Semaglutide Shows Promise for Steatohepatitis Resolution in MASH

As metabolic dysfunction-associated steatohepatitis (MASH) has increasingly been recognized as a multisystem disease rather than a condition confined to the liver, attention has turned toward therapies that can address both hepatic injury and its underlying cardiometabolic drivers.1

A large meta-analysis, published in Diabetology & Metabolic Syndrome, suggested that semaglutide improved several liver-related and metabolic outcomes in people with or at risk of developing MASH, although benefits varied by histologic end point and treatment intensity.2

Semaglutide shows promise in improving liver health and metabolic outcomes in MASH, enhancing steatohepatitis resolution and cardiometabolic measures. | Image credit: Nati - stock.adobe.com

In the systematic review and meta-analysis, investigators pooled data from randomized controlled trials to better define the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely used for type 2 diabetes and obesity, in MASH populations. The analysis was designed to address ongoing uncertainty surrounding dose response, treatment duration, and fibrosis outcomes, areas where individual trials had been limited by small sample sizes, heterogeneous end points, and relatively short follow-up periods.

MASH, formerly known as nonalcoholic steatohepatitis, represents the inflammatory and progressive form of metabolic dysfunction-associated steatotic liver disease and is associated with elevated risks of cirrhosis, hepatocellular carcinoma, and cardiovascular mortality. Despite its growing prevalence, pharmacologic options remain limited, with resmetirom currently the only approved therapy. Although GLP-1 receptor agonists have shown promise in weight loss and metabolic improvement, their direct effects on liver histology remain unclear.

The meta-analysis included 22 randomized controlled trials encompassing 32,013 participants, with 17,560 assigned to semaglutide and 14,453 to comparator groups. Trial durations ranged from 12 to 104 weeks, and dosing regimens were standardized to weekly equivalents to allow dose-response analyses. Participants were predominantly middle-aged adults, many with obesity or type 2 diabetes, and mean body mass index generally ranged from 30 to nearly 40 kg/m² across studies. Only a subset of trials enrolled people with biopsy-confirmed MASH, while others included populations considered at high metabolic risk.

Across 3 trials that reported histologic outcomes in 1191 participants with confirmed disease, semaglutide was associated with a significantly higher likelihood of MASH resolution compared with control, with a pooled risk ratio of 1.98. In contrast, improvement in liver fibrosis of at least 1 stage did not reach statistical significance, and results varied considerably across studies.

Noninvasive liver markers showed more consistent improvement. Semaglutide was associated with a significant reduction in liver steatosis measured by magnetic resonance imaging proton density fat fraction, as well as lower enhanced liver fibrosis scores. Modest but statistically significant reductions were also observed in alanine aminotransferase and aspartate aminotransferase levels, suggesting improvement in liver injury. Dose and duration analyses indicated that higher weekly doses, particularly those at or above 2.0 mg, and treatment durations of at least 12 months were associated with greater hepatic benefit.

Beyond liver-specific outcomes, semaglutide consistently improved cardiometabolic measures, including body weight, glycemic control, lipid parameters, and blood pressure. Pooled analyses also showed reductions in all-cause mortality and cardiovascular events, findings that may be particularly relevant for managed care populations with overlapping metabolic and cardiovascular risk.

Safety outcomes were generally consistent with the known profile of GLP-1 receptor agonists. Gastrointestinal adverse events and treatment discontinuation occurred more frequently with semaglutide than with comparators, although no significant increase in pancreatitis was observed. Gallbladder-related events were modestly more common among those receiving semaglutide.

The authors noted several limitations, including substantial heterogeneity across trials, the inclusion of populations without biopsy-confirmed MASH, and variation in dosing regimens and study design. They emphasized that fibrosis regression may require longer treatment durations or combination approaches, and that many included trials were not originally designed to evaluate liver outcomes.

“Semaglutide represents a promising pharmacotherapeutic option for MASH, demonstrating significant improvements in histologic resolution, liver injury biomarkers, and metabolic parameters, particularly at higher doses and longer intervention durations,” the authors wrote, while noting that “its effect on fibrosis regression remains limited.”

References

1. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258

2. Kan R, Wang S, Meng X, Guo Y, Li D, Yu X. The impact of semaglutide on liver outcomes in patients with or at risk of MASH: a dose and duration response meta-analysis of randomized trials. Diabetol Metab Syndr. 2025;17(1):439. doi: 10.1186/s13098-025-01995-z