MASH Treatment Revolution: Semaglutide, Tirzepatide Lead a New Drug Era
A landmark JCI review maps the expanding pharmacological arsenal for MASH, from GLP-1 agonists to triple receptor therapies and precision medicine.
Summary
Metabolic dysfunction-associated steatohepatitis (MASH) is now a leading cause of liver disease globally, driven by obesity and type 2 diabetes. This major review in the Journal of Clinical Investigation synthesizes the latest pharmacological advances, covering GLP-1 agonists like semaglutide, dual agonists like tirzepatide and survodutide, metabolic modulators including resmetirom, lanifibranor, and pegozafermin, and emerging targets like fatty acid synthase inhibitors. Phase II and III trial data show MASH resolution rates of 46–63% with newer agents versus 11–34% with placebo. The review also addresses unresolved challenges: treatment duration, weight regain after stopping therapy, adherence, genetic response heterogeneity, and risks in patients with advanced fibrosis or cirrhosis.
Detailed Summary
MASH — the inflammatory, fibrosis-prone form of metabolic liver disease — now affects a significant portion of the global population, with MASLD prevalence estimated at 38% and projected to reach 55% by 2040. This comprehensive review by Newsome and Loomba, published in the Journal of Clinical Investigation, synthesizes the current landscape of pharmacological treatments in advanced development, providing one of the most detailed and clinically actionable overviews of the field to date.
GLP-1 receptor agonists have emerged as frontline candidates. Semaglutide's phase III ESSENCE trial in patients with F2/F3 fibrosis demonstrated MASH resolution in 62.9% versus 34.1% with placebo, and fibrosis improvement in 37.0% versus 22.5% — both meeting FDA/EMA surrogate endpoints. Notably, the combined endpoint of MASH resolution plus fibrosis improvement was achieved in 32.8% versus 16.2%, challenging prior assumptions that GLP-1 agents had no direct antifibrotic effect. However, in cirrhotic patients (MASH with compensated cirrhosis), semaglutide produced metabolic improvements but no meaningful histological or imaging improvement in fibrosis.
Dual agonists represent the next therapeutic frontier. Tirzepatide, targeting both GIP and GLP-1 receptors, achieved MASH resolution in 46–62% of patients versus 11% with placebo in a phase IIb trial of 190 patients over 52 weeks, with fibrosis improvement in 51–55% versus 30%. Survodutide, a dual glucagon–GLP-1 agonist, showed MASH resolution in 43–62% versus 14% in 293 patients over 48 weeks, with fibrosis improvement in 34–36% versus 22%. Importantly, glucagon receptors are highly expressed in hepatocytes — unlike GLP-1 receptors — providing a direct liver-centric mechanism for glucagon-containing dual and triple agonists. Retatrutide, a triple GLP-1/GIP/glucagon agonist, showed marked reductions in liver fat in phase II MASLD studies and represents a promising next generation candidate.
Beyond incretin therapies, metabolic modulators address MASH through orthogonal mechanisms. Resmetirom, a thyroid hormone receptor-β agonist, received FDA accelerated approval in 2024 based on the MAESTRO-NASH phase III trial showing MASH resolution in 25.9–29.9% versus 9.7% for placebo and fibrosis improvement in 24.2–25.9% versus 14.2%, with added lipid-lowering benefits. Lanifibranor, a pan-PPAR agonist, showed MASH resolution in 49% versus 22% in the NATIVE trial, with the additional advantage of improving multiple fibrosis stages. Pegozafermin, an FGF21 analog, demonstrated liver fat reductions and biomarker improvements in phase II. Fatty acid synthase inhibitors such as TVB-2640 and firsocostat represent emerging mechanistic approaches targeting de novo lipogenesis, though results have been mixed.
The review identifies several unresolved clinical challenges. Weight regain after stopping GLP-1 therapy is substantial — approximately two-thirds of lost weight returns within one year of discontinuation — raising the question of indefinite or maintenance dosing. Real-world adherence is poor, with discontinuation rates of 30–50% within the first year, driven by gastrointestinal side effects. Genetic heterogeneity, including PNPLA3 polymorphisms and GLP-1 receptor variants, affects treatment response and calls for pharmacogenomic stratification. In patients with advanced fibrosis or cirrhosis, sarcopenia risk from GLP-1-induced lean mass loss (20–30% of total weight loss) warrants careful monitoring. Looking ahead, combination therapies targeting complementary pathways, AI-assisted trial design, and patient-reported outcomes are expected to reshape how therapeutic success is defined in MASH.
Key Findings
- Semaglutide 2.4 mg/week achieved MASH resolution in 62.9% vs 34.1% placebo and fibrosis improvement in 37.0% vs 22.5% in the phase III ESSENCE trial (F2/F3 fibrosis, 72 weeks)
- Tirzepatide (5–15 mg/week) resolved MASH in 46–62% vs 11% placebo and improved fibrosis by ≥1 stage in 51–55% vs 30% in a phase IIb trial (n=190, 52 weeks)
- Survodutide achieved MASH resolution in 43–62% vs 14% placebo and ≥1 stage fibrosis improvement in 34–36% vs 22% in 293 patients over 48 weeks, but discontinuation was 20% vs 3% due to GI side effects
- Resmetirom (FDA-approved 2024) resolved MASH in 25.9–29.9% vs 9.7% placebo and improved fibrosis in 24.2–25.9% vs 14.2% in the MAESTRO-NASH phase III trial
- Lanifibranor (pan-PPAR agonist) resolved MASH in 49% vs 22% placebo in the NATIVE trial, with fibrosis improvements across multiple stages
- GLP-1 receptor agonist discontinuation rates reach 30–50% within the first year in real-world settings, and ~two-thirds of lost weight is regained within 1 year of stopping treatment
- Lean muscle mass accounts for approximately 20–30% of total weight loss with GLP-1 agonists, raising sarcopenia concerns in patients with advanced fibrosis or cirrhosis
Methodology
This is a narrative review article synthesizing data from multiple phase II and phase III randomized controlled trials in MASH, published in the Journal of Clinical Investigation in July 2025. The review covers trials ranging from 48 to 72 weeks in duration, with patient populations defined by biopsy-confirmed MASH and fibrosis stages F1–F3, using histological endpoints (MASH resolution without fibrosis worsening; ≥1 stage fibrosis improvement) accepted by the FDA and EMA as surrogate endpoints for accelerated approval. No original data were generated; the review synthesizes published and reported trial results.
Study Limitations
As a narrative review, this article does not perform a systematic meta-analysis and may reflect selection bias in the trials and data emphasized. Head-to-head comparisons between drug classes are largely absent, limiting direct efficacy comparisons. The authors note that long-term cardiovascular and oncological outcomes data are lacking for most MASH agents, and the review does not fully address potential conflicts of interest given the authors' extensive involvement in industry-sponsored MASH trials.
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