Every Peptide Being Studied for MASH

Semaglutide for MASH

74% MASH resolution with tirzepatide

In the SYNERGY-NASH trial, 74% of patients taking tirzepatide achieved MASH resolution without fibrosis worsening, compared to 13% on placebo. Multiple peptide drug classes are now competing for what may become the largest liver disease market in pharmaceutical history.

Loomba et al., New England Journal of Medicine, 2024

Loomba et al., New England Journal of Medicine, 2024

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Metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) affects an estimated 5-6% of adults globally. It is the progressive form of fatty liver disease: inflammation and hepatocyte injury on top of fat accumulation, leading to fibrosis, cirrhosis, and liver failure. Until 2024, no peptide drug was approved for MASH. By 2025, semaglutide became the first GLP-1 receptor agonist approved for the condition. Behind it, a pipeline of dual agonists, triple agonists, and FGF21 analogs is generating phase 2 and phase 3 data that may redefine treatment within the next two years.

This article maps every major peptide and peptide-related molecule in MASH clinical development as of early 2026. For the foundational clinical data on semaglutide for liver fat, see the pillar article. For the specific candidates with dedicated articles, see survodutide, retatrutide and liver fibrosis, and tirzepatide and liver disease.

Generation 1: GLP-1 Receptor Agonists

Semaglutide

Newsome et al. (2021) published the landmark phase 2 trial in the New England Journal of Medicine: subcutaneous semaglutide at 0.4 mg daily achieved MASH resolution in 59% of patients versus 17% on placebo over 72 weeks. Fibrosis improvement was observed but did not reach statistical superiority over placebo, a finding that shaped the design of subsequent trials.^[1]

Semaglutide received FDA approval for MASH in August 2025 (subcutaneous Wegovy), making it the first GLP-1 receptor agonist approved for this indication. The approval was based on the phase 2 histological data and the ESSENCE trial (phase 3), which confirmed MASH resolution and fibrosis improvement in a larger population.

The mechanism in MASH extends beyond weight loss. Semaglutide reduces hepatic de novo lipogenesis, improves insulin sensitivity in the liver, and decreases hepatic inflammation through both weight-dependent and weight-independent pathways. However, its effect on advanced fibrosis (stage F3-F4) remains modest compared to the dual and triple agonists.

Generation 2: Dual Receptor Agonists

Tirzepatide (GIP/GLP-1)

Loomba et al. (2024) published the SYNERGY-NASH phase 2 results: tirzepatide achieved MASH resolution without fibrosis worsening in 74% of participants at the highest dose (15 mg), compared to 13% on placebo. This was the highest MASH resolution rate reported for any single agent in a controlled trial. Fibrosis improvement of at least one stage occurred in 55% of tirzepatide-treated patients versus 25% on placebo.^[2]

Hartman et al. (2025) performed subgroup analyses of SYNERGY-NASH showing consistent improvements across baseline fibrosis stages, BMI categories, and diabetes status. The effect was not driven by weight loss alone: patients with similar weight loss on tirzepatide versus placebo still showed superior histological outcomes, suggesting direct hepatic effects of GIP receptor signaling.^[3]

Tirzepatide is in phase 3 for MASH (SYNERGY-LIVER program). The dual GIP/GLP-1 mechanism may offer advantages over GLP-1 alone because GIP receptors are expressed on hepatocytes and may directly modulate lipid metabolism in the liver.

Survodutide (Glucagon/GLP-1)

Sanyal et al. (2024) published the phase 2 randomized trial of survodutide in MASH and fibrosis. MASH improvement without fibrosis worsening occurred in 43-62% of survodutide-treated patients (dose-dependent) versus 14% on placebo. Fibrosis improvement of at least one stage occurred in 34-36% versus 22% on placebo.^[4]

Survodutide's mechanism differs from tirzepatide. The glucagon receptor component directly stimulates hepatic fatty acid oxidation and ketogenesis, reducing liver fat through metabolic pathways distinct from weight loss. In MASH mouse and hamster models, Briand et al. (2026) demonstrated that retatrutide (which includes glucagon receptor agonism like survodutide) produced metabolic benefits beyond those attributable to caloric restriction, confirming a direct hepatic mechanism.^[5]

Survodutide is in phase 3 (SYNCHRONIZE program) for both MASH and obesity, with readouts expected in 2026.

Pemvidutide (Glucagon/GLP-1)

Browne et al. (2025) published the IMPACT trial results for pemvidutide in MASLD. Over 24 weeks, pemvidutide reduced liver fat content (measured by MRI-PDFF) and improved multiple fibrosis biomarkers. The dual glucagon/GLP-1 mechanism produced rapid liver fat reduction alongside weight loss, with effects on fibrosis markers suggesting potential benefit beyond fat reduction alone.^[6]

Pemvidutide is differentiated from survodutide by its peptide structure and glucagon-to-GLP-1 potency ratio, which may affect the balance between hepatic fat oxidation (glucagon-driven) and appetite suppression (GLP-1-driven).

Generation 3: Triple Receptor Agonists

Retatrutide (GLP-1/GIP/Glucagon)

Sanyal et al. (2024) published the phase 2a results for retatrutide in MASLD, showing liver fat reduction of up to 81% from baseline at the highest dose over 48 weeks. At the 12 mg dose, 87% of patients achieved at least 70% relative reduction in liver fat, and 82% achieved normalization of liver fat content (below 5%).^[7]

The triple agonism of retatrutide combines three complementary mechanisms: GLP-1 reduces appetite and improves insulin sensitivity, GIP modulates fat metabolism and potentially provides direct hepatoprotection, and glucagon drives hepatic fatty acid oxidation. This combination produced the deepest liver fat reductions seen in any clinical trial for MASLD/MASH.

Retatrutide is in phase 3 (TRIUMPH program) with MASH histological endpoints. Phase 3 readouts are expected in 2026, with potential FDA submission in 2026-2027.

FGF21 Analogs: A Different Mechanism

Efruxifermin

Harrison et al. (2025) published data on efruxifermin (an Fc-FGF21 fusion protein) in combination with a GLP-1 receptor agonist in patients with NASH/MASH and type 2 diabetes. The combination produced greater histological improvement than either agent alone, suggesting that FGF21 and GLP-1 pathways are complementary rather than redundant in MASH.^[8]

FGF21 acts through a different mechanism than incretin-based therapies. It directly improves hepatic lipid metabolism, reduces hepatic inflammation, and modulates bile acid homeostasis. Efruxifermin is in phase 3 trials (HARMONY program) for MASH with F2-F3 fibrosis.

Pegozafermin

Pegozafermin is a PEGylated FGF21 analog in phase 3 for MASH (ENLIVEN-2 trial). In phase 2, it demonstrated dose-dependent MASH resolution and fibrosis improvement. The PEGylation extends half-life to enable weekly subcutaneous dosing.

A large international trial of FGF21 (efruxifermin) plus semaglutide versus either alone is underway in patients with MASH and stage 2-4 fibrosis, directly testing whether combination therapy is superior for advanced disease.

Head-to-Head Comparisons

Souza et al. (2025) published a network meta-analysis comparing all major pharmacological therapies for MASH, ranking them by MASH resolution and fibrosis regression. The analysis included GLP-1 agonists, dual agonists, triple agonists, FGF21 analogs, FXR agonists, and thyroid hormone receptor agonists.^[9]

Singh et al. (2024) reviewed the mechanistic rationale for each receptor class in MASH, comparing GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists. The review distinguished between indirect effects (weight loss reducing liver fat) and direct hepatic effects (receptor-mediated changes in lipid metabolism, inflammation, and fibrosis). Glucagon receptor agonism provided the strongest evidence for direct hepatic fat reduction, while GIP receptor agonism showed emerging evidence for hepatoprotection.^[10]

The competitive landscape in summary:

Combination Strategies

The field is moving toward combination therapy for advanced MASH. A phase IIb trial of semaglutide plus an ACC inhibitor (firsocostat) plus an FXR agonist (cilofexor) showed greater improvements in fibrosis markers than either therapy alone. The FGF21 plus semaglutide combination trial addresses the same rationale: different mechanisms attacking different pathways simultaneously.

The logic is analogous to combination antiretroviral therapy for HIV or combination chemotherapy for cancer. MASH involves multiple simultaneous pathological processes (lipotoxicity, inflammation, insulin resistance, stellate cell activation), and targeting only one may be insufficient for advanced fibrosis reversal.

What This Means for the MASH Landscape

The competitive dynamics are reshaping liver disease treatment. Several observations from the current pipeline:

Weight loss is necessary but not sufficient. Semaglutide produces substantial weight loss but modest fibrosis improvement. Survodutide and retatrutide, which include glucagon receptor agonism, show evidence of direct hepatic effects beyond weight loss. The agents with the best MASH outcomes appear to combine metabolic improvement with direct hepatic mechanisms.

GIP receptor agonism may be directly hepatoprotective. Tirzepatide's 74% MASH resolution rate exceeds what weight loss alone would predict. GIP receptors on hepatocytes may directly modulate lipid handling and inflammation, though the mechanism is still being characterized.

Glucagon receptor agonism drives liver fat oxidation. The glucagon component in survodutide, pemvidutide, and retatrutide stimulates hepatic fatty acid oxidation through cAMP/PKA signaling, reducing liver fat through a mechanism entirely distinct from caloric restriction.

FGF21 addresses fibrosis specifically. FGF21 analogs improve fibrosis through mechanisms that overlap minimally with incretin pathways (bile acid metabolism, adiponectin elevation, hepatic stellate cell deactivation), making them ideal combination partners.

Fibrosis is the endpoint that matters. MASH resolution is clinically meaningful, but fibrosis stage predicts liver-related mortality. Patients with stage F3-F4 fibrosis have elevated risk of decompensation, liver transplantation, and death. The agents that improve fibrosis independently of MASH resolution (survodutide, tirzepatide) may have the greatest impact on hard clinical outcomes. The ongoing phase 3 trials are designed to capture these outcomes over 2-5 years.

Oral versus injectable. All current MASH pipeline peptides require subcutaneous injection. Oral semaglutide (Rybelsus) is approved for type 2 diabetes but has not been specifically tested in MASH histological trials. If oral formulations can achieve equivalent liver effects to injectable versions, the convenience advantage could determine market share in a condition that requires years of treatment.

For the broader epidemic context, see MASH: the liver disease epidemic and peptide solutions.

The Bottom Line

The MASH peptide pipeline spans six drug classes in various stages of clinical development. Semaglutide (GLP-1 agonist, approved 2025) established proof of concept with 59% MASH resolution. Tirzepatide (GIP/GLP-1, phase 3) achieved the highest single-agent MASH resolution rate at 74%. Survodutide and pemvidutide (glucagon/GLP-1, phase 2-3) add direct hepatic fat oxidation. Retatrutide (triple agonist, phase 3) produced the deepest liver fat reductions at 81%. FGF21 analogs (efruxifermin, pegozafermin, phase 3) target fibrosis through non-overlapping mechanisms. Combination strategies pairing incretin agonists with FGF21 analogs are entering late-stage trials. Phase 3 readouts in 2026 will determine which agents advance to approval.

Frequently Asked Questions

What peptide drugs are being studied for MASH?

Six major peptide drug classes are in MASH clinical trials: GLP-1 agonists (semaglutide, approved 2025), dual GIP/GLP-1 agonists (tirzepatide, phase 3), dual glucagon/GLP-1 agonists (survodutide, pemvidutide), triple GLP-1/GIP/glucagon agonists (retatrutide, phase 3), and FGF21 analogs (efruxifermin, pegozafermin, phase 3). Combination trials pairing incretin agonists with FGF21 analogs are also underway.

Which peptide drug works best for MASH?

In head-to-head comparisons through network meta-analysis, tirzepatide achieved the highest MASH resolution rate (74% in SYNERGY-NASH). Retatrutide produced the deepest liver fat reductions (81% from baseline). Survodutide showed the strongest fibrosis improvement among dual agonists (34-36%). No direct head-to-head trial between these agents has been completed, so rankings are based on cross-trial comparisons with their inherent limitations.

Is semaglutide approved for fatty liver disease?

Yes. Semaglutide (subcutaneous Wegovy) received FDA approval for MASH in August 2025, making it the first GLP-1 receptor agonist approved for this indication. In the phase 2 trial, semaglutide achieved MASH resolution in 59% of patients versus 17% on placebo (Newsome et al., NEJM 2021). The approval covers patients with MASH and liver fibrosis.

What is the difference between GLP-1 and dual or triple agonists for MASH?

GLP-1 agonists (semaglutide) reduce liver fat primarily through weight loss and improved insulin sensitivity. Dual agonists add either GIP receptor activation (tirzepatide, potentially directly hepatoprotective) or glucagon receptor activation (survodutide, drives direct hepatic fat oxidation). Triple agonists (retatrutide) combine all three mechanisms. The additional receptor targets appear to produce effects on liver fat and fibrosis beyond what weight loss alone explains.

What are FGF21 analogs and how do they treat MASH?

FGF21 (fibroblast growth factor 21) is a peptide hormone that regulates lipid metabolism, bile acid homeostasis, and inflammation in the liver. Efruxifermin and pegozafermin are engineered FGF21 analogs in phase 3 trials for MASH. They work through different mechanisms than incretin-based therapies, making them ideal combination partners. Harrison et al. (2025) showed efruxifermin plus a GLP-1 agonist improved MASH histology beyond either agent alone.

When will new MASH peptide drugs be approved?

Multiple phase 3 readouts are expected in 2026. Tirzepatide (SYNERGY-LIVER), survodutide (SYNCHRONIZE), retatrutide (TRIUMPH), and efruxifermin (HARMONY) are all in late-stage trials. Based on typical regulatory timelines, the first new approvals beyond semaglutide could come in 2026-2027, pending positive phase 3 results and FDA review.