Semaglutide clears liver inflammation and cuts fibrosis in MASH patients, trial shows

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.May 4 2025

In an interim analysis of an ongoing global trial, semaglutide resolved steatohepatitis in 63% of patients and reduced liver fibrosis, while also promoting weight loss and improving metabolic health in people with advanced fatty liver disease.

Study: Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. Image Credit: Douglas Cliff / Shutterstock

In a recent study published in The New England Journal of Medicine, a group of researchers assessed the efficacy of semaglutide in resolving steatohepatitis and reducing fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH).

Background

Globally, over one billion people are estimated to have some form of fatty liver disease. MASH, a progressive form of fatty liver disease, is marked by liver inflammation, hepatocyte injury, and fibrotic changes. Left untreated, it can lead to cirrhosis, liver failure, and hepatocellular carcinoma. MASH is also closely tied to conditions like type 2 diabetes mellitus and obesity.

Despite its rising burden, treatment options remain limited, with only resmetirom having received accelerated FDA approval specifically for MASH with significant fibrosis. While lifestyle modification remains first-line, pharmacological interventions have shown mixed results.

Given the systemic nature of MASH and its links to cardiometabolic disease, new therapies must target both hepatic and metabolic pathways. Further research is essential to evaluate promising interventions.

About the study

The present phase 3, randomized, double-blind, placebo-controlled trial was conducted across 253 sites in 37 countries. Adults aged 18 years and older with biopsy-confirmed MASH and liver fibrosis of stage 2 or 3 were enrolled. Participants were randomized in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at 2.4 milligrams or placebo for an initial 72 weeks as part of a longer 240-week trial designed to assess clinical outcomes.

Stratification was based on the presence of type 2 diabetes mellitus, fibrosis stage, and geographical region. After an initial dose-escalation period, participants maintained the 2.4-milligram dose unless adverse effects required adjustment.

Liver biopsies were performed at baseline and at week 72 to assess histological changes. Resolution of steatohepatitis without worsening of fibrosis and reduction in fibrosis without worsening of steatohepatitis were defined as the two co-primary endpoints.

Secondary outcomes included body weight change, composite histological improvement, and change in bodily pain score from the 36-Item Short Form Health Survey (SF-36). Noninvasive markers such as liver stiffness, the enhanced liver fibrosis (ELF) score, FibroScan-AST (FAST) score, N-terminal propeptide of type III collagen (PRO-C3) level, and liver enzyme levels were also monitored.

Efficacy analysis followed the intention-to-treat principle and used reference-based multiple imputation for missing data, with adjustments for multiple comparisons. Safety was evaluated through adverse event reporting and laboratory assessments. An external adjudication committee assessed serious clinical events in a blinded fashion.

Study results

This interim analysis included 800 patients, 534 of whom received semaglutide and 266 of whom were assigned to the placebo group. Baseline characteristics were well balanced, with a mean age of 56 and a mean body mass index of 34.6 kg/m². Approximately 56% of participants had type 2 diabetes mellitus, and most (68.8%) had stage 3 fibrosis.

The resolution of steatohepatitis without worsening of fibrosis was achieved in 62.9% of participants in the semaglutide group compared to 34.3% in the placebo group (difference: 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). Reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% in the semaglutide group versus 22.4% in the placebo group (difference: 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Both resolution and fibrosis reduction were observed in 32.7% of the semaglutide group and 16.1% of the placebo group.

Weight loss was significantly greater in the semaglutide group, with a mean reduction of 10.5% compared to 2.0% with placebo. Improvement in bodily pain scores did not reach the trial's prespecified threshold for statistical significance. Noninvasive measures also favored semaglutide, with greater reductions in ELF scores and liver stiffness. Specifically, 55.8% of patients in the semaglutide group had a decrease of at least 0.5 in ELF score compared to 25.5% in the placebo group. A 30% or greater reduction in liver stiffness occurred in 52.0% of semaglutide-treated patients versus 30.3% of those on placebo.

Semaglutide also improved markers of metabolic health. Glycated hemoglobin levels, insulin resistance as measured by the homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, and lipid parameters all showed favorable changes. These histological and metabolic effects were generally consistent across subgroups, including those with and without type 2 diabetes mellitus and regardless of baseline fibrosis stage, age, or sex.

Regarding safety, 86.3% of participants on semaglutide experienced an adverse event compared to 79.7% in the placebo group. Gastrointestinal side effects such as nausea, diarrhea, constipation, and vomiting were more frequent in the semaglutide group but were generally manageable. Serious adverse events occurred at similar rates (13.4%) in both groups, and trial discontinuation due to side effects was low (2.6% vs. 3.3%). No new or unexpected safety signals emerged.

Conclusions

While acknowledging limitations such as the small number of Black participants and lack of data on alcohol consumption biomarkers, this interim analysis demonstrates that once-weekly subcutaneous semaglutide at a dose of 2.4 milligrams significantly improves liver histology in patients with MASH and moderate-to-advanced fibrosis. In addition to resolving steatohepatitis and reducing fibrosis, semaglutide supports weight loss and improves cardiometabolic markers such as insulin resistance and lipid profiles.

These findings are relevant to a broad population affected by fatty liver disease, obesity, and type 2 diabetes mellitus. The safety profile was consistent with known effects of glucagon-like peptide-1 receptor agonists. Semaglutide presents a promising, multi-targeted therapeutic option for addressing the hepatic and systemic consequences of MASH, though final conclusions on long-term clinical outcomes await the completion of the full trial.