S2858 Efficacy and Safety of Semaglutide in Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Nonalcoholic steatohepatitis (NASH) lacks approved pharmacotherapy. We performed a meta-analysis of randomized controlled trials comparing semaglutide to placebo on histological, biochemical, metabolic, and safety outcomes in NASH. Methods: Three trials (n = 1191) were included. Outcomes pooled using random-effects models, reporting risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI), P-values, and heterogeneity (I²). PROSPERO ID: CRD420251045059. Results: Semaglutide markedly increased NASH resolution without fibrosis worsening (RR 3.55, P < 0.0001) but did not significantly improve fibrosis stage (RR 1.31, P = 0.61). It reduced liver-stiffness final scores (MD –1.95, P = 0.02) and Enhanced Liver Fibrosis scores (MD –1.65, P = 0.007). Semaglutide also lowered aspartate aminotransferase (MD –11.23 U/L, P < 0.0001), alanine aminotransferase (MD –15.21 U/L, P < 0.0001), and GGT (MD –24.00 U/L, P < 0.0001). Metabolic benefits included greater weight loss (MD –13.65 kg, P < 0.0001) and HbA1c reduction (MD –1.59%, P < 0.0001). Overall adverse events were comparable (RR 1.02, P = 0.42), with increased gastrointestinal events; nausea (RR 2.88), constipation (RR 2.16), diarrhea (RR 2.07), vomiting (RR 3.98), and decreased appetite (RR 4.59, all P < 0.0001). Serious and other non-GI adverse events did not differ. Conclusion: Semaglutide significantly improves histological, biochemical, and metabolic parameters in NASH with an acceptable safety profile, though gastrointestinal tolerability warrants monitoring.