Therapeutic role of semaglutide in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis: A systematic review and meta-analysis of placebo-controlled trials with GRADE evidence assessment

Background: Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are leading causes of chronic liver disease worldwide. Despite the rising clinical burden, there are currently no approved pharmacologic therapies. Semaglutide, a glucagon-like peptide-1 receptor agonist with established metabolic and weight-loss benefits, is being evaluated for potential disease-modifying effects in NAFLD/NASH. Objective: To assess the efficacy and tolerability of subcutaneous semaglutide versus placebo in adults with NAFLD or NASH, focusing on biochemical, histologic, metabolic, and safety outcomes. Methods: We conducted a systematic review and meta-analysis of placebo-controlled randomized controlled trials evaluating subcutaneous semaglutide in adults (≥18 years) with NAFLD or NASH diagnosed by imaging, histology, and/or biochemical markers. PubMed, CENTRAL, and Scopus were searched from inception to May 15, 2025 using predefined terms related to semaglutide and fatty liver disease. Two independent assessors extracted data and evaluated risk of bias using the Cochrane RoB 2 tool, while certainty of evidence was appraised with Grading of Recommendations, Assessment, Development, and Evaluation. Pooled effect estimates were calculated using a random-effects model and reported as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs). Results: Semaglutide significantly reduced liver enzymes, including aspartate aminotransferase (MD = −6.72 U/L, 95% CI = −11.79 to −1.64; P = .009). Histologically, semaglutide more than doubled the likelihood of NASH resolution without fibrosis progression (RR = 2.14, 95% CI = 1.44–3.17; P = .0002). Improvement in fibrosis stage was not statistically significant (RR = 1.14, 95% CI = 0.63–2.05; P = .67), though the direction of effect favored semaglutide. Metabolic outcomes showed substantial benefits, including weight loss (MD = −6.99%, 95% CI = −13.92 to −0.06; P = .05) and improved glycated hemoglobin (MD = −1.29%, 95% CI = −1.46 to −1.13; P < .00001). Gastrointestinal adverse events and treatment discontinuation occurred more frequently with semaglutide, while serious adverse events were comparable to placebo (95% CI = 0.81–1.41; P = .64; P = .65). Conclusion: Semaglutide demonstrates promising efficacy for NASH resolution and meaningful metabolic improvement with an overall acceptable safety profile. Its effect on fibrosis remains uncertain, and longer-term, adequately powered trials are needed to clarify its role in NAFLD/NASH treatment.