26 findings across 13 drug records. Domain pages are descriptive indexes, not advice.
Most represented records
Multiple (review) (6)
Retatrutide (3)
Efinopegdutide (2)
Efocipegtrutide (2)
Survodutide (2)
Evidence spread
High evidence 1Moderate evidence 16Low evidence 4Very low evidence 5
Multiple (review)MARKETED
hepatic-mashNot directional
Moderate evidence
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...
SourceWang Y, Zhou Y et al. Efficacy of GLP-1-based therapies on MASLD and MASH: systematic rev...Source
Full findingFIELD-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.
Fundingacademic - Chinese government (Ministry of Science and Technology grant 2017ZX09303001; National Natural Science Foundation of China grant 82370814)
Scope limitssurrogate/exploratory endpoint
Comparatorsplacebo
Multiple (review)MARKETED
hepatic-mashNot directional
Moderate evidence
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...
SourceSynthesis across class MASH datasets (reta Sanyal Nat Med 2024 LF tied to weight; survodu...
Full findingWEIGHT-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.
PopulationClass-level mechanistic-attribution question applied to OUTCOMES; reta glucagon arm the specific open case.
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...
SourceRomero-Gomez et al., phase IIa efinopegdutide in NAFLD, J Hepatol 2023 (EASL 2023)Source
Full findingEfinopegdutide (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.
PopulationAdults with NAFLD; phase 2a randomised active-comparator open-label, efinopegdutide 10 mg vs semaglutide 1 mg weekly, 24 wk (NCT04944992)
Scope limitsno outcome data yet (ongoing); open-label (unblinded)
Comparatorssemaglutide
EfocipegtrutideMARKETED
hepatic-mashDecrease
Very low evidence
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...
SourceAbdelmalek MF et al. HM-TRIA-201: phase 2 study of HM15211 (efocipegtrutide) in biopsy-co...Source
Full findingEfocipegtrutide (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.
Fundingindustry - Hanmi (trial sponsor; inferred from registration trial)
Scope limitsno outcome data yet (design/protocol paper); small sample (N~217)
Comparatorsplacebo
EfocipegtrutideMARKETED
hepatic-mashNot directional
Very low evidence
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...
SourceAbdelmalek MF et al. Phase 2 52-week study of HM15211 in biopsy-confirmed NASH - design (...Source
Full findingEfocipegtrutide (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.
Fundingindustry - Hanmi (trial sponsor; inferred from registration trial)
Scope limitsno outcome data yet (ongoing); small sample (N~217)
Comparatorsplacebo
Multiple (review)MARKETED
hepatic-mashNot directional
Low evidence
COMPENSATED-CIRRHOSIS (MASH F4) FRONTIER - EVIDENCE GAP. The landmark registrational MASH programmes systematically EXCLUDE established cirrhosis (ESSENCE F2/F3;...
SourceDerived from ESSENCE and MAESTRO-NASH inclusion criteria, both of which exclude F4 cirrho...
Full findingCOMPENSATED-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.
Populationn/a - characterises absence of F4 evidence; ESSENCE (F2/F3) and MAESTRO-NASH (F1B-F3) cited as the exclusion evidence.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitssurrogate/exploratory endpoint
LiraglutideMARKETED
hepatic-mashDecrease
Moderate evidence
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...
SourceArmstrong MJ, Gaunt P et al. (LEAN). Lancet 2016;387:679-690.Source
Full findingLEAN 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.
SourceFDA accelerated-approval framework for MASH (subpart H; histological surrogate 'reasonabl...
Full findingNATURAL-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.
Populationn/a - regulatory/natural-history framing applicable to the whole MASH field.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitssurrogate/exploratory endpoint
MazdutideINVESTIGATIONAL
hepatic-mashNot directional
Very low evidence
Mazdutide (IBI362; Innovent/Lilly, GLP-1/glucagon dual) has NO published dedicated human MASH histology trial. Human liver benefit is so far described within...
Full findingMazdutide (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.
PopulationPreclinical: high-fat-diet mouse MASLD + FFA hepatocytes (PMID 41901218; rodent MRI PMID 40828048). Human MASH histology trial: not yet published.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorssemaglutide (preclinical comparator)
Multiple (review)MARKETED
hepatic-mashMixed
Low evidence
BALANCED OBSERVATION on the glucagon-anti-fibrosis hypothesis. POLE FOR: the mechanistic rationale (hepatic GCGR action on lipid oxidation/stellate biology) plus...
SourceCross-agent observation from PMID 38847460 (survodutide), 38856224 (tirzepatide), 4123779...
Full findingBALANCED 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.
PopulationCross-agent synthesis of published phase-2 MASH histology trials (survodutide, SYNERGY-NASH, IMPACT, semaglutide ph2b/ESSENCE).
Fundinganalyst cross-agent synthesis (no study funding; not a sponsored output)
Scope limitsNEUTRAL 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.
CONTEXT BENCHMARK (NON-incretin). Resmetirom (Rezdiffra, Madrigal) is the FIRST FDA-approved MASH drug, approved on the MAESTRO-NASH histological co-primaries....
SourceHarrison SA, Bedossa P et al. MAESTRO-NASH. N Engl J Med 2024;390:497-509.Source
Full findingCONTEXT 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).
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-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
SurvodutideINVESTIGATIONAL
hepatic-mashDecrease
Moderate evidence
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...
SourceSanyal et al., Phase 2 Survodutide in MASH and Fibrosis, NEJM 2024; Boehringer phase 3 pressSource
Full findingSurvodutide (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.
Fundingindustry - Boehringer Ingelheim (disclosed in publication)
Scope limitsidentifier not fully verified; no outcome data yet (ongoing)
Comparatorsplacebo
CotadutideMARKETED
hepatic-mashDecrease
Moderate evidence
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...
SourceNahra R et al. Diabetes Care 2021;44:1433-1442Source
Full findingCotadutide 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
PopulationOverweight/obese T2D, phase 2b ad hoc (n=834, 54 wk) and phase 2a glycogen study (NCT03555994)
Fundingindustry-AstraZeneca
Scope limitsconference/abstract-level; identifier not fully verified; open-label (unblinded)
Comparatorsplacebo; liraglutide 1.8 mg
CotadutideMARKETED
hepatic-mashDecrease
Very low evidence
Cotadutide resolved NASH/fibrosis in preclinical models more than liraglutide or OCA at matched weight loss; GcgR drives hepatic lipid/mitochondrial effects
SourceBoland ML et al. Nat Metab 2020;2:413-431Source
PopulationMouse NASH models + GLP-1R KO mice (preclinical mechanism)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain
Comparatorsliraglutide; obeticholic acid
EfinopegdutideMARKETED
hepatic-mashDecrease
Moderate evidence
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...
SourceRomero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the effi...Source
Full findingIn 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.
Fundingindustry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)
Scope limitsopen-label (unblinded)
Comparatorssemaglutide
Multiple (network Meta-analysis)MARKETED
hepatic-mashDecrease
Moderate evidence
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...
SourceKoh B et al. Comparative efficacy of pharmacologic therapies for MASH in reducing liver f...Source
Full findingIn 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.
Population39 RCTs, 3311 participants with MASH, MRI-PDFF endpoint; systematic review and network meta-analysis (search to Dec 2023)
Fundingacademic-Singapore NMRC and NIH (NCATS/NIDDK/NHLBI)/John C Martin Foundation
Scope limitsIndirect 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.
Comparatorsacross-trial indirect comparison
Multiple (review)MARKETED
hepatic-mashDecrease
Moderate evidence
Histology-endpoint review: GLP-1RA-based agents improve MASH disease activity; tirzepatide and survodutide additionally show fibrosis-reduction signals; semaglutide...
SourceZafer M, Tavaglione F, Romero-Gómez M, Loomba R. Review: GLP-1 RAs and glucagon/GIP/GLP-1...Source
Full findingHistology-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.
PopulationComprehensive review of phase 2 (and interim phase 3) MASH trials with histology endpoints
Fundingacademic-NIH (NCATS/NIDDK/NHLBI/NIAAA) and John C Martin Foundation
Scope limitsmagnitude web/secondary-sourced
PemvidutideINVESTIGATIONAL
hepatic-mashDecrease
Low evidence
Reduced liver fat content, ALT and cT1 vs placebo in MASLD
SourceHarrison SA et al. J Hepatol 2024;82:7-17Source
Fundingindustry - Altimmune (trial sponsor; inferred from registration trial)
Scope limitssmall sample (N~94)
Comparatorsplacebo
PemvidutideINVESTIGATIONAL
hepatic-mashMixed
Moderate evidence
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;...
SourceNoureddin M, Harrison SA, Loomba R et al. Pemvidutide vs placebo for MASH (IMPACT): 24-we...Source
Full findingIn 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.
Scope limitsno outcome data yet (ongoing); surrogate/exploratory endpoint
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
SemaglutideMARKETED
hepatic-mashDecrease
High evidence
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...
SourceSanyal AJ, Newsome PN et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associ...Source
Full findingIn 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.
PopulationESSENCE (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).
Fundingindustry - Novo Nordisk
Scope limitsno outcome data yet (ongoing)
Comparatorsplacebo
SemaglutideMARKETED
hepatic-mashMixed
Moderate evidence
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...
SourceNewsome PN et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic ...Source
Full findingIn 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).
Scope limitsBoth 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).
Comparatorsplacebo
SurvodutideINVESTIGATIONAL
hepatic-mashDecrease
Moderate evidence
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...
SourceSanyal AJ et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J...Source
Full findingIn 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%).
PopulationNCT04771273; 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).
Fundingindustry - Boehringer Ingelheim / Zealand
Scope limitsDEEPENS 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.
Comparatorsplacebo
TirzepatideMARKETED
hepatic-mashDecrease
Moderate evidence
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...
SourceLoomba R et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liv...Source
Full findingIn 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.
Scope limitsDEEPENS 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.
The Echo Compendium