Evidence reference only. Not medical advice, not a dosing guide, and not a recommendation to use any drug.
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Liver and MASH

23 findings across 12 drug records. Domain pages are descriptive indexes, not advice.

The grade rates how strong the evidence is, not how good or safe the drug is. A low or very-low grade means the evidence is thin, not that an effect is harmful or ruled out.

Most represented records

Multi-agent review synthesis (6)

Cotadutide (2)

Efinopegdutide (2)

Pemvidutide (2)

Retatrutide (2)

Semaglutide (2)

Survodutide (2)

Liraglutide (1)

Evidence spread

High evidence 1 Moderate evidence 16 Low evidence 4 Very low evidence 2

Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Not 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...

Wang 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.
PopulationClass-level (semaglutide, tirzepatide, survodutide, pemvidutide, efinopegdutide; reta liver-fat only).
Fundingacademic - Chinese government (Ministry of Science and Technology grant 2017ZX09303001; National Natural Science Foundation of China grant 82370814)
Comparatorsplacebo
Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Not 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...

Synthesis 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.
Fundingin-house editorial synthesis - no independent sponsor; underlying primaries separately funded
Comparatorsplacebo
Efinopegdutide INVESTIGATIONAL
Liver and MASH Decrease
Moderate evidence

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...

Romero-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)
Fundingindustry - Merck Sharp & Dohme LLC (efinopegdutide licensed from Hanmi)
Comparatorssemaglutide
Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Not directional
Low evidence

COMPENSATED-CIRRHOSIS (MASH F4) FRONTIER - EVIDENCE GAP. The landmark registrational MASH programmes systematically EXCLUDE established cirrhosis (ESSENCE F2/F3;...

Derived 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)
Liraglutide MARKETED
Liver and MASH Decrease
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...

Armstrong 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.
PopulationLEAN (NCT01237119), phase 2 double-blind RCT, 4 UK centres. n=52 (26/26); biopsy NASH; 48 wk; analysed among ~45 end-of-treatment biopsies. A'Hern single-group design.
Fundingacademic / non-commercial (LEAN; investigator-initiated NIHR/Wellcome; disclosed)
Comparatorsplacebo
Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Not directional
Low evidence

NATURAL-HISTORY / REGULATORY CONTEXT: MASH fibrosis stage predicts liver-related clinical outcomes (decompensation, HCC, liver death), risk rising steeply at advanced...

FDA 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)
Mazdutide MARKETED
Liver and MASH Not 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...

Gan L, Duan L, Zheng X. Mazdutide ameliorates MASLD (rodent). Pharmaceuticals 2026;19(3):... Source
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)
Comparatorssemaglutide (preclinical comparator)
Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Mixed
Low evidence

BALANCED OBSERVATION on the glucagon-anti-fibrosis hypothesis. POLE FOR: the mechanistic rationale (hepatic GCGR action on lipid oxidation/stellate biology) plus...

Cross-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)
Comparatorsplacebo; semaglutide; tirzepatide; survodutide; pemvidutide
Resmetirom MARKETED
Liver and MASH Decrease
Moderate evidence

CONTEXT BENCHMARK (NON-incretin). Resmetirom (Rezdiffra, Madrigal) is the FIRST FDA-approved MASH drug, approved on the MAESTRO-NASH histological co-primaries....

Harrison 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).
PopulationMAESTRO-NASH (NCT03900429), phase 3, 3 arms (80/100 mg/placebo), n=966 primary-analysis. Biopsy NASH fibrosis F1B/F2/F3; F4/CIRRHOSIS EXCLUDED. 52 wk.
Fundingindustry - Madrigal Pharmaceuticals
Comparatorsplacebo; resmetirom 80 mg; resmetirom 100 mg
Retatrutide INVESTIGATIONAL
Liver and MASH Decrease
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.

Sanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024 Source
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)
Comparatorsplacebo
Survodutide INVESTIGATIONAL
Liver and MASH Decrease
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...

Sanyal et al., Phase 2 Survodutide in MASH and Fibrosis, NEJM 2024; Boehringer phase 3 press Source
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.
PopulationMASH: 293 adults, biopsy-confirmed MASH + fibrosis F1-F3, once-weekly s.c. 2.4/4.8/6.0 mg vs placebo, 48 wk; obesity phase 2: adults obesity/overweight, 46 wk
Fundingindustry - Boehringer Ingelheim (disclosed in publication)
Comparatorsplacebo
Cotadutide DISCONTINUED
Liver and MASH Decrease
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...

Nahra R et al. Diabetes Care 2021;44:1433-1442 Source
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
Comparatorsplacebo; liraglutide 1.8 mg
Cotadutide DISCONTINUED
Liver and MASH Decrease
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

Boland ML et al. Nat Metab 2020;2:413-431 Source
PopulationMouse NASH models + GLP-1R KO mice (preclinical mechanism)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsliraglutide; obeticholic acid
Efinopegdutide INVESTIGATIONAL
Liver and MASH Decrease
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...

Romero-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.
PopulationNCT04944992; N=145 (efinopegdutide 72 / semaglutide 73); NAFLD LFC >=10%, 33% T2D; open-label; 24 wk.
Fundingindustry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)
Comparatorssemaglutide
Multi-agent network meta-analysis STATUS UNKNOWN
Liver and MASH Decrease
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...

Koh 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
Comparatorsacross-trial indirect comparison
Multi-agent review synthesis STATUS UNKNOWN
Liver and MASH Decrease
Moderate evidence

Histology-endpoint review: GLP-1RA-based agents improve MASH disease activity; tirzepatide and survodutide additionally show fibrosis-reduction signals; semaglutide...

Zafer 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
Pemvidutide INVESTIGATIONAL
Liver and MASH Decrease
Low evidence

Reduced liver fat content, ALT and cT1 vs placebo in MASLD

Harrison SA et al. J Hepatol 2024;82:7-17 Source
PopulationBMI ≥28, LFC ≥10% MASLD (n=94), phase 1b/2a, 12 wk, RCT placebo-controlled (NCT05006885)
Fundingindustry - Altimmune (trial sponsor; inferred from registration trial)
Comparatorsplacebo
Pemvidutide INVESTIGATIONAL
Liver and MASH Mixed
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;...

Noureddin 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.
PopulationNCT05989711 (IMPACT); 212 randomised (1:2:2 placebo:1.2:1.8 mg); biopsy MASH fibrosis F2/F3; phase-2b randomised double-blind placebo-controlled trial; 24-week readout of a 48-week trial.
Fundingindustry - Altimmune, Inc.
Comparatorsplacebo
Retatrutide INVESTIGATIONAL
Liver and MASH Decrease
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...

Sanyal 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
Comparatorsplacebo
Semaglutide MARKETED
Liver and MASH Decrease
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...

Sanyal 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
Comparatorsplacebo
Semaglutide MARKETED
Liver and MASH Mixed
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...

Newsome 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).
Population320 patients (230 with F2/F3) biopsy-confirmed NASH, F1-F3; 72-week double-blind placebo-controlled phase 2 RCT; daily SC dosing
Fundingindustry-Novo Nordisk
Comparatorsplacebo
Survodutide INVESTIGATIONAL
Liver and MASH Decrease
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...

Sanyal 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
Comparatorsplacebo
Tirzepatide MARKETED
Liver and MASH Decrease
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...

Loomba 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.
PopulationNCT04166773 (SYNERGY-NASH); N=190 randomised, 157 evaluable wk-52 biopsy (imputation); biopsy MASH fibrosis F2/F3; tirzepatide 5/10/15 mg vs placebo; 52 wk.
Fundingindustry - Eli Lilly and Company
Comparatorsplacebo