21 findings across 7 drug records. Domain pages are descriptive indexes, not advice.
Most represented records
Tirzepatide (7)
Orforglipron (4)
Semaglutide (3)
Tirzepatide|semaglutide (head-to-head) (2)
Multiple (network Meta-analysis) (2)
Evidence spread
High evidence 5Moderate evidence 14Low evidence 2Very low evidence 0
Tirzepatide|semaglutide (head-to-head)MARKETED
comparative-efficacyNot directional
Moderate evidence
FOLK-CLAIM VERDICTS (strength hierarchy): (1) 'reta > tirz > sema' = TRUE directionally, OVERSTATED on certainty - the tirz>sema rung is head-to-head proven...
SourceAronne LJ, et al. N Engl J Med 2025 (SURMOUNT-5); presented ECO 2025Source
Full findingFOLK-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'.
PopulationCross-trial comparison of the pivotal weight-loss trials + the one head-to-head (SURMOUNT-5).
Across 56 trials, semaglutide and tirzepatide are the leading agents on weight and carry the broadest proven extra-glycaemic benefits.
SourceGLP-1-based therapies for obesity: systematic review and network meta-analysis, Nat Med 2025Source
PopulationPeer-reviewed RCT / meta-analysis
Fundingacademic / non-commercial
Scope limitsNetwork meta-analysis -> moderate; indirect comparisons. Useful as a class-comparative synthesis anchor.
Multiple (network Meta-analysis)MARKETED
comparative-efficacyDecrease
Moderate evidence
Bariatric surgery still beats GLP-1 drugs on weight overall, but tirzepatide narrows the gap to non-significance versus surgery.
SourceBariatric surgery versus GLP-1 receptor agonists: network meta-analysis, Obesity 2025Source
PopulationPeer-reviewed RCT / meta-analysis
Fundingacademic / non-commercial
Scope limitsNetwork meta-analysis (indirect) -> moderate. Both-poled: surgery superior overall, tirzepatide-vs-surgery NS.
TirzepatideMARKETED
comparative-efficacyIncrease
Moderate evidence
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;...
SourceFrias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2)Source
Full findingDIRECT 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).
Population1879 adults with T2D on metformin, open-label, 40 weeks, randomised 1:1:1:1; comparator semaglutide 1 mg s.c. weekly
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...
SourceAronne LJ, et al. N Engl J Med 2025 (SURMOUNT-5); presented ECO 2025Source
Full findingDIRECT 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%).
PopulationAdults 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
Comparatorssemaglutide 2.4 mg (max tolerated 1.7 or 2.4 mg)
TirzepatideMARKETED
comparative-efficacyIncrease
Moderate evidence
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...
SourceNeves JS, Leite AR, Vale C, et al. Diabetologia 2025/2026Source
Full findingDIRECT 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.
PopulationPost hoc of 1879 SURPASS-2 participants (T2D), 40 weeks; tirz 5/10/15 vs sema 1 mg
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitspost-hoc (not prespecified)
Comparatorssemaglutide 1 mg
SemaglutideMARKETED
comparative-efficacyIncrease
Moderate evidence
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...
SourcePratley RE, Aroda VR, Lingvay I, et al. Lancet Diabetes Endocrinol 2018 (SUSTAIN 7)Source
Full findingDIRECT 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).
Population1201 adults with T2D on metformin, open-label phase 3b, 40 weeks, randomised 1:1:1:1; 16 countries
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
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...
SourceGarvey WT, Blüher M, et al. N Engl J Med 2025 (REDEFINE 1)Source
Full findingACTIVE-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.
Population3417 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)
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...
SourceDavies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2)Source
Full findingACTIVE/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).
Population1206 adults with T2D and BMI >=27, double-blind, 68 weeks, randomised 3:1 vs placebo
Fundingindustry-Novo Nordisk
Scope limitsT2D 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).
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
comparative-efficacyDecrease
High evidence
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...
SourceRosenstock J, Hsia S, et al. N Engl J Med 2025 (ACHIEVE-1)Source
Full findingPLACEBO-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.
Population559 adults with early T2D (diet/exercise only), double-blind placebo-controlled phase 3, 40 weeks, 1:1:1:1
Fundingindustry-Eli Lilly
Scope limitsOrforglipron 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.
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
comparative-efficacyDecrease
High evidence
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...
SourceGiorgino F, D'Souza S, et al. JAMA 2026 (ACHIEVE-5)Source
Full findingPLACEBO-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.
Population546 adults with T2D inadequately controlled on insulin glargine (+/- metformin/SGLT2i), double-blind phase 3, 40 weeks
Fundingindustry-Eli Lilly
Scope limitsInsulin-background population - weight loss attenuated vs monotherapy ACHIEVE-1. Placebo-controlled; cross-class comparison remains indirect.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
comparative-efficacyIncrease
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingPhase 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.
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...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingDIRECT 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).
Population281 adults with T2D (HbA1c 7-10.5%, BMI 25-50), double-blind, placebo- AND active-comparator (dulaglutide 1.5 mg), 36 weeks
Fundingindustry - Eli Lilly and Company
Scope limitsThis 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.
Comparatorsplacebo; dulaglutide 1.5 mg
TirzepatideMARKETED
comparative-efficacyNot directional
Moderate evidence
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,...
Full findingINDIRECT (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).
PopulationNetwork meta-analysis, 76 RCTs, 39,246 adults with T2D, follow-up >=12 weeks; all estimates vs placebo
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsINDIRECT 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.
Comparatorsplacebo; semaglutide; dulaglutide; CagriSema; all GLP-1RAs
GLP-1 RA classMARKETED
comparative-efficacyIncrease
Moderate evidence
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%...
Full findingEFFICACY 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).
PopulationMIXED across trials/doses/durations/populations - NOT a single comparison
Fundingindustry - multiple, each disclosed per component: Eli Lilly / Novo Nordisk
Scope limitsEXPLICIT 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.
Comparatorscross-trial; placebo within each
TirzepatideMARKETED
comparative-efficacyIncrease
Low evidence
REAL-WORLD comparative effectiveness (Truveta EHR, overweight/obesity). Tirzepatide associated with significantly greater on-treatment weight loss than semaglutide...
SourceRodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. JAMA Intern Med 2024Source
Full findingREAL-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.
Population41,222 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
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspossible confounding by indication
Comparatorssemaglutide
TirzepatideMARKETED
comparative-efficacyIncrease
Low evidence
REAL-WORLD comparative effectiveness (US clinical practice, obesity WITHOUT diabetes). At 6 months tirzepatide -11.15% vs semaglutide -8.83% (adjusted difference -2.32...
Sourcele Roux CW, Done N, Brnabic AJM, et al. J Endocrinol Invest 2026Source
Full findingREAL-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.
Population2396 on-treatment adults (1003 tirz, 1393 sema) with obesity/overweight WITHOUT diabetes, retrospective EHR cohort, Dec 2023-Jun 2024, 6-month follow-up
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsNon-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.
Comparatorssemaglutide
TirzepatideMARKETED
comparative-efficacyIncrease
High evidence
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...
SourceNicholls SJ et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 ...Source
Full findingDIRECT 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).
Population13,299 (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
Fundingindustry - Eli Lilly (trial sponsor)
Scope limitsactive-comparator (dulaglutide) non-inferiority design - not placebo-controlled; superiority not met (P=0.09)
Comparatorsdulaglutide 1.5 mg
OrforglipronINVESTIGATIONAL
comparative-efficacyMixed
Moderate evidence
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...
SourceOrforglipron versus oral semaglutide head-to-head (ACHIEVE-3), Lancet 2026Source
Full findingHead-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.
PopulationPeer-reviewed RCT / meta-analysis
FundingEli Lilly
Scope limitsOPEN-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.
Tirzepatide|semaglutide (head-to-head)MARKETED
comparative-efficacyNot directional
Moderate evidence
FOLK-CLAIM VERDICT ('tirzepatide is gentler than semaglutide despite being stronger', attributed to GIP): MIXED, leaning TRUE - the robust HUMAN finding is LOWER...
SourceAronne LJ et al. Tirzepatide vs semaglutide for obesity (SURMOUNT-5). N Engl J Med 2025 (...Source
Full findingFOLK-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'.
PopulationSURMOUNT-5 randomised head-to-head (tirzepatide vs semaglutide, obesity) + indirect/network meta-analyses + preclinical GIP-antiemetic mechanism (shrew/rat area postrema).
Fundingindustry-Eli Lilly
Scope limitsanimal data; human relevance uncertain; conference/abstract-level
Comparatorssemaglutide
OrforglipronINVESTIGATIONAL
comparative-efficacyDecrease
Moderate evidence
ACHIEVE-2 (T2D on metformin): orforglipron non-inferior and statistically superior to dapagliflozin for HbA1c reduction at 40 weeks (active-comparator head-to-head).
SourceWelch M et al. Orforglipron compared with dapagliflozin... (ACHIEVE-2): a phase 3 trial. ...Source
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