Efficacy and safety of GLP-1 receptor agonists in MASH with fibrosis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a risk factor for progressive hepatic fibrosis and cirrhosis. The role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of patients with MASH with fibrosis remains under investigation. This meta-analysis evaluates the efficacy and safety of GLP-1 RAs in patients with 'at-risk' MASH. METHODS: We reviewed and analyzed all randomized controlled trials (RCTs) from PubMed, Embase, and Cochrane databases. Primary outcomes included MASH resolution without worsening fibrosis or fibrosis improvement without worsening of MASH. Secondary outcomes included adverse events (AEs), laboratory, and anthropometric data. Studies evaluating dual agonists of the GLP-1 receptor with glucagon or glucose-dependent insulinotropic polypeptide agonists were also included. We performed meta-regression analyses to assess whether histologic outcomes were mediated by changes in body weight and glycemic control. RESULTS: Seven RCTs (1,800 patients, mean follow-up: 136.8 weeks) were included. In the population with baseline F2-F3 fibrosis stage, GLP-1 RAs were superior to placebo for histological resolution of MASH without worsening fibrosis (risk ratio 2.96; 95% CI 1.70-5.15, 0.001; I = 75.4%) and improvement of fibrosis without worsening MASH (risk ratio 1.59; 95% CI 1.32-1.90, 0.001; I = 0%). GLP-1 RAs also improved aminotransferases, MRI-proton density fat fraction, HbA1c, serum lipids, blood pressure, and anthropometric parameters in RCTs of MASH with F2-F3 fibrosis. GLP-1 RA treatment was associated with higher rates of treatment-emergent gastrointestinal AEs, but no significant differences in serious AEs when compared to placebo. CONCLUSION: GLP-1 RAs improve MASH and MASH-associated hepatic fibrosis while also improving cardiometabolic risk factors in patients with MASH. Ongoing studies will define whether these surrogate endpoints translate into a decrease in liver-related and all-cause morbidity and mortality in patients at risk for adverse clinical outcomes attributable to MASH. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is a major driver of liver-related morbidity and mortality, yet effective pharmacologic options remain limited. This meta-analysis shows that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly increase histologic resolution of MASH without worsening fibrosis and improve fibrosis stage without worsening MASH. Simultaneously, they improve metabolic risk factors, supporting their role as disease-modifying agents in patients with at-risk MASH. These benefits, together with a favorable safety profile, highlight their potential as a dual-target therapeutic strategy for hepatologists and endocrinologists managing this high-risk population. Future trials assessing long-term clinical outcomes will be essential to guide guideline development, inform access policies, and support the extension of GLP-1 RA use.