S2756 GLP-1 Receptor Agonists in Metabolic Dysfunction-Associated Steatohepatitis: A Meta-Analysis of Efficacy and Safety

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated fatty liver disease (MAFLD), is linked to a high risk of liver-related complications as well as all-cause morbidity and mortality. Despite the advent of multiple therapeutic targets currently in late phase of drug development, there is limited consensus regarding the efficacy of these regimens. Given the limited high-quality evidence for first-line regimens, this meta-analysis aims to investigate the efficacy and safety of the glucagon-like peptide-1 analogues (semaglutide and liraglutide) for the treatment of MASH. Methods: PubMed, Embase, Cochrane, ClinicalTrials.gov, and WHO ICTRP were searched for randomized controlled-trials (RCTs). Outcomes were analyzed using a random-effects model. For dichotomous outcomes Mantel-Haenszel method, and for contrast-level data inverse variance method was used. Heterogeneity was assessed by DerSimonian and Laird, and confidence intervals by the Wald method. All analyses were conducted using RevMan Web. Results: Five RCTs consisting of 1,264 patients with confirmed MASH were included. Compared with placebo, treatment with semaglutide and liraglutide in a significantly higher rate of MASH resolution (OR: 3.29; 95%-CI: 2.50, 4.32; P < 0.00001) and demonstrated a pooled mean reduction in liver stiffness of −1.86 kPa (95%-CI: -3.43, -0.30). However, no significant difference was observed in the proportion of patients achieving a reduction in liver fibrosis stage (OR: 1.43; 95%-CI: 0.75, 2.74; P = 0.28). While treatment was associated with a significantly increased risk of gastrointestinal adverse events (OR: 3.51; 95%-CI: 2.70, 4.56; P < 0.00001), there was no statistically significant difference in the incidence of serious adverse events (OR: 1.10; 95%-CI: 0.81, 1.51; P = 0.54) or treatment discontinuations (OR: 1.01; 95%-CI: 0.58, 1.77; P = 0.97). Conclusion: GLP-1 receptor agonists, particularly semaglutide, significantly improve liver histology in patients with MASH, especially among those with moderate to advanced fibrosis. The overall favorable safety profile, aside from an increased incidence of gastrointestinal adverse events, supports the potential role of these agents as first-line therapy in MASH management. Nevertheless, studies with broader population groups and longer duration are needed to determine the long-term impact of gastrointestinal side effects on treatment adherence and patient quality of life.