indirect comparison (network meta-analysis), not head-to-head RCT — ranking is hypothesis-generating. Incretin agents did not top absolute PDFF reduction vs FGF21 analogues, a tension with the obesity/glycaemic emphasis on incretins.", "crossRef": "", "grade": "moderate", "source": { "citation": "Koh B et al. Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: systematic review and network meta-analysis. Hepatology 2024;83(1):117-126.", "url": "https://doi.org/10.1097/HEP.0000000000001028", "identifiers": "PMID:39028914 / DOI:10.1097/HEP.0000000000001028", "date": "2024-07-19", "design": "network meta-analysis", "maturity": "review", "funding": "academic-Singapore NMRC and NIH (NCATS/NIDDK/NHLBI)/John C Martin Foundation", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-MULTI-MASH-02", "sourceId": "PMID40364529", "drug": "multiple (review)", "drugRoot": "multiple (review)", "drugSlug": "multiple-review", "drugLabel": "Multiple (review)", "drugClass": "GLP-1RA and glucagon/GIP/GLP-1 dual/triple agonists", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Narrative synthesis (no pooled estimate); restricted to liver-biopsy-endpoint trials.", "finding": "Histology-endpoint review: GLP-1RA-based agents improve MASH disease activity; tirzepatide and survodutide additionally show fibrosis-reduction signals; semaglutide phase-3 interim confirmed steatohepatitis improvement and potential fibrosis benefit.", "population": "Comprehensive review of phase 2 (and interim phase 3) MASH trials with histology endpoints", "comparators": "", "endpointType": "surrogate/biomarker", "notes": "Review/secondary source; useful for cross-drug framing of the fibrosis-pole tension (GIP and glucagon receptor agonism fibrosis benefit still needs larger/longer trials).", "crossRef": "", "grade": "moderate", "source": { "citation": "Zafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review: GLP-1 RAs and glucagon/GIP/GLP-1 dual or triple agonists — mechanism and emerging landscape in MASLD. Aliment Pharmacol Ther 2025;61(12):1872-1888.", "url": "https://doi.org/10.1111/apt.70196", "identifiers": "PMID:40364529 / DOI:10.1111/apt.70196", "date": "2025-05-13", "design": "phase-2 RCT", "maturity": "review", "funding": "academic-NIH (NCATS/NIDDK/NHLBI/NIAAA) and John C Martin Foundation", "scopeLimits": "magnitude web/secondary-sourced", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-ORFOR-CMP-05", "sourceId": "PMID42259339", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "comparative-efficacy", "domainLabel": "comparative-efficacy", "domainSlug": "comparative-efficacy", "direction": "decrease", "magnitude": "HbA1c -1.56 pp vs dapagliflozin -0.81 pp", "finding": "ACHIEVE-2 (T2D on metformin): orforglipron non-inferior and statistically superior to dapagliflozin for HbA1c reduction at 40 weeks (active-comparator head-to-head).", "population": "ACHIEVE-2, N=962 (49% female; mean age 56.1; HbA1c 8.14%; BMI 32.6; T2D ~8 y), metformin background; 40 wk; phase 3 open-label (dose-blinded) RCT (NCT06192108)", "comparators": "dapagliflozin 10 mg", "endpointType": "other", "notes": "Head-to-head vs an SGLT2 inhibitor. Trade-off: more GI AEs (46-54% vs 12%) and more discontinuations (15-20% vs 6%) with orforglipron. Lilly press also describes ACHIEVE-3 superiority vs oral semaglutide (conference/press, not captured as a verified PMID here).", "crossRef": "", "grade": "moderate", "source": { "citation": "Welch M et al. Orforglipron compared with dapagliflozin... (ACHIEVE-2): a phase 3 trial. Lancet. 2026;407(10547):? (online 2026-06-08).", "url": "https://doi.org/10.1016/S0140-6736(26)00800-7", "identifiers": "PMID:42259339", "date": "2026-06-08", "design": "open-label RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-GLY-03", "sourceId": "PMID40544435", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change -1.24 (3 mg), -1.47 (12 mg), -1.48 (36 mg) pp vs -0.41 pp placebo at 40 wk (diff from placebo -0.83 to -1.07 pp; p<0.001 all)", "finding": "ACHIEVE-1 (early T2D, drug-naive): HbA1c reduction superior to placebo at 40 weeks; mean week-40 HbA1c 6.5-6.7%.", "population": "ACHIEVE-1, N=559 adults, early T2D managed by diet/exercise, baseline HbA1c ~8.0%; 40 wk; phase 3 double-blind placebo-controlled RCT (NCT05971940); 3/12/36 mg vs placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "No severe hypoglycaemia. Body-weight also fell (-4.5% to -7.6% vs -1.7% placebo) — see WL record.", "crossRef": "C2-ORFOR-WL-04", "grade": "high", "source": { "citation": "Rosenstock J, Hsia S, et al. N Engl J Med 2025 (ACHIEVE-1)", "url": "https://doi.org/10.1056/NEJMoa2505669", "identifiers": "PMID 40544435; DOI 10.1056/NEJMoa2505669; NCT05971940", "date": "2025-06-21", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-PHARM-07", "sourceId": "PMID41275875", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Once-daily oral dosing; no food/water restriction; small-molecule (non-peptide) chemotype", "finding": "Oral, non-peptide, once-daily GLP-1R agonist with no food or fluid intake restrictions (unlike peptide oral semaglutide).", "population": "Mechanistic/formulation description across phase 3 program", "comparators": "oral semaglutide (peptide)", "endpointType": "other", "notes": "Lack of food/fluid restriction is a key differentiator from peptide oral GLP-1 (oral semaglutide). Manufacturing scalability is a stated commercial advantage (press).", "crossRef": "", "grade": "high", "source": { "citation": "Horn DB et al. Orforglipron... for obesity in people with type 2 diabetes (ATTAIN-2): a phase 3 trial. Lancet. 2025;406(10522):2927-2944.", "url": "https://doi.org/10.1016/S0140-6736(25)02165-8", "identifiers": "PMID:41275875", "date": "2025-11-20", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-TOLGI-06", "sourceId": "PMID41275875", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "AE-related discontinuation: ATTAIN-2 6.1-9.9% vs 4.1% placebo; ACHIEVE-1 4.4-7.8% vs 1.4% placebo; ACHIEVE-2 GI AEs 46-54% vs 12% dapagliflozin", "finding": "Predominantly mild-to-moderate GI adverse events, mostly during dose escalation; higher AE-related discontinuation than placebo/active comparators.", "population": "Pooled across ATTAIN-2, ACHIEVE-1, ACHIEVE-2 phase 3 RCTs", "comparators": "placebo; dapagliflozin", "endpointType": "other", "notes": "Safety profile stated as consistent with the GLP-1RA class. No drug-induced-liver-injury signal reported for orforglipron (contrast with Pfizer oral GLP-1s).", "crossRef": "", "grade": "high", "source": { "citation": "Horn DB et al. Orforglipron... for obesity in people with type 2 diabetes (ATTAIN-2): a phase 3 trial. Lancet. 2025;406(10522):2927-2944.", "url": "https://doi.org/10.1016/S0140-6736(25)02165-8", "identifiers": "PMID:41275875", "date": "2025-11-20", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-WL-01", "sourceId": "DOI10.1056/NEJMOA2511774", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "36 mg: mean -11.2% vs -2.1% placebo at 72 wk (treatment-regimen estimand, ATTAIN-1 NEJM); 54.6% lost >=10%, 36.0% >=15% at top dose", "finding": "ATTAIN-1 (obesity, no diabetes): superior body-weight reduction vs placebo at all three doses at 72 weeks.", "population": "ATTAIN-1, adults with obesity (or overweight + comorbidity) without diabetes; 72 wk; phase 3 double-blind placebo-controlled RCT (NCT05869903); doses 6/12/36 mg vs placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "ATTAIN-1 obesity result is press/conference-reported (NEJM publication announced by Lilly); specific PMID for the obesity ATTAIN-1 paper not independently verified here — flagged. Magnitudes from Lilly press; the ~11.2% is somewhat below injectable incretins, consistent with an oral GLP-1 mono-agonist. [VERIFIED 2026-06-20]: ATTAIN-1 obesity now published (PMID 40960239 / DOI 10.1056/NEJMoa2511774); re-pointed from press stub to the peer-reviewed source.", "crossRef": "", "grade": "high", "source": { "citation": "Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results", "url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2511774", "identifiers": "DOI:10.1056/NEJMoa2511774 (ATTAIN-1); NCT05872464", "date": "2025-09-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly", "scopeLimits": "identifier not fully verified; no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-WL-02", "sourceId": "PMID41275875", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -9.6% vs placebo -2.5% at 72 weeks", "finding": "ATTAIN-2 (obesity + T2D): dose-dependent weight reduction superior to placebo at 72 weeks.", "population": "ATTAIN-2, N=1613 (47% female; mean baseline weight 101.4 kg, BMI 35.6, HbA1c 8.05%); 72 wk; phase 3 RCT (NCT05872620); 6/12/36 mg vs placebo", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Weight loss attenuated in T2D (as expected for class). All prespecified weight/cardiometabolic measures incl. HbA1c improved.", "crossRef": "", "grade": "high", "source": { "citation": "Horn DB et al. Orforglipron... for obesity in people with type 2 diabetes (ATTAIN-2): a phase 3 trial. Lancet. 2025;406(10522):2927-2944.", "url": "https://doi.org/10.1016/S0140-6736(25)02165-8", "identifiers": "PMID:41275875", "date": "2025-11-20", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFOR-WL-04", "sourceId": "PMID40544435", "drug": "Orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "Oral small-molecule (non-peptide) GLP-1 receptor agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-4.5% (3 mg), -5.8% (12 mg), -7.6% (36 mg) vs -1.7% placebo at 40 wk", "finding": "ACHIEVE-1 secondary: body-weight reduction at 40 weeks in early T2D.", "population": "ACHIEVE-1, N=559; 40 wk; phase 3 RCT (NCT05971940)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "C2-ORFOR-GLY-03", "grade": "high", "source": { "citation": "Rosenstock J, Hsia S, et al. N Engl J Med 2025 (ACHIEVE-1)", "url": "https://doi.org/10.1056/NEJMoa2505669", "identifiers": "PMID 40544435; DOI 10.1056/NEJMoa2505669; NCT05971940", "date": "2025-06-21", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFORGLIPRON-APP-01", "sourceId": "PMID37344954", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "weight up to -5.4 kg vs -2.4 kg placebo at 4 wk (P<0.05); gastric emptying delayed on Day 28", "finding": "In a phase 1a single/multiple-ascending-dose study in healthy participants, 4 weeks of orforglipron produced body-weight reductions up to 5.4 kg vs 2.4 kg placebo, decreased fasting glucose, and delayed gastric emptying on Day 28 — pharmacodynamics consistent with class GLP-1R appetite/satiety effects (intake not formally measured here).", "population": "Healthy adults, n=92 (32 SAD, 60 MAD), phase 1a", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "COI-flag (all-Lilly authorship). Newly added (not in corpus). Weight/gastric-emptying surrogate; ad-libitum intake and VAS not the primary readout. Direction inferred from class + weight loss.", "crossRef": "", "grade": "low", "source": { "citation": "Pratt E et al., Diabetes Obes Metab 2023;25(9):2634-2641", "url": "https://doi.org/10.1111/dom.15184", "identifiers": "PMID:37344954", "date": "2023-06-21", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~92); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFORGLIPRON-GLY-01", "sourceId": "PMID37369232", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral non-peptide GLP-1 receptor agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change up to -2.10% (-1.67% placebo-adjusted) vs -0.43% placebo and -1.10% dulaglutide; estimated treatment difference vs placebo -0.8% to -1.7%. Weight change up to -10.1 kg. Baseline HbA1c 8.1%.", "finding": "In a phase 2 T2D dose-response study, orforglipron (≥12 mg) gave significant HbA1c reductions vs placebo and numerically exceeded dulaglutide 1.5 mg at 26 weeks.", "population": "383 adults with T2D (diet/exercise ± metformin, HbA1c 7.0-10.5%, BMI ≥23); 26-week double-blind phase 2 RCT; USA, Hungary, Poland, Slovakia", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "Dulaglutide comparison descriptive (not a powered head-to-head). Dose-ranging with two escalation regimens for 36 mg and 45 mg cohorts.", "crossRef": "", "grade": "low", "source": { "citation": "Frías JP et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a phase 2 study. Lancet 2023;402(10400):472-483.", "url": "https://doi.org/10.1016/S0140-6736(23)01302-8", "identifiers": "PMID:37369232 / DOI:10.1016/S0140-6736(23)01302-8 / NCT05048719", "date": "2023-06-24", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-ORFORGLIPRON-INS-01", "sourceId": "PMID37369232", "drug": "orforglipron", "drugRoot": "orforglipron", "drugSlug": "orforglipron", "drugLabel": "Orforglipron", "drugClass": "oral small-molecule GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "decrease", "magnitude": "HbA1c change up to -2.10% (-1.67% placebo-adjusted) vs -0.43% placebo, -1.10% dulaglutide; weight up to -10.1 kg (-7.9 kg placebo-adjusted)", "finding": "In a 26-week phase 2 T2D trial, oral orforglipron (>=12 mg) produced significant HbA1c reductions vs placebo and dulaglutide alongside dose-dependent weight loss, consistent with class GLP-1R glucose-lowering (incretin-driven insulin secretion + glucagon suppression). Discrete clamp/HOMA insulin-sensitivity endpoints were not the primary readouts of this trial.", "population": "Adults with T2D, n=383, 26 weeks (NCT05048719)", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "COI-flag (Lilly-funded, Lilly authors). Newly added. HbA1c/weight surrogate for the insulin-beta-cell axis; per-mechanism insulin-sensitivity/secretion endpoints not isolated here. Direction = glucose-lowering.", "crossRef": "", "grade": "low", "source": { "citation": "Frías JP et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a phase 2 study. Lancet 2023;402(10400):472-483.", "url": "https://doi.org/10.1016/S0140-6736(23)01302-8", "identifiers": "PMID:37369232 / DOI:10.1016/S0140-6736(23)01302-8 / NCT05048719", "date": "2023-06-24", "design": "observational cohort", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-OXYNTOMODULIN-APP-01", "sourceId": "PMID14557443", "drug": "oxyntomodulin (endogenous GLP-1R/GCGR dual)", "drugRoot": "oxyntomodulin (endogenous GLP-1R/GCGR dual)", "drugSlug": "oxyntomodulin-endogenous-glp-1r-gcgr-dual", "drugLabel": "Oxyntomodulin (endogenous GLP-1R/GCGR Dual)", "drugClass": "GLP-1/glucagon dual agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "-19.3% buffet intake (P<0.01); -11.3% cumulative 12-h intake (P<0.05)", "finding": "Intravenous oxyntomodulin reduced ad libitum energy intake at a buffet meal by ~19.3% and cumulative 12-h energy intake by ~11.3% in healthy normal-weight humans, with reduced hunger, no nausea, no change in food palatability, and suppressed preprandial ghrelin. Combination (GLP-1R+GCGR) intake reduction; the glucagon-arm contribution cannot be isolated from this datum.", "population": "Healthy normal-weight humans", "comparators": "saline", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GCGR-05. Combination-only; per-receptor split not possible. Mechanistic contrast (Baggio 2004) indicates the satiety is GLP-1R-driven — not a positive GCGR satiety attribution.", "crossRef": "T9-GCGR-05", "grade": "moderate", "source": { "citation": "Cohen MA et al. (Bloom group), J Clin Endocrinol Metab 2003;88(10):4696-4701", "url": "https://doi.org/10.1210/jc.2003-030421", "identifiers": "PMID:14557443", "date": "2003-10-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "academic - UK Medical Research Council and Wellcome Trust", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-OXYNTOMODULIN-APP-02", "sourceId": "PMID15300587", "drug": "oxyntomodulin (Gcgr-/- vs Glp1r-/- dissection)", "drugRoot": "oxyntomodulin (Gcgr-/- vs Glp1r-/- dissection)", "drugSlug": "oxyntomodulin-gcgr-vs-glp1r-dissection", "drugLabel": "Oxyntomodulin (Gcgr-/- Vs Glp1r-/- Dissection)", "drugClass": "GLP-1/glucagon dual agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "no-change", "magnitude": "GCGR contribution to OXM intake suppression: none detectable (anorexia intact in Gcgr-/-)", "finding": "In mice, oxyntomodulin's acute food-intake suppression is mediated through the GLP-1 receptor, NOT the glucagon receptor: anorexia preserved in Gcgr-/- but abolished in Glp1r-/-; only exendin-4 (not OXM) additionally reduced VO2/RQ, dissociating the intake effect (GLP-1R) from energy expenditure.", "population": "Mice (receptor knockouts)", "comparators": "vehicle; exendin-4", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GCGR-07. Negative/isolating-OUT for GCGR: GCGR arm does NOT carry the dual-agonist acute satiety. Mouse genetic KO; species caveat.", "crossRef": "T9-GCGR-07", "grade": "very-low", "source": { "citation": "Baggio LL, Huang Q, Brown TJ, Drucker DJ, Gastroenterology 2004;127(2):546-558", "url": "https://doi.org/10.1053/j.gastro.2004.04.063", "identifiers": "PMID:15300587", "date": "2004-08-01", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PEMVIDUTIDE-BC-01", "sourceId": "NCTNCT05295875", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "mixed", "magnitude": "78.1% of weight loss from fat; mean lean-mass loss 21.9% of total weight lost (n=50 substudy)", "finding": "High lean-mass preservation in MRI body-composition substudy", "population": "MOMENTUM MRI substudy (n=50), 48 wk", "comparators": "placebo", "endpointType": "imaging/physiological surrogate", "notes": "Company-framed 'class-leading'; comparative claim not head-to-head", "crossRef": "", "grade": "very-low", "source": { "citation": "Altimmune MOMENTUM topline / ADA 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-positive-topline-results-momentum-48-week", "identifiers": "NCT05295875", "date": "2024-06-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; identifier not fully verified; no outcome data yet (ongoing); small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-PEMVIDUTIDE-BP-01", "sourceId": "NCTNCT05295875", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "BP improved; no clinically meaningful HR increase (press, no numerics)", "finding": "Improvements in blood pressure without meaningful heart-rate increase or cardiac/arrhythmia imbalance", "population": "MOMENTUM obesity phase 2 (n=391), 48 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Company-reported absence of HR signal notable for glucagon-containing dual; cross-ref C2-PEMVIDUTIDE-HR-01", "crossRef": "", "grade": "very-low", "source": { "citation": "Altimmune MOMENTUM topline / ADA 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-positive-topline-results-momentum-48-week", "identifiers": "NCT05295875", "date": "2024-06-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; identifier not fully verified; no outcome data yet (ongoing); small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-PEMVIDUTIDE-HEP-01", "sourceId": "PMID39002641", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "relative LFC reduction 68.5% vs placebo 4.4% at week 12", "finding": "Reduced liver fat content, ALT and cT1 vs placebo in MASLD", "population": "BMI ≥28, LFC ≥10% MASLD (n=94), phase 1b/2a, 12 wk, RCT placebo-controlled (NCT05006885)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Harrison SA et al. J Hepatol 2024;82:7-17", "url": "https://doi.org/10.1016/j.jhep.2024.07.006", "identifiers": "PMID:39002641", "date": "2024-07-11", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~94)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-PEMVIDUTIDE-HR-01", "sourceId": "NCTNCT05295875", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "heart-rate-chronotropy", "domainLabel": "heart-rate-chronotropy", "domainSlug": "heart-rate-chronotropy", "direction": "no-change", "magnitude": "No clinically meaningful HR increase (company-reported)", "finding": "No clinically meaningful heart-rate increase reported", "population": "MOMENTUM obesity phase 2 (n=391), 48 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Unconfirmed; contrasts with HR-increase signal common to GLP-1 class", "crossRef": "", "grade": "very-low", "source": { "citation": "Altimmune MOMENTUM topline / ADA 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-positive-topline-results-momentum-48-week", "identifiers": "NCT05295875", "date": "2024-06-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; identifier not fully verified; no outcome data yet (ongoing); small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-PEMVIDUTIDE-LIP-01", "sourceId": "NCTNCT05295875", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "decrease", "magnitude": "Robust serum-lipid reduction reported (numeric in conference data not specified in press)", "finding": "Robust reductions in serum lipids", "population": "MOMENTUM obesity phase 2 (n=391), 48 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed", "crossRef": "", "grade": "very-low", "source": { "citation": "Altimmune MOMENTUM topline / ADA 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-positive-topline-results-momentum-48-week", "identifiers": "NCT05295875", "date": "2024-06-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; identifier not fully verified; no outcome data yet (ongoing); small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-PEMVIDUTIDE-MASH-01", "sourceId": "PMID41237796", "drug": "pemvidutide", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "mixed", "magnitude": "IMPACT phase-2b wk24, dual-primary vs placebo: MASH resolution without worsening fibrosis 58% (1.2 mg; diff 38%, 95% CI 21-56; p<0.0001) and 52% (1.8 mg; diff 32%, 19-46; p<0.0001) vs 20% - HIT. Fibrosis improvement >=1 stage without worsening MASH 33% (1.2 mg; diff 5%, 95% CI -13 to 22; p=0.59) and 36% (1.8 mg; diff 8%, -6 to 22; p=0.27) vs 28% - MISSED (CIs cross zero).", "finding": "In IMPACT (phase 2b, F2-F3), the GLP-1/glucagon dual pemvidutide MET one dual-primary (MASH resolution) but DID NOT MEET the other (fibrosis improvement) at 24 weeks; the fibrosis differences vs placebo were small and non-significant (p=0.59 and p=0.27). Reported honestly: fibrosis was a MISS at 24 weeks.", "population": "NCT05989711 (IMPACT); 212 randomised (1:2:2 placebo:1.2:1.8 mg); biopsy MASH fibrosis F2/F3; phase-2b randomised double-blind placebo-controlled trial; 24-week readout of a 48-week trial.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DEEPENS AND CORRECTS the prior pemvidutide topline (this id), which implied a fibrosis signal: the PUBLISHED 24-wk primary fibrosis endpoint was a MISS (p=0.59/0.27). SURROGATE caveat. This is the key cross-agent data point AGAINST a simple glucagon=anti-fibrotic story (a glucagon dual that hit resolution but missed fibrosis). Authors note 24 wk may be too short for fibrosis. Small per-arm N (41 in 1.2 mg). Sponsor Altimmune. Reta relevance: shares glucagon arm but is a dual not a triple; not transferable to reta.", "crossRef": "C2-PEMVIDUTIDE-HEP-01; C-MULTI-MASH-GLUCAGON-FIBROSIS; C2-MULTI-MASH-02", "grade": "moderate", "source": { "citation": "Noureddin M, Harrison SA, Loomba R et al. Pemvidutide vs placebo for MASH (IMPACT): 24-week results. Lancet 2025;406(10520):2644-2655.", "url": "https://doi.org/10.1016/S0140-6736(25)02114-2", "identifiers": "PMID41237796", "date": "2025-11-11", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Altimmune, Inc.", "scopeLimits": "no outcome data yet (ongoing); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-PEMVIDUTIDE-TOLGI-01", "sourceId": "PMID39002641", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "No severe or serious AEs at any dose (12-wk MASLD); GI predominant", "finding": "Well tolerated in MASLD study with no severe/serious AEs", "population": "MASLD phase 1b/2a (n=94), 12 wk", "comparators": "placebo", "endpointType": "other", "notes": "", "crossRef": "", "grade": "low", "source": { "citation": "Harrison SA et al. J Hepatol 2024;82:7-17", "url": "https://doi.org/10.1016/j.jhep.2024.07.006", "identifiers": "PMID:39002641", "date": "2024-07-11", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~94)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-PEMVIDUTIDE-WL-01", "sourceId": "NCTNCT05295875", "drug": "pemvidutide (ALT-801)", "drugRoot": "pemvidutide", "drugSlug": "pemvidutide", "drugLabel": "Pemvidutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "-10.3% (1.2mg), -11.2% (1.8mg), -15.6% (2.4mg) vs -2.2% placebo at wk48; 2.4mg not plateaued", "finding": "Dose-dependent weight loss over 48 wk in obesity/overweight without diabetes (MOMENTUM)", "population": "Obese/overweight + ≥1 comorbidity, no diabetes (n=391), phase 2 MOMENTUM, 48 wk, RCT 1:1:1:1", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Conference/press; peer-reviewed obesity paper pending. NCT identifier unverified against registry", "crossRef": "", "grade": "very-low", "source": { "citation": "Altimmune MOMENTUM topline / ADA 2024", "url": "https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-positive-topline-results-momentum-48-week", "identifiers": "NCT05295875", "date": "2024-06-01", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Altimmune (trial sponsor; inferred from registration trial)", "scopeLimits": "conference/abstract-level; identifier not fully verified; no outcome data yet (ongoing); small sample (N~50)", "pressSourced": true }, "flags": { "investigational": true, "pressSourced": true } }, { "id": "C2-PETRELINTIDE-BC-01", "sourceId": "CIT:zealand-pharma-press-release-20-jun-2024", "drug": "petrelintide (ZP8396)", "drugRoot": "petrelintide", "drugSlug": "petrelintide", "drugLabel": "Petrelintide", "drugClass": "long-acting amylin analogue (DACRA-class)", "domain": "body-composition", "domainLabel": "Body composition", "domainSlug": "body-composition", "direction": "n/a", "magnitude": "Lean-mass preservation asserted (preclinical/clinical framing, no quantified human data)", "finding": "Positioned for high-quality weight loss with lean-mass preservation (company claim)", "population": "Company positioning / preclinical", "comparators": "", "endpointType": "imaging/physiological surrogate", "notes": "Aspirational claim, not yet quantified in humans", "crossRef": "", "grade": "very-low", "source": { "citation": "Zealand Pharma press release, 20 Jun 2024", "url": "https://www.globenewswire.com/news-release/2024/06/20/2901879/0/en/Zealand-Pharma-announces-positive-topline-results-from-the-Phase-1b-16-week-multiple-ascending-dose-clinical-trial-with-long-acting-amylin-analog-petrelintide.html", "identifiers": "NCT-unverified", "date": "2024-06-20", "design": "unspecified", "maturity": "press", "funding": "industry - Zealand / Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-PETRELINTIDE-PHARM-01", "sourceId": "PMID40608546", "drug": "petrelintide (ZP8396)", "drugRoot": "petrelintide", "drugSlug": "petrelintide", "drugLabel": "Petrelintide", "drugClass": "long-acting amylin analogue (DACRA-class)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Once-weekly long-acting profile; SAR basis for BGM1812 follow-on", "finding": "Long-acting amylin analogue / dual amylin-calcitonin receptor agonist (DACRA); used as reference scaffold for next-gen DACRA optimisation", "population": "Medicinal-chemistry / SAR (in-vitro + in-vivo)", "comparators": "BGM1812; natural amylin/calcitonin", "endpointType": "other", "notes": "Paper characterises petrelintide's agonism as 'insufficient vs natural agonists' (third-party framing)", "crossRef": "", "grade": "low", "source": { "citation": "Zong L et al. J Med Chem 2025;68:14907-14918", "url": "https://doi.org/10.1021/acs.jmedchem.5c01120", "identifiers": "PMID:40608546", "date": "2025-07-03", "design": "unspecified", "maturity": "in-vitro", "funding": "industry - Zealand / Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PETRELINTIDE-TOLGI-01", "sourceId": "CIT:zealand-pharma-topline-press-release-20-jun-2024", "drug": "petrelintide (ZP8396)", "drugRoot": "petrelintide", "drugSlug": "petrelintide", "drugLabel": "Petrelintide", "drugClass": "long-acting amylin analogue (DACRA-class)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "no-change", "magnitude": "Safe/well tolerated all doses (no numerics in topline)", "finding": "Reported safe and well tolerated at all dose levels (company)", "population": "Phase 1b MAD (n=48), 16 wk", "comparators": "placebo", "endpointType": "other", "notes": "Company tolerability framing; independent data pending", "crossRef": "", "grade": "very-low", "source": { "citation": "Zealand Pharma topline press release, 20 Jun 2024", "url": "https://www.globenewswire.com/news-release/2024/06/20/2901879/0/en/Zealand-Pharma-announces-positive-topline-results-from-the-Phase-1b-16-week-multiple-ascending-dose-clinical-trial-with-long-acting-amylin-analog-petrelintide.html", "identifiers": "NCT-unverified", "date": "2024-06-20", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "press", "funding": "industry - Zealand / Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing); small sample (N~48)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-PETRELINTIDE-WL-01", "sourceId": "CIT:zealand-pharma-topline-press-release-20-jun-2024", "drug": "petrelintide (ZP8396)", "drugRoot": "petrelintide", "drugSlug": "petrelintide", "drugLabel": "Petrelintide", "drugClass": "long-acting amylin analogue (DACRA-class)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Up to mean -8.6% (high dose, completers) vs -1.7% placebo at wk16", "finding": "Phase 1b MAD: dose-dependent weight loss over 16 weekly doses", "population": "Overweight/obese, median BMI 29, median age 49 (n=48), phase 1b MAD, 16 wk, RCT placebo-controlled", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Topline press; NCT not stated; phase 2b initiated H2 2024. Lower BMI cohort limits comparability", "crossRef": "", "grade": "very-low", "source": { "citation": "Zealand Pharma topline press release, 20 Jun 2024", "url": "https://www.globenewswire.com/news-release/2024/06/20/2901879/0/en/Zealand-Pharma-announces-positive-topline-results-from-the-Phase-1b-16-week-multiple-ascending-dose-clinical-trial-with-long-acting-amylin-analog-petrelintide.html", "identifiers": "NCT-unverified", "date": "2024-06-20", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "press", "funding": "industry - Zealand / Roche (trial sponsor; inferred from registration trial)", "scopeLimits": "no outcome data yet (ongoing); small sample (N~48)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-PRAMLINTIDE-GLY-01", "sourceId": "CIT:symlin-pramlintide-acetate-fda-label-2015", "drug": "pramlintide", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (marketed, Symlin)", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c reduction ~0.2-0.7%; label T2D ~-0.18% to -0.5% over 6 mo vs placebo+insulin", "finding": "Modest HbA1c reduction as mealtime-insulin adjunct in T1D/T2D", "population": "T1D/T2D on mealtime insulin, FDA registration trials, ≥6 mo, RCT placebo-controlled", "comparators": "placebo + insulin", "endpointType": "surrogate/biomarker", "notes": "Marketed precedent; effect small relative to newer agents", "crossRef": "", "grade": "high", "source": { "citation": "SYMLIN (pramlintide acetate) FDA label, 2015", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021332s025lbl.pdf", "identifiers": "NDA021332", "date": "2015-01-01", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PRAMLINTIDE-PHARM-01", "sourceId": "CIT:symlin-fda-label-2015", "drug": "pramlintide", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (marketed, Symlin)", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Short-acting; given before major meals", "finding": "Synthetic human amylin analogue; slows gastric emptying, suppresses glucagon, promotes satiety; t.i.d. mealtime dosing", "population": "Pharmacology / label", "comparators": "", "endpointType": "other", "notes": "First marketed amylin analogue — mechanistic precedent for cagrilintide/amycretin/petrelintide", "crossRef": "", "grade": "high", "source": { "citation": "SYMLIN FDA label 2015", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021332s025lbl.pdf", "identifiers": "NDA021332", "date": "2015-01-01", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PRAMLINTIDE-SAF-01", "sourceId": "CIT:symlin-fda-label-2015", "drug": "pramlintide", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (marketed, Symlin)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Mandated 30-50% reduction of short/rapid-acting insulin at initiation to mitigate severe hypoglycaemia", "finding": "Boxed warning for insulin-induced severe hypoglycaemia; requires mealtime-insulin dose reduction", "population": "T1D/T2D on mealtime insulin", "comparators": "placebo + insulin", "endpointType": "safety-event/signal", "notes": "Hypoglycaemia is insulin-co-administration effect, not amylin-intrinsic", "crossRef": "", "grade": "high", "source": { "citation": "SYMLIN FDA label 2015", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021332s025lbl.pdf", "identifiers": "NDA021332", "date": "2015-01-01", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PRAMLINTIDE-TOLGI-01", "sourceId": "CIT:symlin-fda-label-2015", "drug": "pramlintide", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (marketed, Symlin)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Nausea, vomiting, anorexia common, generally resolve within first weeks", "finding": "Nausea most common AE; slows gastric emptying", "population": "T1D/T2D registration trials", "comparators": "placebo + insulin", "endpointType": "other", "notes": "", "crossRef": "", "grade": "high", "source": { "citation": "SYMLIN FDA label 2015", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021332s025lbl.pdf", "identifiers": "NDA021332", "date": "2015-01-01", "design": "regulatory document / agency review", "maturity": "regulatory-doc", "funding": "regulatory agency (FDA/EMA/MHRA/WHO)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-PRAMLINTIDE-WL-01", "sourceId": "PMID12610038", "drug": "pramlintide", "drugRoot": "pramlintide", "drugSlug": "pramlintide", "drugLabel": "Pramlintide", "drugClass": "amylin analogue (marketed, Symlin)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "~-1.4 to -1.6 kg vs +0.1 to +0.3 kg placebo (FDA label); up to ~1.6 kg", "finding": "Modest weight loss vs weight gain on insulin alone", "population": "T2D on mealtime insulin, FDA registration trials", "comparators": "placebo + insulin", "endpointType": "surrogate/biomarker", "notes": "Magnitude far below modern amylin analogues — historical anchor", "crossRef": "", "grade": "high", "source": { "citation": "Hollander PA, Levy P, Fineman MS, et al. 'Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial.' Diabetes Care 2003;26(3):784-790.", "url": "https://doi.org/10.2337/diacare.26.3.784", "identifiers": "PMID:12610038", "date": "2003-03-01", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Amylin Pharmaceuticals (pramlintide developer)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-APP-01", "sourceId": "PMID40916752", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "overall Appetite VAS LSM difference vs placebo at Wk24: 4 mg +8.3, 8 mg +9.4, 12 mg +10.7 (higher VAS = less appetite; all p<0.05)", "finding": "In the retatrutide phase 2 T2D trial, pre-specified exploratory Appetite VAS showed retatrutide >=4 mg produced greater reductions in OVERALL appetite vs placebo (dose-dependent); the 0.5 mg group did not differ from placebo. First direct retatrutide appetite readout (in adults with T2D specifically).", "population": "Adults with T2D, n=275 efficacy set, phase 2", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "COI-flag (Lilly-funded/Lilly-employee authorship). Self-reported VAS, NOT measured intake; exploratory, not multiplicity-corrected. Attribution held open (cannot assign to GLP-1R/GIPR/GCGR arm). Reused from corpus T9-RD-01. DOI to be confirmed.", "crossRef": "T9-RD-01", "grade": "moderate", "source": { "citation": "Kanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998", "url": "https://doi.org/10.1111/dom.70063", "identifiers": "PMID:40916752", "date": "2025-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "not multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-APP-02", "sourceId": "PMID40916752", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "mixed", "magnitude": "Hunger LSMD Wk24: 4 mg -15.9, 8 mg -15.3, 12 mg -15.7; PFC: 4 mg -11.4, 8 mg -16.0, 12 mg -14.3 (all p<0.05); satiety/fullness null", "finding": "In the same retatrutide phase 2 T2D appetite analysis, individual VAS items moved heterogeneously: HUNGER fell vs placebo and PROSPECTIVE FOOD CONSUMPTION fell vs placebo, but SATIETY and FULLNESS showed NO significant retatrutide-vs-placebo difference at any timepoint over 36 weeks.", "population": "Adults with T2D, phase 2, over 36 weeks", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "DISCREPANCY-INTERNAL: appetite signal carried by hunger/PFC (drive-to-eat), NOT satiety/fullness — the common 'satiety' framing is not supported for retatrutide on the VAS. COI-flag. Reused from corpus T9-RD-02.", "crossRef": "T9-RD-02", "grade": "moderate", "source": { "citation": "Kanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998", "url": "https://doi.org/10.1111/dom.70063", "identifiers": "PMID:40916752", "date": "2025-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "not multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-APP-03", "sourceId": "PMID40916752", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "Wk36 vs placebo: Perceived Hunger 8 mg -1.9/12 mg -2.4; Disinhibition 8 mg -2.1/12 mg -2.6; Restraint +3.7 (12 mg); reta-12mg vs dulaglutide -1.5 and -1.8 (all p<0.05)", "finding": "In the retatrutide phase 2 T2D Three-Factor Eating Inventory, higher doses reduced Perceived Hunger and Disinhibition and increased Dietary Restraint; retatrutide 12 mg also beat the dulaglutide arm on Perceived Hunger and Disinhibition at Week 36. No dietary calorie-intake records were collected, so no measured intake exists for retatrutide.", "population": "Adults with T2D, phase 2", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "reta-12mg-minus-dulaglutide contrast is NOT clean isolation (sub-maximal single dulaglutide dose). COI-flag. Reused from corpus T9-RD-03/T9-RD-04 (no calorie-intake records collected).", "crossRef": "T9-RD-03", "grade": "moderate", "source": { "citation": "Kanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998", "url": "https://doi.org/10.1111/dom.70063", "identifiers": "PMID:40916752", "date": "2025-12-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "not multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-01", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change at 24 wk (abstract-verified): -0.43% (0.5 mg), -1.39% (4 mg esc), -1.99% (8 mg slow esc), -2.02% (12 mg) vs -0.01% placebo and -1.41% dulaglutide 1.5 mg; superior to dulaglutide at 8 mg-slow (p=0.0019) and 12 mg (p=0.0002); up to ~-2.16% at 36 wk. Target attainment [figure-data, NOT abstract-verified]: HbA1c <7.0% in ~80%, <=6.5% up to 82%, <5.7% up to 31%; fasting glucose down up to ~69 mg/dL. Baseline HbA1c mean ~8.3%. No hypoglycaemia reported.", "finding": "In the phase-2 T2D trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks (HbA1c is a SURROGATE endpoint), significantly greater than placebo at all doses bar 0.5 mg and greater than dulaglutide 1.5 mg at the 8 mg slow-escalation and 12 mg doses, with no hypoglycaemia reported. (High HbA1c target attainment is reported, but as secondary/figure data - see magnitude, flagged not-abstract-verified.)", "population": "Rosenstock phase-2 (NCT04867785): 281 adults with T2D (HbA1c 7.0-10.5%, BMI 25-50), on diet/exercise +/- stable metformin; 36-week double-blind placebo- and dulaglutide-1.5mg-controlled RCT, USA; 24-week primary.", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "DEEPENED (D3): adds HbA1c target-attainment and fasting-glucose detail to the existing row. GLUCAGON-OFFSET caveat: the GCGR arm RAISES hepatic glucose in isolation, so net HbA1c lowering is a COMBINATION result; the incretin and weight-loss effects are PRESUMED to outweigh any glucagon-driven rise, but the trial cannot partition this and does NOT establish that an offset 'holds' (weight-mediation and HbA1c-floor equally explain the absence of net blunting). Cross-ref thread-3. Dulaglutide capped at 1.5 mg (below the 4.5 mg max), so the active-comparator superiority is framed cautiously. Background med reduction/insulin-sparing was NOT a reported endpoint. Validation: PMID 37385280 confirmed as the Rosenstock Lancet 2023 reta T2D trial, DISTINCT from the Jastreboff NEJM obesity trial (37366315). NOTE: the HbA1c-change and dulaglutide figures are abstract-verified; the target-attainment percentages (<7.0% ~80%, <=6.5% up to 82%) and the ~69 mg/dL FPG drop are SECONDARY/figure data not in the abstract (directionally consistent, flagged not-abstract-verified).", "crossRef": "C-RETATRUTIDE-LANDSCAPE-02; C2-RETATRUTIDE-GLY-04; thread-3", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-02", "sourceId": "PMID42250575", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change to week 40 -1.94% vs placebo -0.81%", "finding": "TRANSCEND-T2D-1, the first phase-3 confirmation: in adults with T2D inadequately controlled by diet and exercise, retatrutide produced graduated, dose-dependent HbA1c reductions significantly greater than placebo at 40 weeks, corroborating the phase-2 dose-response. Headline caveats: HbA1c is a SURROGATE (not a hard CV/microvascular outcome), and this is MONOTHERAPY in short-duration (mean 2.5 y), diet-and-exercise-only, placebo-only T2D, so generalisability to established/treated T2D is not established.", "population": "TRANSCEND-T2D-1 (NCT06354660): 537 adults with T2D on diet/exercise only (HbA1c 7.0-9.5%, mean diabetes duration 2.5 y), retatrutide 4/9/12 mg vs placebo; 40-week phase-3 double-blind monotherapy RCT.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "NEW compendium row for TRANSCEND-T2D-1 (already in the per-receptor corpus as L2-040 / T7-039 - cross-ref, confirm same PMID 42250575 / NCT06354660). Pivotal phase-3 but monotherapy in a SHORT-duration (mean 2.5 y), diet-and-exercise-only population, placebo-only (no active comparator) - generalisability to established/treated T2D is limited. Glucagon-offset caveat as in GLY-01. VALIDATOR: confirm PMID 42250575 and reconcile with L2-040.", "crossRef": "C2-RETATRUTIDE-GLY-01; L2-040; T7-039", "grade": "high", "source": { "citation": "Bajaj HS et al., Lancet, 2026", "url": "https://doi.org/10.1016/S0140-6736(26)00967-0", "identifiers": "PMID42250575", "date": "2026-06-06", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-03", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Retatrutide 12 mg HbA1c -2.02% (24 wk) / ~-2.16% (36 wk), baseline ~8.3% (phase-2); tirzepatide 15 mg -2.30% (40 wk, baseline 8.28%, SURPASS-2); semaglutide 1.0 mg -1.55% (30 wk, baseline 8.05%, SUSTAIN-1); dulaglutide 1.5 mg -1.41% (within the reta trial). All from SEPARATE trials.", "finding": "CROSS-TRIAL juxtaposition (NOT head-to-head, NOT a non-inferiority test): the bare HbA1c point estimates from three SEPARATE trials are reta 12 mg -2.02 to -2.16% (phase-2), tirzepatide 15 mg -2.30% (SURPASS-2), semaglutide 1.0 mg -1.55% (SUSTAIN-1). The point estimates OVERLAP, but with different populations, baselines, durations and designs the comparison cannot establish non-inferiority or superiority in EITHER direction and NO potency rank-order can be drawn. The only within-trial (true) comparison is reta superior to dulaglutide 1.5 mg (a submaximal dose). Class glycaemic rank-ordering, and whether reta's glucagon arm costs net glycaemia, remain UNESTABLISHED until the registered reta-vs-sema head-to-head (TRANSCEND-T2D-2) reports.", "population": "CROSS-TRIAL juxtaposition: reta phase-2 (N=281, 24-36 wk) vs SURPASS-2 (tirz, N=1879 on metformin, 40 wk) vs SUSTAIN-1 (sema, N=388 drug-naive, 30 wk). Different populations/baselines/durations.", "comparators": "placebo; dulaglutide 1.5 mg; tirzepatide (separate trial); semaglutide (separate trial)", "endpointType": "surrogate/biomarker", "notes": "CROSS-TRIAL caveat is LOAD-BEARING: this is a juxtaposition of three separate RCTs, NOT a head-to-head; do not present as evidence reta is more/less potent than tirzepatide. No direct reta-vs-tirz or reta-vs-sema T2D efficacy exists yet (the reta-vs-sema head-to-head TRANSCEND-T2D-2 is registered but UNREAD, see C2-RETATRUTIDE-GLY-06). GRADE: although anchored on primary RCTs, the CROSS-TRIAL juxtaposition itself is a LOW-confidence indirect comparison (per-source grading limit, OQ-DB-01: the moderate grade attaches to Rosenstock, NOT to the juxtaposition drawn across trials). COI: reta and tirzepatide (SURPASS-2) are BOTH Eli Lilly-sponsored (same sponsor on both sides of the comparison); semaglutide (SUSTAIN-1) is Novo - this is NOT independent benchmarking. The glucagon-offset inference is NOT drawn in this row (it lives, bounded, in GLY-04). Competitive context: orforglipron/mazdutide/CagriSema T2D HbA1c sit in an overlapping ~-1.2 to -2.2% band (existing rows). Validation: SURPASS-2 PMID 34170647 and SUSTAIN-1 PMID 28110911 confirmed.", "crossRef": "C2-RETATRUTIDE-GLY-01; C2-TIRZEPATIDE-GLY-01; C2-RETATRUTIDE-GLY-06", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-04", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "Reta 12 mg: HbA1c -2.16% (36 wk) vs dulaglutide -1.41% (~1.5x); weight -16.94% vs dulaglutide -2.02% (~8.4x). HbA1c flat across top doses (-1.99% at 8 mg slow vs -2.02% at 12 mg) while weight kept the larger effect. No severe hypoglycaemia, no hyperglycaemia signal at any dose.", "finding": "Glucagon-offset net-efficacy and glycaemic-ceiling observation (NEUTRAL): no NET glycaemic blunting was observed at any dose (the glycaemic outcome is a combination result - no per-arm penalty can be observed OR excluded from trial data). There is a directional signal that retatrutide's WEIGHT efficacy outruns its HbA1c efficacy relative to a submaximal-dose pure incretin (at 12 mg, ~8.4x dulaglutide's weight effect but only ~1.5x its HbA1c effect), and HbA1c plateaued across 8-12 mg. Recorded as an observation, NOT a per-receptor decomposition.", "population": "Reta phase-2 (NCT04867785), 281 adults with T2D, 36 wk, vs placebo and dulaglutide 1.5 mg.", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "DO NOT OVER-CLAIM (cross-ref thread-3, human-court ruling 2026-06-19): the weight>HbA1c disproportion and the HbA1c plateau are NOT a clean measure of glucagon-driven glycaemic blunting - both are equally consistent with weight-mediation (OQ-T3-A) and with HbA1c being floor-limited near target (HbA1c <=6.5% in up to 82%). A reta-direct clamp + EGP tracer study would only BOUND, not partition, the offset. The class caveat (GLP-1/glucagon duals can show blunted glycaemia if glucagon weighting is too high) does NOT visibly manifest for reta at studied doses, which is CONSISTENT WITH an intact incretin-vs-glucagon balance but does NOT establish it: the 8-12 mg HbA1c plateau is equally consistent with (a) HbA1c floor-limited near target, (b) weight-mediation, (c) the disproportion ratio being inflated by the submaximal dulaglutide 1.5 mg comparator, OR (d) the glucagon arm beginning to blunt glycaemia at the top dose - these cannot be partitioned, so do NOT conclude the offset is definitively intact at the highest doses. Cross-ref OQ-SW-A (dose-headroom).", "crossRef": "C2-RETATRUTIDE-GLY-01; C2-RETATRUTIDE-GLY-03; thread-3; OQ-SW-A", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-05", "sourceId": "NCTNCT05929079", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "n/a", "magnitude": "No results. Primary endpoint: percent change in body weight to wk80 (and Apnoea-Hypopnoea Index for the OSA subset); HbA1c is a SECONDARY endpoint. Enrolment ~1000; status active, not recruiting; estimated primary completion May 2026.", "finding": "REGISTRY (no results): TRIUMPH-2 (NCT05929079) is a phase-3 master protocol of once-weekly retatrutide in adults with T2D who have obesity/overweight, including an obstructive sleep apnoea (OSA) subset. Confirmed as a reta phase-3 T2D trial; its primary endpoint is body weight (and AHI for the OSA arm), NOT HbA1c, so its glycaemic outcomes are secondary and unreported.", "population": "TRIUMPH-2 (NCT05929079): adults with T2D for >=90 days, BMI >=27, incl. an OSA subset; retatrutide (3 doses) vs placebo; phase-3.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Registered per the D3 remit. Promissory note (very-low). Primary is weight/AHI not HbA1c; glycaemic data will be a secondary readout. Also the anchor for the OSA indication (backlog D8). VALIDATOR: confirm NCT05929079 population + primary endpoint on clinicaltrials.gov.", "crossRef": "C2-RETATRUTIDE-GLY-01", "grade": "very-low", "source": { "citation": "Eli Lilly. TRIUMPH-2 master protocol of retatrutide in T2D with obesity/overweight (incl. OSA subset). ClinicalTrials.gov, confirmed 2026-06-21.", "url": "https://clinicaltrials.gov/study/NCT05929079", "identifiers": "NCT05929079", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-06", "sourceId": "NCTNCT06260722", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "n/a", "magnitude": "No results. Primary endpoint: change in HbA1c to wk80. Two reta doses vs semaglutide. Enrolment ~1250; open-label; status active, not recruiting; estimated primary completion August 2026.", "finding": "REGISTRY (no results): NCT06260722 is TRANSCEND-T2D-2, a phase-3 OPEN-LABEL trial of once-weekly retatrutide versus once-weekly semaglutide in adults with T2D inadequately controlled on metformin +/- an SGLT2 inhibitor, with an HbA1c primary endpoint. This is the within-class HEAD-TO-HEAD that will, for the first time, pit the triple agonist directly against the leading GLP-1 monoagonist on glycaemia - until it reports, every reta-vs-sema glycaemic comparison is cross-trial only.", "population": "TRANSCEND-T2D-2 (NCT06260722): adults with T2D, HbA1c 7.0-10.5%, on stable metformin +/- SGLT2i, BMI >=25; retatrutide (2 doses) vs semaglutide; phase-3 open-label.", "comparators": "semaglutide", "endpointType": "surrogate/biomarker", "notes": "Registered per the D3 remit; official name TRANSCEND-T2D-2 (the backlog did not give the name). The key future head-to-head for D3's comparative question. Open-label (not double-blind). Promissory note (very-low). VALIDATOR: confirm NCT06260722 is the reta-vs-sema T2D trial with an HbA1c primary.", "crossRef": "C2-RETATRUTIDE-GLY-03; C2-RETATRUTIDE-GLY-07", "grade": "very-low", "source": { "citation": "Eli Lilly. TRANSCEND-T2D-2: retatrutide vs semaglutide in T2D inadequately controlled on metformin +/- SGLT2i. ClinicalTrials.gov, confirmed 2026-06-21.", "url": "https://clinicaltrials.gov/study/NCT06260722", "identifiers": "NCT06260722", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "open-label (unblinded)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-GLY-07", "sourceId": "NCTNCT06297603", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "n/a", "magnitude": "No results. Primary endpoint: change in HbA1c to wk52. Three reta doses vs placebo. Enrolment ~320; double-blind; status active, not recruiting; estimated primary completion October 2026.", "finding": "REGISTRY (no results): NCT06297603 is TRANSCEND-T2D-3, a phase-3 double-blind trial of once-weekly retatrutide versus placebo in adults with T2D AND moderate-to-severe renal impairment, inadequately controlled on basal insulin (+/- metformin and/or SGLT2i), with an HbA1c primary. It IS a reta-vs-placebo T2D trial, but in a renal-impairment, basal-insulin-background subgroup - NOT the generic T2D-vs-placebo cohort the backlog implied.", "population": "TRANSCEND-T2D-3 (NCT06297603): adults with T2D, HbA1c 7.0-10.5%, moderate-to-severe renal impairment, on stable basal insulin +/- metformin and/or SGLT2i; retatrutide (3 doses) vs placebo; phase-3 double-blind.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Registered per the D3 remit; BRIEF CORRECTED - this is a renal-impairment / basal-insulin population (TRANSCEND-T2D-3), the closest of the registered set to an insulin-background / insulin-sparing context, though no insulin-reduction endpoint is stated. Also relevant to the renal effect-domain. Promissory note (very-low). VALIDATOR: confirm NCT06297603 population (renal impairment + basal insulin) and HbA1c primary.", "crossRef": "C2-RETATRUTIDE-GLY-06", "grade": "very-low", "source": { "citation": "Eli Lilly. TRANSCEND-T2D-3: retatrutide vs placebo in T2D with renal impairment on basal insulin. ClinicalTrials.gov, confirmed 2026-06-21.", "url": "https://clinicaltrials.gov/study/NCT06297603", "identifiers": "NCT06297603", "date": "2026-06-21", "design": "trial registry (ongoing/no-data)", "maturity": "registry-result", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-INS-01", "sourceId": "PMID38858523", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "decrease", "magnitude": "insulin-resistance biomarkers (fasting insulin, C-peptide, HOMA2-IR) down up to ~50%+ from baseline", "finding": "Higher retatrutide doses reduced biomarkers of insulin resistance (fasting insulin, fasting C-peptide and HOMA2-IR) by up to 50% or more from baseline — a combination and weight-mediated effect not isolable per receptor.", "population": "MASLD substudy of phase 2 obesity trial (NCT04881760)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor (Lilly); COI-flag. Reused from corpus L2-022. Combination + weight-mediated; per-receptor split not isolable (caveat C6). PMC11271400.", "crossRef": "L2-022", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-INS-02", "sourceId": "PMID40563436", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "decrease", "magnitude": "fasting glucagon fell at 4.5/6 mg (24 h to day 15); fasting glucose ~ placebo", "finding": "In phase 1, fasting glucagon decreased under retatrutide from 24 h to day 15 at 4.5/6 mg, while fasting-glucose changes were similar to placebo — net neutrality on fasting glucose despite an engaged glucagon arm (the glucagon-offset in action at the drug level). Whether the glucagon fall reflects GLP-1R glucagonostasis, weight loss, improved glycaemia, or direct islet effects is unresolved.", "population": "Phase 1 SAD, humans", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DOWN-WEIGHT: review restatement (PMC12190491) of the Coskun phase 1 primary, not the primary itself — maturity=review; the underlying phase-1 primary numbers not independently fetched by this collector (FLAG). Reused from corpus L2-021/L2-026. Combination-only.", "crossRef": "L2-021", "grade": "low", "source": { "citation": "Coskun T et al. phase 1 SAD, as restated in Biomolecules 2025 review (PMC12190491)", "url": "https://doi.org/10.3390/biom15060801", "identifiers": "PMID:40563436", "date": "2025-06-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "review", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-INS-03", "sourceId": "PMID42135195", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triagonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "decrease", "magnitude": "clamp/EGP tracer: not measured (null search result); IR-metabolite signature shifts favourably (qualitative); FAO cluster mediated 23.2% of weight response (12.7% in T2D)", "finding": "No study indexed under these search terms as of 2026 has performed a hyperinsulinaemic-euglycaemic clamp or stable-isotope endogenous-glucose-production tracer study under retatrutide; the drug-level decomposition of net glycaemic benefit into insulin secretion, glucagon suppression and hepatic-clearance-driven insulin sensitivity remains unmeasured directly. A post-hoc metabolomic analysis of both phase 2 trials found retatrutide shifted an insulin-resistance metabolite signature (BCAAs, 2-aminoadipic acid, 2-hydroxybutyrate, urate, short-chain/saturated triglycerides) toward improved metabolic health.", "population": "Humans; PubMed null + post-hoc metabolomics (obesity n=282, T2D n=213)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-001/T3-002/T3-017/T3-018. The clamp/EGP NULL is bounded to 'no study indexed under these search terms as of 2026'. Metabolomics is a non-flux constraint (NOT a clamp M-value or EGP tracer), confounded with weight loss. All-Lilly + one Duke (Newgard) authorship — COI-flag.", "crossRef": "T3-001", "grade": "moderate", "source": { "citation": "Pearson SM et al., J Clin Endocrinol Metab 2026 (metabolomics); PubMed null result 2026 (clamp/tracer)", "url": "https://doi.org/10.1210/clinem/dgag201", "identifiers": "PMID:42135195", "date": "2026-05-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "post-hoc (not prespecified); small sample (N~282)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-INS-04", "sourceId": "PMID37385280", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GLP-1/GIP/glucagon triple agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "n/a", "magnitude": "n/a - not measured. No HOMA-B, fasting/stimulated C-peptide, proinsulin:insulin ratio, disposition index or clamp insulin secretion rate reported in the reta T2D phase-2; a targeted PubMed search returned zero indexed reta beta-cell-secretion studies.", "finding": "RETATRUTIDE BETA-CELL GAP (the absence is the finding): the reta phase-2 T2D trial reported HbA1c, fasting glucose, weight and tolerability but NO beta-cell-FUNCTION readout, and no other indexed study reports one. Retatrutide's only insulin-axis numbers are insulin-RESISTANCE biomarkers (HOMA2-IR, fasting insulin/C-peptide as IR surrogates) from the obesity/MASLD substudies, NOT secretion/function. Whether retatrutide improves beta-cell function is therefore UNKNOWN, not negative - a notable gap given tirzepatide and semaglutide both have direct human beta-cell-FUNCTION (secretion/clamp/HOMA) data. TRIPLE JEOPARDY (Council Red-team): reta's beta-cell story is the LEAST-evidenced (zero function data) AND the MOST weight-confounded (largest weight loss in class) of any agent here, plus it uniquely adds a glucagon arm - so even a future positive reta beta-cell signal could not be read as a direct beta-cell effect.", "population": "Reta phase-2 T2D (Rosenstock, Lancet 2023, NCT04867785), N=281; plus a null PubMed search for reta beta-cell secretion/function as of 2026.", "comparators": "placebo; dulaglutide 1.5 mg", "endpointType": "surrogate/biomarker", "notes": "Deepens C2-RETATRUTIDE-INS-03 (which bounded the absence of a reta clamp/EGP tracer) by extending the absence specifically to beta-cell SECRETION/FUNCTION markers in the dedicated T2D trial. The robustness grade rates the trial, not the gap. Contrast tirzepatide (C2-TIRZEPATIDE-INS-01..04) and semaglutide (C2-SEMAGLUTIDE-INS-01), which DO have human beta-cell-function data.", "crossRef": "C2-RETATRUTIDE-INS-03; C2-CLASS-INS-01", "grade": "moderate", "source": { "citation": "Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023", "url": "https://doi.org/10.1016/S0140-6736(23)01053-X", "identifiers": "PMID 37385280; DOI 10.1016/S0140-6736(23)01053-X; NCT04867785", "date": "2023-06-26", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-RETATRUTIDE-MASH-01", "sourceId": "PMID38858523", "drug": "retatrutide", "drugRoot": "retatrutide", "drugSlug": "retatrutide", "drugLabel": "Retatrutide", "drugClass": "GIP/GLP-1/glucagon triple agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Phase-2a MASLD substudy, mean relative liver-fat (MRI-PDFF) change at 24 wk: -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) vs +0.3% placebo (all P<0.001). Normal liver fat (<5%) reached by 27/52/79/86% (1/4/8/12 mg) vs 0% placebo.", "finding": "In the published phase-2a MASLD substudy of the reta obesity phase-2 trial, retatrutide produced large dose-dependent MRI-PDFF liver-fat reductions at 24 wk with a high proportion reaching normal liver fat. CRITICAL SCOPE LIMIT: the endpoint was liver FAT (steatosis) by MRI-PDFF, an IMAGING SURROGATE; the substudy included NO liver biopsy and assessed NEITHER MASH resolution NOR fibrosis. Reta therefore has NO histological MASH or fibrosis outcome data.", "population": "n=98 adults with obesity, MASLD and >=10% liver fat (substudy of the 48-wk obesity phase-2); double-blind placebo-controlled; reta 1/4/8/12 mg vs placebo; primary at 24 wk.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DEEPENS the reta MASLD topline (this id) with published detail + the explicit surrogate caveat. Reta's ONLY liver evidence is imaging steatosis; it has NO histological MASH-resolution or fibrosis data, so reta must NEVER be implied to have MASH/fibrosis OUTCOMES. The paper reports LF reductions were significantly related to weight and abdominal-fat loss, leaving the weight-mediated-vs-direct-hepatic (glucagon-arm) question unresolved for outcomes (OQ-F-K / Thread 8).", "crossRef": "C-RETATRUTIDE-LANDSCAPE-03; C-RETATRUTIDE-MASH-TRIAL-GAP; C-CLASS-MASH-SURROGATE-GAP; C-CLASS-MASH-WEIGHT-MEDIATION-OUTCOMES", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048.", "url": "https://doi.org/10.1038/s41591-024-03018-2", "identifiers": "PMID:38858523 / DOI:10.1038/s41591-024-03018-2 / NCT04881760", "date": "2024-06-10", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "small sample (N~98); prespecified/exploratory secondary of RCT (substudy)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-APP-01", "sourceId": "PMID33269530", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "ad libitum energy intake -35% vs placebo (ETD -940 kJ; 1736 vs 2676 kJ; P<0.0001); gastric emptying P=0.12 (no delay)", "finding": "Once-weekly semaglutide 2.4 mg reduced ad libitum energy intake at an unrestricted lunch by 35% vs placebo at week 20; also reduced hunger and prospective food consumption, increased fullness/satiety, and improved Control of Eating with fewer/weaker cravings. The same study found NO delayed gastric emptying at week 20 (paracetamol AUC0-5h +8%, NS once body-weight corrected, P=0.12), attributing the intake drop to central appetite suppression rather than gastric slowing.", "population": "Adults with obesity; randomised placebo-controlled, week 20", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-authored (Novo Nordisk); COI-flag. Reused from corpus T9-GLP1R-01 (validated 2026-06-20). Central-vs-peripheral mechanism: intake reduction without persistent gastric-emptying delay.", "crossRef": "T9-GLP1R-01", "grade": "moderate", "source": { "citation": "Friedrichsen M et al., Diabetes Obes Metab 2021;23(3):754-762", "url": "https://doi.org/10.1111/dom.14280", "identifiers": "PMID:33269530", "date": "2021-03-01", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-APP-02", "sourceId": "PMID28266779", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "total daily ad libitum energy intake -24% vs placebo (-3036 kJ; P<0.0001)", "finding": "Once-weekly semaglutide (escalated to 1.0 mg, 12 wk) reduced total ad libitum energy intake across all meals by 24% vs placebo, with less hunger and fewer food cravings, better control of eating, and a lower preference for high-fat/energy-dense foods; resting metabolic rate adjusted for lean mass did not differ (i.e. weight loss is intake-driven, not expenditure-driven).", "population": "Subjects with obesity, n=30 crossover, 12 weeks", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-authored (Novo Nordisk); COI-flag. Reused from corpus T9-GLP1R-02. Adds the food-preference/craving dimension.", "crossRef": "T9-GLP1R-02", "grade": "moderate", "source": { "citation": "Blundell J et al., Diabetes Obes Metab 2017;19(9):1242-1251", "url": "https://doi.org/10.1111/dom.12932", "identifiers": "PMID:28266779", "date": "2017-09-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "small sample (N~30)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-APP-03", "sourceId": "PMID33184979", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "total ad libitum energy intake -38.9% vs placebo (ETD -5096 kJ; 95% CI -7000,-3192; P=0.0001)", "finding": "Oral semaglutide (escalated to 14 mg, 12 wk) reduced total daily ad libitum energy intake by 38.9% vs placebo in type 2 diabetes, with increased satiety/fullness after a fat-rich breakfast, fewer cravings and better eating control.", "population": "Subjects with T2D, n=15 (13 evaluable), crossover, 12 weeks", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-authored; COI-flag. Reused from corpus T9-GLP1R-03 (NCT02773381). Second route (oral) and population (T2D) replicating central intake suppression.", "crossRef": "T9-GLP1R-03", "grade": "moderate", "source": { "citation": "Gibbons C et al., Diabetes Obes Metab 2021;23(2):581-588", "url": "https://doi.org/10.1111/dom.14255", "identifiers": "PMID:33184979", "date": "2021-02-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "small sample (N~15)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-APP-04", "sourceId": "PMID39082206", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "ad libitum energy intake -39.2 percentage points vs placebo (95% CI -59.0,-19.4); gastric emptying NS", "finding": "Once-daily oral semaglutide 50 mg (20 wk) reduced ad libitum energy intake by 39.2 percentage points vs placebo in adults with obesity, with reduced hunger, increased fullness/satiety, fewer cravings and better control of eating, and no statistically significant difference in gastric emptying at week 20.", "population": "Adults with obesity, 20 weeks", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Sponsor-authored; COI-flag. Reused from corpus T9-GLP1R-04. Reinforces central (not gastric) mechanism at steady state.", "crossRef": "T9-GLP1R-04", "grade": "moderate", "source": { "citation": "Gabe MBN et al., Diabetes Obes Metab 2024;26(10):4480-4489", "url": "https://doi.org/10.1111/dom.15802", "identifiers": "PMID:39082206", "date": "2024-10-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - Novo Nordisk (with Steno Diabetes Center Copenhagen)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-INS-01", "sourceId": "PMID28526920", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "IVGTT insulin AUC first-phase estimated treatment ratio 3.02 (95% CI 2.53,3.60) and second-phase 2.10 (1.86,2.37) vs placebo (P<0.0001); 24-h glucose & glucagon reduced (P<0.0001)", "finding": "Twelve weeks of once-weekly semaglutide 1.0 mg significantly improved beta-cell function and glycaemic control in T2D: both first- and second-phase insulin secretion (IVGTT) increased markedly; the arginine stimulation test showed increased maximal insulin capacity; a graded glucose infusion test restored insulin secretion rate to levels similar to healthy participants; and a 24-h meal test showed reduced fasting/postprandial/overall glucose AND glucagon responses.", "population": "Adults with T2D, n=75 (37 sema / 38 placebo), 12 weeks (NCT02212067)", "comparators": "placebo; untreated healthy reference (GGIT)", "endpointType": "surrogate/biomarker", "notes": "Sponsor (Novo Nordisk); COI-flag. Newly added (not in corpus). The canonical pure-GLP-1R human beta-cell-function/insulin-secretion isolation, incl. glucagon suppression on the 24-h meal test. PMC5491562 (open).", "crossRef": "", "grade": "low", "source": { "citation": "Kapitza C, Dahl K, Jacobsen JB, Axelsen MB, Flint A, Diabetologia 2017;60(8):1390-1399", "url": "https://doi.org/10.1007/s00125-017-4289-0", "identifiers": "PMID:28526920", "date": "2017-05-19", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor; inferred from registration trial)", "scopeLimits": "small sample (N~75)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-MASH-01", "sourceId": "PMID40305708", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist (mono-agonist)", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "ESSENCE phase-3, wk72 part-1 interim (first 800 of 1197), semaglutide 2.4 mg vs placebo, BOTH co-primaries: (1) RESOLUTION of steatohepatitis without worsening fibrosis 62.9% vs 34.3% (diff 28.7 pp, 95% CI 21.1-36.2, P<0.001); (2) >=1-stage FIBROSIS IMPROVEMENT without worsening MASH 36.8% vs 22.4% (diff 14.4 pp, 95% CI 7.5-21.3, P<0.001). Key secondary (both) 32.7% vs 16.1%. Weight -10.5% vs -2.0%.", "finding": "In ESSENCE (the landmark phase-3 registrational MASH trial), once-weekly s.c. semaglutide 2.4 mg met BOTH distinct co-primary histological endpoints at week 72 vs placebo: it roughly doubled MASH resolution (62.9% vs 34.3%) AND improved fibrosis by >=1 stage (36.8% vs 22.4%). These are two SEPARATE endpoints, reported separately. Both are histological SURROGATES supporting FDA accelerated (subpart H) approval; the hard clinical-outcome part (part 2, ~240 wk) has not yet read out and is UNPROVEN.", "population": "ESSENCE (NCT04822181), phase 3 double-blind placebo-controlled. Part-1 interim of first 800 (semaglutide 534, placebo 266, 2:1). Biopsy MASH fibrosis F2 (31%) or F3 (69%); F0/F1 and F4/CIRRHOSIS EXCLUDED. 55.5% T2D. 72 wk (full trial 240 wk).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DEEPENS the prior ESSENCE topline (this id) to PUBLISHED registrational detail. DISCIPLINE: resolution (62.9 vs 34.3) and fibrosis improvement (36.8 vs 22.4) are SEPARATE endpoints - never conflate. All endpoints SURROGATES; no hard liver-outcome benefit established (part 2 ~240 wk not yet read out). Design paper (PMID 39412509) confirms F2/F3-only enrolment and the two-part surrogate-then-clinical structure. Sponsor: Novo Nordisk - flagged. Reta relevance: ESSENCE is the GLP-1-mono registrational benchmark a triple agonist must beat; reta has only dose-finding-stage liver-FAT (imaging) data (C2-RETATRUTIDE-MASH-01), no histology. ANTI-PROXIMITY FENCE: ESSENCE's 62.9%/36.8% are SEMAGLUTIDE results and must NOT be read across to retatrutide, which has NO MASH histology (liver-fat imaging only).", "crossRef": "C2-SEMAGLUTIDE-MASH-02; C2-RETATRUTIDE-MASH-01; C-INCRETIN-MASH-F4-GAP; C-CLASS-MASH-SURROGATE-GAP", "grade": "high", "source": { "citation": "Sanyal AJ, Newsome PN et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med 2025;392(21):2089-2099 (ESSENCE).", "url": "https://doi.org/10.1056/NEJMoa2413258", "identifiers": "PMID:40305708 / DOI:10.1056/NEJMoa2413258 / NCT04822181", "date": "2025-04-30", "design": "double-blind RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk", "scopeLimits": "no outcome data yet (ongoing)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SEMAGLUTIDE-MASH-02", "sourceId": "PMID33185364", "drug": "semaglutide", "drugRoot": "semaglutide", "drugSlug": "semaglutide", "drugLabel": "Semaglutide", "drugClass": "GLP-1 receptor agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "mixed", "magnitude": "NASH resolution without worsening fibrosis: 40% (0.1 mg), 36% (0.2 mg), 59% (0.4 mg) vs 17% placebo (0.4 mg vs placebo p<0.001). Fibrosis improvement ≥1 stage: 43% (0.4 mg) vs 33% placebo (p=0.48, NS). Mean weight loss 13% (0.4 mg) vs 1%.", "finding": "In the phase 2b NASH trial, semaglutide 0.4 mg/day significantly increased NASH resolution vs placebo, but did NOT significantly improve fibrosis stage (fibrosis pole negative).", "population": "320 patients (230 with F2/F3) biopsy-confirmed NASH, F1-F3; 72-week double-blind placebo-controlled phase 2 RCT; daily SC dosing", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Both poles present: resolution positive, fibrosis NOT improved (p=0.48). Imbalance in neoplasms noted (15% semaglutide vs 8% placebo). Daily formulation (vs weekly 2.4 mg in ESSENCE).", "crossRef": "C2-SEMAGLUTIDE-MASH-01", "grade": "moderate", "source": { "citation": "Newsome PN et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021;384(12):1113-1124.", "url": "https://doi.org/10.1056/NEJMoa2028395", "identifiers": "PMID:33185364 / DOI:10.1056/NEJMoa2028395 / NCT02970942", "date": "2020-11-13", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Novo Nordisk", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-BP-01", "sourceId": "DOI10.1111/DOM.16052", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "blood-pressure", "domainLabel": "Blood pressure", "domainSlug": "blood-pressure", "direction": "decrease", "magnitude": "SBP -6.2 mmHg, DBP -2.9 mmHg (placebo-corrected) at 46 wk, 4.8 mg", "finding": "Placebo-corrected reductions in systolic and diastolic BP at 4.8 mg", "population": "Adults with obesity, phase 2 post hoc analysis (n=387), 46 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "PMID not separately verified for this post hoc; DOI verified via journal", "crossRef": "", "grade": "moderate", "source": { "citation": "le Roux CW et al. Diabetes Obes Metab 2025 (post hoc, DOI 10.1111/dom.16052)", "url": "https://doi.org/10.1111/dom.16052", "identifiers": "DOI:10.1111/dom.16052", "date": "2025-01-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Novo Nordisk (trial sponsor)", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-EE-01", "sourceId": "PMID36356832", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "energy-expenditure-thermogenesis", "domainLabel": "Energy expenditure and thermogenesis", "domainSlug": "energy-expenditure-thermogenesis", "direction": "increase", "magnitude": "Greater body-weight reduction than max-dose semaglutide in mice via increased EE + reduced intake", "finding": "Weight loss driven by increased energy expenditure plus reduced food intake (preclinical)", "population": "Mouse obesity models (preclinical pharmacology)", "comparators": "semaglutide", "endpointType": "imaging/physiological surrogate", "notes": "EE mechanism preclinical; human EE not directly quantified", "crossRef": "", "grade": "very-low", "source": { "citation": "Zimmermann T et al. Mol Metab 2022;66:101633", "url": "https://doi.org/10.1016/j.molmet.2022.101633", "identifiers": "PMID:36356832", "date": "2022-11-07", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-LIP-01", "sourceId": "PMID38330987", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "lipids-lipoprotein", "domainLabel": "Lipids and lipoproteins", "domainSlug": "lipids-lipoprotein", "direction": "mixed", "magnitude": "TC/LDL/TG decreased, HDL increased (direction reported; numeric not in press summary)", "finding": "Reductions in total cholesterol, LDL-C, triglycerides; increase in HDL-C", "population": "Adults with obesity, phase 2 (n=387), 46 wk", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Magnitude unconfirmed (directional)", "crossRef": "", "grade": "moderate", "source": { "citation": "le Roux CW et al. Lancet Diabetes Endocrinol 2024;12:162-173", "url": "https://doi.org/10.1016/S2213-8587(23)00356-X", "identifiers": "PMID:38330987", "date": "2024-02-05", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Boehringer Ingelheim", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-MASH-01", "sourceId": "PMID38847460", "drug": "survodutide", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "Phase-2 wk48, primary (histologic MASH improvement without fibrosis worsening): 47% (2.4 mg), 62% (4.8 mg), 43% (6.0 mg) vs 14% placebo (P<0.001 best-fit quadratic; NON-monotonic). >=30% liver-fat reduction 63/67/57% vs 14%. Secondary >=1-stage fibrosis improvement 34/36/34% vs 22% (modest separation).", "finding": "In a 48-week phase 2 trial (biopsy MASH, fibrosis F1-F3), the GLP-1/glucagon dual survodutide was superior to placebo for histologic MASH improvement without fibrosis worsening, with a NON-monotonic (quadratic) dose-response peaking at 4.8 mg. Liver fat strongly separated; the fibrosis-improvement secondary favoured survodutide only modestly (34-36% vs 22%).", "population": "NCT04771273; N=293 dosed (survodutide 2.4/4.8/6.0 mg vs placebo); biopsy MASH fibrosis F1-F3; 48 wk (24-wk escalation then maintenance).", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DEEPENS the survodutide topline (this id) to PUBLISHED detail. SURROGATE caveat: histological surrogates, hard liver outcomes unproven. DISTINCTION: PRIMARY was MASH IMPROVEMENT without fibrosis worsening (does NOT require fibrosis improvement); the fibrosis-IMPROVEMENT signal (34-36% vs 22%) is a SEPARATE, weaker secondary - do not conflate. Non-monotonic dose-response. Sponsor Boehringer Ingelheim. Phase-3 (LIVERAGE) registered, no published results (registry-only). Reta relevance: survodutide is a GLP-1/glucagon DUAL sharing reta's glucagon arm, but reta has NO MASH histology trial - not transferable as if observed.", "crossRef": "C-SURVODUTIDE-LANDSCAPE-01; C-MULTI-MASH-GLUCAGON-FIBROSIS; C2-MULTI-MASH-02", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 2024;391(4):311-319.", "url": "https://doi.org/10.1056/NEJMoa2401755", "identifiers": "PMID:38847460 / DOI:10.1056/NEJMoa2401755 / NCT04771273", "date": "2024-06-07", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim / Zealand", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-PHARM-01", "sourceId": "PMID36356832", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "pharmacology", "domainLabel": "Pharmacology and mechanism", "domainSlug": "pharmacology", "direction": "n/a", "magnitude": "Half-life supports weekly dosing; dual target engagement shown via KO/reporter mice", "finding": "Acylated (C18) GCGR/GLP-1R dual agonist, once-weekly; engages both receptors in vivo", "population": "In-vitro + in-vivo preclinical", "comparators": "semaglutide", "endpointType": "other", "notes": "", "crossRef": "", "grade": "very-low", "source": { "citation": "Zimmermann T et al. Mol Metab 2022;66:101633", "url": "https://doi.org/10.1016/j.molmet.2022.101633", "identifiers": "PMID:36356832", "date": "2022-11-07", "design": "preclinical (rodent)", "maturity": "rodent-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-SAF-01", "sourceId": "PMID38847460", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "no-change", "magnitude": "SAEs 8% survodutide vs 7% placebo (MASH trial)", "finding": "Serious adverse events comparable to placebo; no safety signal attributed to glucagon receptor agonism", "population": "MASH phase 2 (n=293), 48 wk", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "SYNCHRONIZE phase 3 CV outcomes trial ongoing", "crossRef": "", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 2024;391(4):311-319.", "url": "https://doi.org/10.1056/NEJMoa2401755", "identifiers": "PMID:38847460 / DOI:10.1056/NEJMoa2401755 / NCT04771273", "date": "2024-06-07", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim / Zealand", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-TOLGI-01", "sourceId": "PMID38847460", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "Nausea 66% vs 23%, diarrhoea 49% vs 23%, vomiting 41% vs 4% (MASH trial); GI AEs in 75% (obesity trial)", "finding": "GI events dominant; higher than placebo", "population": "MASH (n=293) and obesity (n=387) phase 2 trials", "comparators": "placebo", "endpointType": "other", "notes": "Rapid dose escalation in MASH trial may drive higher GI rates", "crossRef": "", "grade": "moderate", "source": { "citation": "Sanyal AJ et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 2024;391(4):311-319.", "url": "https://doi.org/10.1056/NEJMoa2401755", "identifiers": "PMID:38847460 / DOI:10.1056/NEJMoa2401755 / NCT04771273", "date": "2024-06-07", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Boehringer Ingelheim / Zealand", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-SURVODUTIDE-WL-01", "sourceId": "PMID38330987", "drug": "survodutide (BI 456906)", "drugRoot": "survodutide", "drugSlug": "survodutide", "drugLabel": "Survodutide", "drugClass": "GLP-1/glucagon dual agonist", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "weight -14.9% vs placebo -2.8%", "finding": "Dose-dependent weight loss vs placebo over 46 weeks in obesity without diabetes", "population": "Adults BMI ≥27 without diabetes (n=387), phase 2 dose-finding, 46 wk, RCT double-blind, placebo-controlled (NCT04667377)", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "Weight loss not plateaued at 46 wk; 60% completion", "crossRef": "", "grade": "moderate", "source": { "citation": "le Roux CW et al. Lancet Diabetes Endocrinol 2024;12:162-173", "url": "https://doi.org/10.1016/S2213-8587(23)00356-X", "identifiers": "PMID:38330987", "date": "2024-02-05", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry-Boehringer Ingelheim", "scopeLimits": "identifier not fully verified", "pressSourced": false }, "flags": { "investigational": true, "pressSourced": false } }, { "id": "C2-TERN601-SAFE-02", "sourceId": "CIT:terns-pharmaceuticals-press-release-21-oct-2025", "drug": "TERN-601", "drugRoot": "TERN-601", "drugSlug": "tern-601", "drugLabel": "TERN-601", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "safety-other", "domainLabel": "Safety signals", "domainSlug": "safety-other", "direction": "increase", "magnitude": "Asymptomatic, reversible grade-3 transaminase elevations in 3 participants during post-treatment follow-up; 2 deemed drug-related", "finding": "Reversible grade-3 liver enzyme elevations in the phase 2 follow-up period.", "population": "FALCON phase 2 (obesity/overweight); post-treatment follow-up", "comparators": "placebo", "endpointType": "safety-event/signal", "notes": "Adds TERN-601 to the oral small-molecule GLP-1 hepatic-signal pattern (alongside Pfizer's lotiglipron/danuglipron); recorded neutrally — events asymptomatic and reversible. Press-sourced; identifiers unverified.", "crossRef": "C2-DANU-SAFE-03", "grade": "very-low", "source": { "citation": "Terns Pharmaceuticals press release, 21 Oct 2025.", "url": "https://www.globenewswire.com/news-release/2025/10/21/3170632/0/en/Terns-Pharmaceuticals-Reports-Topline-12-week-Data-from-its-Phase-2-Trial-Evaluating-Oral-GLP-1-Receptor-Agonist-TERN-601-in-Obesity.html", "identifiers": "identifier unverified", "date": "2025-10-21", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Terns (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; small sample (N~30)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-TERN601-TOLGI-03", "sourceId": "CIT:terns-pharmaceuticals-press-release-21-oct-2025", "drug": "TERN-601", "drugRoot": "TERN-601", "drugSlug": "tern-601", "drugLabel": "TERN-601", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "tolerability-gi", "domainLabel": "Gastrointestinal tolerability", "domainSlug": "tolerability-gi", "direction": "increase", "magnitude": "12% discontinuation due to adverse events (phase 2, 12 wk)", "finding": "AE-related discontinuation in phase 2 higher than the favourable phase 1 profile suggested.", "population": "FALCON phase 2 (n=30 per active cohort + placebo)", "comparators": "placebo", "endpointType": "other", "notes": "Phase 1 (28-day) had reported no treatment-related discontinuations; phase 2 12% — recorded as reported. Press-sourced.", "crossRef": "", "grade": "very-low", "source": { "citation": "Terns Pharmaceuticals press release, 21 Oct 2025.", "url": "https://www.globenewswire.com/news-release/2025/10/21/3170632/0/en/Terns-Pharmaceuticals-Reports-Topline-12-week-Data-from-its-Phase-2-Trial-Evaluating-Oral-GLP-1-Receptor-Agonist-TERN-601-in-Obesity.html", "identifiers": "identifier unverified", "date": "2025-10-21", "design": "phase-2 RCT", "maturity": "press", "funding": "industry - Terns (trial sponsor; inferred from registration trial)", "scopeLimits": "identifier not fully verified; small sample (N~30)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-TERN601-WL-01", "sourceId": "CIT:terns-pharmaceuticals-press-release-topline-12-w", "drug": "TERN-601", "drugRoot": "TERN-601", "drugSlug": "tern-601", "drugLabel": "TERN-601", "drugClass": "Oral small-molecule GLP-1 receptor agonist (once-daily)", "domain": "weight-loss", "domainLabel": "Weight change", "domainSlug": "weight-loss", "direction": "decrease", "magnitude": "Maximum placebo-adjusted weight loss 4.6% at 12 wk (across 250/500/500-slow/750 mg arms)", "finding": "FALCON phase 2 (12-week topline): modest placebo-adjusted weight loss; program subsequently discontinued.", "population": "FALCON phase 2 RCT, US multicentre, adults with obesity/overweight without diabetes; n=30 per active cohort + placebo; 12-wk topline", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DISCONTINUED: Terns announced it will not advance TERN-601 or invest further in metabolic assets (refocusing on TERN-701 for CML). Phase 1 (ADA 2025) had shown up to 5.5% (4.9% placebo-adjusted) over 28 days. Press-sourced; identifiers unverified.", "crossRef": "", "grade": "very-low", "source": { "citation": "Terns Pharmaceuticals press release: Topline 12-week data from Phase 2 trial of oral GLP-1R agonist TERN-601 in obesity, 21 Oct 2025.", "url": "https://www.globenewswire.com/news-release/2025/10/21/3170632/0/en/Terns-Pharmaceuticals-Reports-Topline-12-week-Data-from-its-Phase-2-Trial-Evaluating-Oral-GLP-1-Receptor-Agonist-TERN-601-in-Obesity.html", "identifiers": "identifier unverified", "date": "2025-10-21", "design": "observational cohort", "maturity": "press", "funding": "industry - Terns", "scopeLimits": "identifier not fully verified; small sample (N~30)", "pressSourced": true }, "flags": { "investigational": false, "pressSourced": true } }, { "id": "C2-TIRZEPATIDE-APP-01", "sourceId": "PMID40203836", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "decrease", "magnitude": "reduced ad-libitum test-meal calorie intake vs placebo (effect size in full text)", "finding": "In a phase 1 mechanism-of-action trial in people with obesity (NCT04081337), tirzepatide reduced appetite and reduced calorie intake during an ad-libitum test meal vs placebo, with increased fat oxidation and no impact on metabolic adaptation; energy expenditure was not increased. This is direct measured intake (unlike the retatrutide VAS-only data).", "population": "People with obesity, phase 1 MoA trial", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "COI-flag (Lilly co-authorship). Attribution open between GIP and GLP-1; no read on GCGR arm. Reused from corpus T9-PX-01 (DOI to be confirmed against full text). MAGNITUDE FLAG: exact intake effect size not confirmed against full text by this collector.", "crossRef": "T9-PX-01", "grade": "low", "source": { "citation": "Ravussin E, Sanchez-Delgado G, Martin CK, et al. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation. Cell Metab. 2025;37(5):1060-1074.e4", "url": "https://doi.org/10.1016/j.cmet.2025.03.011", "identifiers": "PMID 40203836; DOI 10.1016/j.cmet.2025.03.011; NCT04081337", "date": "2025-04-08", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor; inferred from registration trial)", "scopeLimits": "animal data; human relevance uncertain", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-APP-02", "sourceId": "PMID36857477", "drug": "tirzepatide vs semaglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual agonist vs GLP-1R agonist", "domain": "appetite-intake", "domainLabel": "Appetite and food intake", "domainSlug": "appetite-intake", "direction": "no-change", "magnitude": "lunch ad libitum intake difference insufficient to explain the fat-mass differential; broader intake unmeasured", "finding": "Tirzepatide 15 mg gave greater fat-mass loss than semaglutide 1 mg in T2D, but the difference was NOT explained by ad libitum lunch energy intake, and 24-h intake / substrate utilisation / energy expenditure were not measured. No clean human tirzepatide-vs-semaglutide appetite/satiety differential isolating a GIP appetite contribution was located.", "population": "T2D, tirzepatide 15 mg vs semaglutide 1 mg", "comparators": "semaglutide", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T9-GIPR-06. Measured-null on the single acute intake readout; broader endpoints unmeasured. The within-molecule GIP appetite contribution in humans is proxy-only/unresolved.", "crossRef": "T9-GIPR-06", "grade": "moderate", "source": { "citation": "Heise T et al., Diabetes Care 2023;46(5):998-1004", "url": "https://doi.org/10.2337/dc22-1710", "identifiers": "PMID:36857477", "date": "2023-05-01", "design": "RCT (design unspecified)", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-GLY-01", "sourceId": "PMID34170647", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 receptor dual agonist", "domain": "glycaemic", "domainLabel": "Glycaemic control", "domainSlug": "glycaemic", "direction": "decrease", "magnitude": "HbA1c change -2.30% vs semaglutide -1.86%", "finding": "In SURPASS-2, all three tirzepatide doses were non-inferior and superior to semaglutide 1 mg for HbA1c reduction from baseline at 40 weeks (head-to-head).", "population": "1879 adults with T2D on metformin; mean age 56.6 y, mean weight 93.7 kg; 40-week open-label phase 3 RCT; comparator semaglutide 1 mg SC once weekly", "comparators": "semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "Definitive head-to-head HbA1c difference. Open-label design (not double-blind). Semaglutide capped at 1 mg (max approved T2D dose at the time was 1 mg; 2 mg approved later), which some commentators flag as limiting the comparison ceiling.", "crossRef": "", "grade": "moderate", "source": { "citation": "Frias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2)", "url": "https://doi.org/10.1056/NEJMoa2107519", "identifiers": "PMID 34170647; DOI 10.1056/NEJMoa2107519; NCT03987919", "date": "2021-06-25", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry-Eli Lilly", "scopeLimits": "open-label (unblinded); post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-INS-01", "sourceId": "PMID35468322", "drug": "tirzepatide vs semaglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual agonist vs GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "disposition index +1.9 from 0.3 baseline; ETD vs sema +0.84 pmol/mL/min/kg; tirz-minus-sema ISR ETD ~102 pmol/min/m2, M-value ETD ~1.52 mg/min/kg", "finding": "In a 28-week randomised phase 1 clamp trial, tirzepatide improved the clamp disposition index more than placebo and more than semaglutide, reflecting greater total insulin secretion rate and greater clamp insulin sensitivity (M-value), with greater glucagon lowering. The tirzepatide-minus-semaglutide differential isolates a human GIP increment on insulin secretion and sensitivity.", "population": "Humans (T2D), 28-week randomised phase 1 clamp", "comparators": "placebo; semaglutide", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-003/T3-004. Drug-level decomposition is combination-only; the human tirz-minus-sema differential is the permitted GIP isolation (caveat C1 not triggered — human, not mouse). No glucagon-agonist arm, so does not model retatrutide's GCGR offset.", "crossRef": "T3-003", "grade": "low", "source": { "citation": "Heise T et al., Lancet Diabetes Endocrinol 2022;10(6):418-429", "url": "https://doi.org/10.1016/S2213-8587(22)00085-7", "identifiers": "PMID:35468322", "date": "2022-06-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "not-stated", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-INS-02", "sourceId": "PMID40694059", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "GIR 3.21 to 5.16 mg/min/kg (+1.95; p<0.001); glucagon 28.8 to 20.8 pg/ml (-8.0); post-hoc: greater M-value gain per kg lost vs sema (slope diff p=0.0461)", "finding": "In a single-arm 12-week clamp study (obese T2D, tirzepatide up to 5 mg) the glucose infusion rate rose and glucagon fell, with no significant correlation between GIR change and weight change, indicating early insulin sensitisation not solely attributable to weight loss. A separate post-hoc analysis found a greater M-value improvement per unit weight loss for tirzepatide than semaglutide.", "population": "Obese T2D, single-arm n=16, 12 weeks (Yamaguchi); 28-wk post-hoc (Mather)", "comparators": "none (single-arm); semaglutide (post-hoc)", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T3-005 (+ T3-006, Mather PMID:39762971, DOI 10.1111/dom.16159). Combination-only. Supports sensitivity gain beyond weight; single-arm, low dose, no comparator (Yamaguchi).", "crossRef": "T3-005", "grade": "low", "source": { "citation": "Yamaguchi S et al., Diabetologia 2025; Mather KJ et al., Diabetes Obes Metab 2025", "url": "https://doi.org/10.1007/s00125-025-06493-5", "identifiers": "PMID:40694059", "date": "2025-07-01", "design": "early-phase RCT (phase 1/1b-2a)", "maturity": "human-primary", "funding": "academic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)", "scopeLimits": "post-hoc (not prespecified); small sample (N~16)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-INS-03", "sourceId": "PMID38252888", "drug": "tirzepatide vs semaglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual agonist vs GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "mixed", "magnitude": "HOMA2-B ETD (tirz-sema) +7.0%/+15.0%/+19.8% (5/10/15 mg); HOMA2-IR ETD -11.0%/-15.2%/-19.9%; fasting insulin ETD -9.5/-15.1/-21.4%; fasting glucagon ETD -1.9%(NS)/-10.0%/-14.5%; FSG ETD -7.3/-13.0/-14.7 mg/dL", "finding": "SURPASS-2 biomarker substudy (week 40): the tirzepatide-minus-semaglutide differential isolates a GIP-attributable islet increment — greater beta-cell function (HOMA2-B), greater insulin-sensitisation (HOMA2-IR / fasting insulin), and greater fasting-glucagon suppression at higher doses.", "population": "T2D, SURPASS-2 substudy, week 40 (tirz 5/10/15 mg vs sema 1 mg)", "comparators": "semaglutide 1 mg", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T11-S2-08/09/10/03. CONFOUNDS (flagged, not resolved): (a) GIP-or-different-GLP-1 (sema dosed 1 mg not 2.4 mg); (b) the larger HOMA2-IR/insulin improvement is substantially WEIGHT-confounded (tirzepatide lost more weight); (c) greater glucagon suppression is mechanistically counter-intuitive for GIP (GIP is glucagonotropic at fasting), so likely GLP-1-led or downstream of greater glycaemia/weight. HOMA2-B is the axis where GIP attribution is most coherent. COI (sponsor framing).", "crossRef": "T11-S2-09", "grade": "moderate", "source": { "citation": "Frias JP et al., J Clin Endocrinol Metab 2024;109(7):1745-1753", "url": "https://doi.org/10.1210/clinem/dgae038", "identifiers": "PMID:38252888", "date": "2024-06-01", "design": "prespecified/exploratory secondary of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-INS-04", "sourceId": "PMID42002673", "drug": "tirzepatide vs semaglutide", "drugRoot": "tirzepatide|semaglutide (head-to-head)", "drugSlug": "tirzepatide-semaglutide-head-to-head", "drugLabel": "Tirzepatide|semaglutide (head-to-head)", "drugClass": "GIP/GLP-1 dual agonist vs GLP-1R agonist", "domain": "insulin-beta-cell", "domainLabel": "Insulin and beta-cell function", "domainSlug": "insulin-beta-cell", "direction": "increase", "magnitude": "HbA1c ETD -0.12% (95% CI -0.18,-0.06; P<0.001); normoglycaemia 89.9% vs 76.2%; weight ETD -7.1%", "finding": "SURMOUNT-5 prediabetes subgroup (post-hoc, n=425): tirzepatide produced greater HbA1c reduction, higher reversion to normoglycaemia, and greater improvements in fasting insulin and HOMA2-IR than semaglutide, alongside greater weight loss.", "population": "Obesity + prediabetes subgroup, post-hoc, n=425", "comparators": "semaglutide", "endpointType": "surrogate/biomarker", "notes": "Reused from corpus T11-S5-06. CONFOUND: insulin-sensitivity gain not separable from greater weight loss (ETD -7.1%) or a different GLP-1 moiety. Post-hoc subgroup, Lilly-co-authored — down-weight.", "crossRef": "T11-S5-06", "grade": "moderate", "source": { "citation": "Galindo RJ, Aronne LJ, Horn DB et al., J Endocrinol Invest 2026", "url": "https://doi.org/10.1007/s40618-026-02895-3", "identifiers": "PMID:42002673", "date": "2026-01-01", "design": "post-hoc analysis of RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly (trial sponsor)", "scopeLimits": "post-hoc (not prespecified)", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } }, { "id": "C2-TIRZEPATIDE-MASH-01", "sourceId": "PMID38856224", "drug": "tirzepatide", "drugRoot": "tirzepatide", "drugSlug": "tirzepatide", "drugLabel": "Tirzepatide", "drugClass": "GIP/GLP-1 dual agonist", "domain": "hepatic-mash", "domainLabel": "hepatic-mash", "domainSlug": "hepatic-mash", "direction": "decrease", "magnitude": "SYNERGY-NASH phase-2 wk52, primary (MASH resolution without fibrosis worsening): 44% (5 mg; diff 34 pp, 95% CI 17-50), 56% (10 mg; diff 46 pp, 29-62), 62% (15 mg; diff 53 pp, 37-69) vs 10% placebo (P<0.001). Key secondary (>=1-stage fibrosis improvement without MASH worsening): 55/51/51% vs 30% (lower CI bounds ~1 pp; NO monotonic dose-response).", "finding": "In SYNERGY-NASH (phase 2, F2-F3), the GIP/GLP-1 dual tirzepatide was superior to placebo for MASH resolution without fibrosis worsening at 52 wk across all doses. The fibrosis-improvement key-secondary was numerically higher than placebo but with WIDE CIs (lower bounds near 1 pp) and no clear dose-response.", "population": "NCT04166773 (SYNERGY-NASH); N=190 randomised, 157 evaluable wk-52 biopsy (imputation); biopsy MASH fibrosis F2/F3; tirzepatide 5/10/15 mg vs placebo; 52 wk.", "comparators": "placebo", "endpointType": "surrogate/biomarker", "notes": "DEEPENS the SYNERGY-NASH topline (this id) to PUBLISHED detail. SURROGATE caveat. DISTINCTION: PRIMARY MASH RESOLUTION was robust (CIs far from 0); the fibrosis-IMPROVEMENT key-secondary is fragile (lower CIs ~1 pp, no dose-response) - never conflate. ~17% biopsies imputed. Sponsor Eli Lilly. Reta relevance: tirzepatide is GIP/GLP-1 (NO glucagon arm) - informative for the GIP contribution but does NOT isolate glucagon; reta (triple) has no MASH histology trial.", "crossRef": "C-MULTI-MASH-GLUCAGON-FIBROSIS; C2-MULTI-MASH-02", "grade": "moderate", "source": { "citation": "Loomba R et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med 2024;391(4):299-310 (SYNERGY-NASH).", "url": "https://doi.org/10.1056/NEJMoa2401943", "identifiers": "PMID:38856224 / DOI:10.1056/NEJMoa2401943 / NCT04166773", "date": "2024-06-08", "design": "phase-2 RCT", "maturity": "human-primary", "funding": "industry - Eli Lilly and Company", "scopeLimits": "", "pressSourced": false }, "flags": { "investigational": false, "pressSourced": false } } ], "caveats": [ { "id": "C1", "title": "Mouse tirzepatide is not a GIP attribution", "text": "The mouse GIPR is weak/partial for tirzepatide (~3-60x reduced potency vs human; El K et al., Nat Metab 2023). Mouse tirzepatide effects largely reflect the GLP-1 component. Apply every time mouse tirzepatide data appears." }, { "id": "C2", "title": "Acute vs chronic glucagon energy-expenditure differ", "text": "Acute human glucagon EE shows no detectable acute BAT recruitment in the one imaging study (Salem et al., DOM 2016); chronic rodent glucagon EE involves a UCP1/FGF21/sympathetic BAT component. Different time-frames and species; do not conflate." }, { "id": "C3", "title": "Human GIP-on-EE: separate two epistemic states", "text": "(a) Human GIP-on-EE is measured-null under acute infusion (REE shows no effect across isolating acute-infusion datasets). (b) It is unmeasured under chronic selective agonism (LY3537021 / T2-003 never measured EE/substrate/BAT). Do not fuse 'measured negative' with 'no data'. A low-power vasodilation-confounded skin-temperature surrogate does NOT establish thermogenesis. Treat the chronic-selective-agonism gap as permanent until a selective-agonist calorimetry study says otherwise." }, { "id": "C4", "title": "Retatrutide human EE is inferred, not measured", "text": "No published retatrutide trial has directly measured energy expenditure by calorimetry; the EE story rests on glucagon physiology plus a pair-fed mouse." }, { "id": "C5", "title": "Supra-additive EE synergy is unproven", "text": "The energy-expenditure effect is best described as additive/glucagon-driven, not supra-additive." }, { "id": "C6", "title": "Only the GCGR arm is isolated within retatrutide itself", "text": "The Coskun GCGR-antibody experiment isolates the GCGR arm. GLP-1R and GIPR contributions within the molecule are proxy-based; several are permanently unresolvable in humans." }, { "id": "C7", "title": "Commercial/vendor sources are marketing, not evidence", "text": "Never cited as primary (e.g. peptide-vendor 'activates brown fat in humans' claims)." }, { "id": "C8", "title": "Rodent EE/adaptation datasets carry no recorded housing/ambient-temperature condition", "text": "Load-bearing rodent EE/adaptation sources do not record ambient housing temperature. Sub-thermoneutral housing (standard ~22 C) systematically inflates rodent adaptive thermogenesis and UCP1 share. Mouse-human EE discordance must not therefore be read as purely a species difference; part of it may be a housing artefact." }, { "id": "C9", "title": "Retatrutide lean-mass reassurance is provisional, proportional, and combination-level", "text": "It rests on a single Phase 2 T2D, fat-primary-endpoint, sponsor-authored, completer-only DXA substudy. Absolute lean-kg lost is unquantified; proportional parity can hide the largest absolute lean loss of any agent. DXA 'lean mass' conflates muscle with organ/bone/fluid. Treat 'no disproportionate lean penalty' as provisional, proportional-only, and combination-level - not as demonstrated equivalence." }, { "id": "C10", "title": "In-vitro receptor potency does not map to in-vivo arm contribution", "text": "Relative EC50/potency ratios describe in-vitro pharmacology only. They do NOT establish in-vivo functional arm-dominance: at therapeutic doses receptors approach saturation so the ratio stops governing occupancy. Never carry a potency ratio into a functional/arm-contribution conclusion without this flag." }, { "id": "ACB", "title": "Asymmetric-confidence baseline (do not flatten into one confident voice)", "text": "GCGR-driven energy expenditure: HIGH (acute pharmacology) / UNRESOLVED (chronic) - the HIGH attaches only to the acute human EE rise; the chronic decision-bearing claim is unstudied. GLP-1-driven browning: MODERATE (rodent isolating only; weak human translation). GIP-on-EE / thermogenesis: UNRESOLVED (no isolating human evidence)." } ] }