Investigational and unapproved. Findings below describe what trials and reports have observed. Nothing here is an endorsement, a claim of safety or effectiveness, or a clinical recommendation.
Retatrutide
INVESTIGATIONAL
GLP-1 RA / multi-agonist
61
graded findings
20
effect domains
Evidence spread
High evidence 2Moderate evidence 45Low evidence 1Very low evidence 13
Retatrutide is shown as an investigational or pipeline evidence record. Findings describe what studies and reports observed; they do not endorse use or establish personal suitability.
RetatrutideINVESTIGATIONAL
Safety signalsMixed
Moderate evidence
Significantly increased pancreatitis risk overall, but NOT significant when stratified by background medication; pancreatic cancer not associated overall, but a signal...
SourceWen J et al., Endocrinol Diabetes Metab 2025Source
Full findingSignificantly 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.
Population62 RCTs, 66,232 patients, mean follow-up 43.5 wk; meta-analysis
Fundingnone-declared (independent meta-analysis)
Scope limitsIncludes retatrutide among pooled trials. Contested pancreatitis signal attenuates on stratification - both poles within one study.
Comparatorsplacebo; active comparators
RetatrutideINVESTIGATIONAL
Safety signalsDecrease
Moderate evidence
In the JCEM metabolite substudy of the two phase-2 retatrutide trials, retatrutide lowered circulating uric acid dose-dependently versus baseline and placebo,...
SourcePearson SM et al., J Clin Endocrinol Metab 2026 (metabolomics); PubMed null result 2026 (...Source
Full findingIn 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.
PopulationRetatrutide phase-2 obesity + T2D metabolomics substudy (Pearson et al., post hoc of NCT04881760 / NCT05929066).
Fundingindustry - Eli Lilly and Company
Scope limitspost-hoc (not prespecified); small sample (N~282)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Safety signalsNot directional
Moderate evidence
EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial (Sanyal 2024) did not report any uric-acid or gout endpoint.
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
PopulationRetatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for any uric-acid/gout endpoint - none present.
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Safety signalsNot directional
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any uric-acid/gout endpoint - none present in the trial report.
EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial did not report any iron, ferritin, hepcidin, anaemia or haemoglobin endpoint; its biomarker panel was...
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
Full findingEXPLICIT 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.
PopulationRetatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for iron/ferritin/hepcidin/anaemia/haemoglobin reporting - none present.
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Safety signalsNot directional
Moderate evidence
EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial did not report any iron, ferritin, hepcidin or anaemia endpoint; its adverse events were gastrointestinal plus...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for iron/ferritin/hepcidin/anaemia reporting - none present.
EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial did not report any non-iron micronutrient (vitamin D/B12/folate/magnesium/calcium) endpoint - no retatrutide...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any non-iron micronutrient (vitamin D/B12/folate/Mg/Ca) endpoint - none present.
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingRETATRUTIDE 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).
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingFOLK-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).
PopulationRetatrutide 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.
TRANSCEND-T2D-1, the first phase-3 confirmation: in adults with T2D inadequately controlled by diet and exercise, retatrutide produced graduated, dose-dependent HbA1c...
Full findingTRANSCEND-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.
PopulationTRANSCEND-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.
Fundingindustry-Eli Lilly
Scope limitsNEW 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.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Glycaemic controlDecrease
Moderate evidence
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.
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 (retatrutide phase 2 in T2D)Source
PopulationPhase 2 NCT04867785: adults with T2D, USA, randomised double-blind, placebo- and dulaglutide-1.5mg-controlled, 36 wk (24-wk primary).
Fundingindustry - Eli Lilly (disclosed in publication)
Scope limitsNotable 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.
Comparatorsplacebo; dulaglutide
RetatrutideINVESTIGATIONAL
Glycaemic controlNo change
Moderate evidence
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...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingIn 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.
PopulationPeer-reviewed RCT (measured null)
Fundingindustry - Eli Lilly and Company
Scope limitsThe ONLY true retatrutide measured null in the corpus: a sub-therapeutic dose-floor effect, NOT 'retatrutide does not work'.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Glycaemic controlDecrease
Moderate evidence
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...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingIn 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.)
PopulationRosenstock 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.
Fundingindustry - Eli Lilly and Company
Scope limitsDEEPENED (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).
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Glycaemic controlDecrease
Moderate evidence
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%...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingCROSS-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.
PopulationCROSS-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.
Fundingindustry - Eli Lilly and Company
Scope limitsCROSS-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.
Glucagon-offset net-efficacy and glycaemic-ceiling observation (NEUTRAL): no NET glycaemic blunting was observed at any dose (the glycaemic outcome is a combination...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingGlucagon-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.
PopulationReta phase-2 (NCT04867785), 281 adults with T2D, 36 wk, vs placebo and dulaglutide 1.5 mg.
Fundingindustry - Eli Lilly and Company
Scope limitsDO 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).
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Glycaemic controlNot directional
Very low evidence
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...
SourceEli Lilly. TRIUMPH-2 master protocol of retatrutide in T2D with obesity/overweight (incl....Source
Full findingREGISTRY (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.
PopulationTRIUMPH-2 (NCT05929079): adults with T2D for >=90 days, BMI >=27, incl. an OSA subset; retatrutide (3 doses) vs placebo; phase-3.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsRegistered 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.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Glycaemic controlNot directional
Very low evidence
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...
SourceEli Lilly. TRANSCEND-T2D-2: retatrutide vs semaglutide in T2D inadequately controlled on ...Source
Full findingREGISTRY (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.
PopulationTRANSCEND-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.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsopen-label (unblinded)
Comparatorssemaglutide
RetatrutideINVESTIGATIONAL
Glycaemic controlNot directional
Very low evidence
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...
SourceEli Lilly. TRANSCEND-T2D-3: retatrutide vs placebo in T2D with renal impairment on basal ...Source
Full findingREGISTRY (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.
PopulationTRANSCEND-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.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsRegistered 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.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Appetite and food intakeDecrease
Moderate evidence
Retatrutide's ONLY appetite/eating-behaviour data is a prespecified exploratory analysis in T2D (appetite VAS + Eating Inventory) showing reduced appetite, hunger and...
SourceKanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998Source
Full findingRetatrutide'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.
PopulationPrespecified 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.
Fundingindustry-Eli Lilly
Scope limitsnot multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Appetite and food intakeDecrease
Moderate evidence
In the retatrutide phase 2 T2D trial, pre-specified exploratory Appetite VAS showed retatrutide >=4 mg produced greater reductions in OVERALL appetite vs placebo...
SourceKanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998Source
Full findingIn 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).
PopulationAdults with T2D, n=275 efficacy set, phase 2
Fundingindustry-Eli Lilly
Scope limitsnot multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Appetite and food intakeMixed
Moderate evidence
In the same retatrutide phase 2 T2D appetite analysis, individual VAS items moved heterogeneously: HUNGER fell vs placebo and PROSPECTIVE FOOD CONSUMPTION fell vs...
SourceKanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998Source
Full findingIn 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.
PopulationAdults with T2D, phase 2, over 36 weeks
Fundingindustry-Eli Lilly
Scope limitsnot multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Appetite and food intakeDecrease
Moderate evidence
In the retatrutide phase 2 T2D Three-Factor Eating Inventory, higher doses reduced Perceived Hunger and Disinhibition and increased Dietary Restraint; retatrutide 12...
SourceKanu C et al., Diabetes Obes Metab 2025;27(12):6988-6998Source
Full findingIn 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.
PopulationAdults with T2D, phase 2
Fundingindustry-Eli Lilly
Scope limitsnot multiplicity-controlled; small sample (N~275); surrogate/exploratory endpoint
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Appetite and food intakeNot directional
Very low evidence
FOLK-CLAIM VERDICT ('appetite/food noise comes ROARING BACK on retatrutide, on treatment'): UNPROVEN. The self-report SIGNAL is real (a striking, oft-repeated...
SourceSelf-Reported Side Effects Among Reddit Users Taking Unapproved Retatrutide. medRxiv 2026...Source
Full findingFOLK-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).
PopulationNon-peer-reviewed medRxiv Reddit text-mining preprint (grey-market reta users); contrasted with the reta phase-2 trial AE profile.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsno outcome data yet (ongoing)
RetatrutideINVESTIGATIONAL
Body compositionDecrease
Moderate evidence
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...
SourceCoskun T et al. (Eli Lilly), Lancet Diabetes Endocrinol, 2025Source
Full findingRetatrutide 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.
PopulationSubstudy 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.
Fundingindustry-Eli Lilly
Scope limitsDEEPENED (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.
SourceSanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024Source
Full findingPhase 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).
PopulationPre-specified substudy of phase 2 obesity trial, participants with MASLD; MRI-PDFF
Fundingindustry - Eli Lilly (disclosed; retatrutide MASLD substudy)
Scope limitssmall sample (N~98)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Body compositionNot directional
Moderate evidence
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...
SourceGap row derived from absence across the retatrutide phase-2 reports (PMID 37366315 weight...Source
Full findingRETATRUTIDE 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.
PopulationRetatrutide 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.
Fundingacademic - Canadian Institutes for Health Research (CIHR grant 154321), Drucker review
Scope limitsExplicit 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.
Comparatorsplacebo; dulaglutide
RetatrutideINVESTIGATIONAL
Body compositionNot directional
Moderate evidence
EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial (Sanyal 2024) did not report any DXA/BMD, bone-turnover or fracture endpoint.
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
PopulationRetatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present.
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Body compositionNot directional
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present in the trial report.
OPEN QUESTION: no outcome trial isolates a glucagon (GCGR) arm, so the net CV-OUTCOME consequence of glucagon agonism is unresolved. The concern, whether...
SourceAbsence established via PubMed sweep (2026-06-21): no dual-agonist CV-outcome-trial recor...Source
Full findingOPEN 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.
PopulationNo isolating trial exists. The only dedicated triple-agonist CVOT is TRIUMPH-Outcomes (NCT06383390), hard endpoints ~2029.
Fundingacademic / non-commercial (De Fano GIP review; no industry sponsor; disclosed)
Scope limitsanimal data; human relevance uncertain; surrogate/exploratory endpoint
RetatrutideINVESTIGATIONAL
Cardiovascular outcomesNot directional
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingThe 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.
PopulationJastreboff 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.
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...
Full findingThe 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.
PopulationTRIUMPH-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.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsno outcome data yet (ongoing)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Cardiovascular outcomesNot directional
Very low evidence
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,...
SourceEli Lilly. TRIUMPH-3: Phase 3 study of LY3437943 once weekly vs placebo in severe obesity...Source
Full findingCLARIFYING 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).
PopulationTRIUMPH-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.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsADDED 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.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Moderate evidence
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...
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
Full findingHigher 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.
PopulationMASLD substudy of phase 2 obesity trial (NCT04881760)
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Moderate evidence
No study indexed under these search terms as of 2026 has performed a hyperinsulinaemic-euglycaemic clamp or stable-isotope endogenous-glucose-production tracer study...
SourcePearson SM et al., J Clin Endocrinol Metab 2026 (metabolomics); PubMed null result 2026 (...Source
Full findingNo 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.
Scope limitspost-hoc (not prespecified); small sample (N~282)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionNot directional
Moderate evidence
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...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingRETATRUTIDE 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.
PopulationReta phase-2 T2D (Rosenstock, Lancet 2023, NCT04867785), N=281; plus a null PubMed search for reta beta-cell secretion/function as of 2026.
Fundingindustry - Eli Lilly and Company
Scope limitsDeepens 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.
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Low evidence
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...
SourceCoskun T et al. phase 1 SAD, as restated in Biomolecules 2025 review (PMC12190491)Source
Full findingIn 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.
PopulationPhase 1 SAD, humans
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsDOWN-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.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Lipids and lipoproteinsDecrease
Moderate evidence
Retatrutide produced strong dose-dependent triglyceride and LDL lowering in phase 2 obesity (glucagon-agonism-enhanced lipid effect).
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
PopulationN=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).
In post-hoc analyses of two phase-2 retatrutide trials, circulating ANGPTL3/8 complex concentrations fell dose-dependently and these decreases paralleled the...
SourceWen Y, Lemen D, ... Konrad RJ, Diabetes Obes Metab 2025;27(10):5985-5995Source
Full findingIn 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.
PopulationPost-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.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitspost-hoc (not prespecified)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Lipids and lipoproteinsDecrease
Moderate evidence
In the phase-2a MASLD substudy, retatrutide was associated with a significant reduction in fasting triglycerides (and improved insulin-sensitivity markers); the paper...
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
Full findingIn 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.
PopulationPhase-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.
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Weight changeDecrease
High evidence
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...
Full findingIn 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).
PopulationTRANSCEND-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).
Fundingindustry-Eli Lilly
Scope limitsReta'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.
RetatrutideINVESTIGATIONAL
Weight changeDecrease
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingTriple 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.
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%...
Full findingEli 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.
PopulationTRIUMPH-1 (NCT05929066): n=2,339, obesity without diabetes, 80 weeks +/- high-BMI extension to 104 weeks
Fundingindustry - Eli Lilly (trial sponsor; corporate topline announcement of its own TRIUMPH-1 trial)
Scope limitspress/topline only - no peer-reviewed publication; no DXA/EE/per-receptor mechanism detail; results not posted to ClinicalTrials.gov (hasResults=FALSE 2026-06-21)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
hepatic-mashDecrease
Moderate evidence
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.
SourceSanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024Source
PopulationN=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.
Fundingindustry - Eli Lilly (disclosed; retatrutide MASLD substudy)
Scope limitssmall sample (N~98)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
hepatic-mashDecrease
Moderate evidence
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...
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
Full findingIn 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.
Populationn=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.
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
hepatic-mashNot directional
Very low evidence
REGISTRATIONAL GAP: no dedicated retatrutide MASH / MASH-with-fibrosis phase-2b or phase-3 histology trial could be identified. PubMed returns no reta histological...
SourceNo dedicated reta MASH-histology trial located in PubMed or via trial-registry knowledge ...
Full findingREGISTRATIONAL 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.
Populationn/a - registry/landscape gap statement.
Fundingn/a - absence-of-evidence landscape note (no study, no sponsor)
Scope limitsno outcome data yet (ongoing); surrogate/exploratory endpoint
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
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
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
heart-rate-chronotropyIncrease
Moderate evidence
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.
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
PopulationN=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).
In isolated mouse right atria, retatrutide itself exerted positive chronotropy that was antagonised by the GCGR antagonist adomeglivant, potentiated by rolipram (PDE4...
SourceNeumann J et al., Naunyn Schmiedebergs Arch Pharmacol 2025;398(12):17147-17160Source
Full findingIn 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.
Populationisolated mouse right atria (and left atria for force of contraction)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Energy expenditure and thermogenesisIncrease
Moderate evidence
FOLK-CLAIM VERDICT ('retatrutide runs hot / sweating / feels hot, via glucagon'): MIXED - the MECHANISM is real and plausibly reta-distinct (glucagon thermogenesis is...
SourceSalem V et al. Glucagon increases energy expenditure independently of brown adipose tissu...Source
Full findingFOLK-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.
PopulationHuman glucagon-infusion thermogenesis study (Salem 2016) for the mechanism; reta phase-2 obesity/T2D trials (no temperature endpoint) for the direct-data gap.
Fundingacademic-MRC/BBSRC/NIHR/Wellcome Trust
Scope limitsGRADE: 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).
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Energy expenditure and thermogenesisNot directional
Very low evidence
Glucagon-mediated increased energy expenditure is PROPOSED for retatrutide (mechanistic/preclinical reviews); not measured in the cited human phase-2 trial.
PopulationPreclinical (rodent) models with calorie-intake-matched controls; reported via reviews/secondary sources
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain; magnitude web/secondary-sourced
Comparatorscalorie-intake-matched control
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Maintenance and regainNot directional
Moderate evidence
RETATRUTIDE GAP: no maintenance, withdrawal/regain or intermittent-dosing data specific to retatrutide exist. The phase-2 obesity trial reported continuous...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingRETATRUTIDE 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.
REGISTRY (no results): TRIUMPH-6 (NCT06859268) is the registered phase-3b retatrutide weight-MAINTENANCE trial with a continued-vs-withdrawal (re-randomisation) design...
SourceEli Lilly. TRIUMPH-6: maintenance of weight reduction with retatrutide. ClinicalTrials.go...Source
Full findingREGISTRY (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.
PopulationTRIUMPH-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.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsRegistered 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.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Obstructive sleep apnoeaNot directional
Very low evidence
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...
SourceClinicalTrials.gov TRIUMPH-1 (NCT05929066) and TRIUMPH-2 (NCT05929079), Eli Lilly; regist...Source
Full findingRetatrutide 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.
PopulationTRIUMPH-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.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsno outcome data yet (ongoing)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Obstructive sleep apnoeaNot directional
Very low evidence
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)...
SourcePosition derived from TRIUMPH design (Giblin K et al., Diabetes Obes Metab 2025, PMID 410...
Full findingRETATRUTIDE-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.
Populationn/a (positional/inferential row). Weight-loss anchor: reta phase-2 (Jastreboff 2023, obesity, 48 wk) up to ~24% mean weight loss (weight-loss domain).
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsNON-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.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Blood pressureDecrease
Moderate evidence
Retatrutide lowered SBP/DBP dose-dependently (exploratory) in phase 2 obesity.
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
PopulationN=338 adults with obesity; retatrutide 1-12 mg vs placebo; 48 weeks; phase 2 (NCT04881760).
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
Moderate evidence
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.
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
cns-neuropsychiatricNot directional
Moderate evidence
RETATRUTIDE GAP: retatrutide has essentially NO dedicated CNS, addiction, cognition or psychiatric data beyond routine adverse-event capture in its two phase-2 trials....
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingRETATRUTIDE 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.
PopulationReta phase-2 obesity (Jastreboff, NCT04881760, N=338) + T2D (Rosenstock, NCT04867785, N=281); psychiatric AEs captured only as routine treatment-emergent events, not instrumented.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
Pharmacology and mechanismNot directional
Moderate evidence
EXPLICIT ABSENCE: there is no retatrutide gut-microbiome data of any kind - human or animal. Unlike liraglutide and semaglutide (rodent + small human compositional...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide 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.
Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.
RetatrutideINVESTIGATIONAL
special-populationsNot directional
Moderate evidence
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...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT 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.
PopulationRetatrutide 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.
The Echo Compendium