DAY 2: Glucagon-Like Peptide-1 Receptor Agonists May Change the Course of Metabolic Liver Disease

New data presented at the 2025 Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Arizona highlight the potential role of glucagon-like peptide-1 (GLP-1) receptor agonists in changing the natural history of metabolic dysfunction-associated steatohepatitis (MASH) by reversing hepatic fibrosis.

MASH is a progressive form of fatty liver disease characterized by inflammation, hepatocellular injury, and fibrosis. When left untreated, MASH significantly increases the long-term risk for morbidity, including cirrhosis, liver failure, and hepatocellular carcinoma, with fibrosis progression being the strongest predictor of morbidity and mortality. MASH is closely connected to metabolic conditions such as obesity, type 2 diabetes mellitus, and hypertension.

GLP-1 receptor agonists, which were initially developed for the management of type 2 diabetes, have shown promise for the improvement of liver histology and the resolution of steatohepatitis. In August 2025, the U.S. Food and Drug Administration approved injectable semaglutide for the treatment of noncirrhotic MASH in adults with moderate-to-advanced liver fibrosis (defined as stages F2 to F3 fibrosis). The recommended dosage for this indication is 2.4 mg per week, which is identical to the dose approved for the treatment of obesity. The approval was based on preliminary data from a study that showed a high rate of resolution of steatohepatitis in a cohort of 800 adults with biopsy-confirmed MASH and stage 2 or 3 fibrosis (Sanyal AJ et al. N Engl J Med 2025;392:2089-99). Semaglutide is the second agent to gain approval for the treatment of MASH and moderate-to-advanced fibrosis, after resmetirom, a liver-targeted thyroid hormone receptor-beta agonist. 
Given the emerging role of GLP-1 receptor agonists in treating liver disease, a meta-analysis was designed to evaluate the efficacy and safety of these therapies compared to placebo for MASH resolution, fibrosis improvement, and gastrointestinal adverse effects. Lead author Rahul Tripathi, MD, an internal medicine physician at Stony Brook University Hospital, in Stony Brook, New York, presented the findings in a poster session.

Tripathi and colleagues performed a comprehensive search of several medical databases, including PubMed and Embase, and selected six randomized controlled trials including 1273 patients with MASH, with a median age of 54 years. Of those, 782 patients were treated with GLP-1 receptor agonists and 491 patients received placebo. Participants were followed up for an average period of 57 weeks.

The analysis showed that GLP-1 receptor agonists were strongly associated with an overall improvement in MASH. Moreover, these therapies had nearly a 4-fold higher likelihood of resolving steatohepatitis compared with placebo. When looking at the stage of fibrosis, GLP-1 receptor agonists nearly doubled the odds of fibrosis regression compared with placebo. Gastrointestinal side effects, including nausea, vomiting, and diarrhea, were more common with GLP-1 receptor agonists, which was consistent with their side effect profile. While adverse events were much more frequent in treated participants than in those who received placebo, these events were generally mild and self-limited.

“Our findings demonstrate that GLP-1 receptor agonists significantly improve histological resolution of MASH, fibrosis, and fibrosis regression compared with placebo,” Tripathi concluded. “This suggests that GLP-1 [receptor agonist] therapies may modify the natural history of metabolic liver disease beyond glycemic control or weight loss. Although gastrointestinal intolerance remains a common limitation, the benefits appear to outweigh these risks in most patients.”