Abstract
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual agonists have been shown to induce histological improvements in patients with metabolic dysfunction-associated steatohepatitis (MASH). However, current clinical evidence on their effectiveness in improving hepatic fibrosis and cardiovascular outcomes remains limited and inconsistent. METHODS: This study synthesized randomized controlled trials (RCTs) from major databases up to August 30, 2025, focusing on patients with biopsy-confirmed MASH. Pooled mean differences were calculated using either a fixed-effects or random-effects model, depending on the degree of heterogeneity observed among the studies. RESULTS: Six studies including 1,726 participants were analyzed. Compared with placebo, GLP-1RAs and dual agonists significantly increased the likelihood of histological improvement in MASH without worsening hepatic fibrosis. (OR: 4.51, 95% CI: 3.68 to 5.52). It was associated with a ≥1-stage improvement in hepatic fibrosis without worsening MASH (OR: 1.78; 95% CI: 1.47to2.16). In addition, it contributed to MASH resolution accompanied by a ≥1-stage improvement in hepatic fibrosis (OR: 7.42; 95% CI: 2.98to18.48). In subgroup analyses based on post-treatment weight loss, GLP-1RAs and dual agonists demonstrated significant efficacy in promoting hepatic fibrosis resolution without worsening MASH among patients achieving a ≥10% weight loss (OR: 9.59; 95% CI: 4.01to15.18). However, in patients with <10% weight loss, GLP-1RAs and dual agonists did not demonstrate significant differences (OR: 1.30; 95% CI: 0.92to1.83). Moreover, GLP-1RAs and dual agonists achieved a significant pooled reduction in cardiovascular parameters, including total cholesterol (WMD: -4.15 mmol/L; 95% CI: -13.13 to 4.82) and triglycerides (WMD: -17.70 mmol/L; 95% CI: -21.95 to -13.44). Nevertheless, no significant improvement was observed in Low-Density Lipoprotein Cholesterol (LDL-C) levels (WMD: -0.67 mmol/L; 95% CI: -6.55 to 5.21). CONCLUSION: In patients with MASH who achieve a ≥10% weight loss, GLP-1RAs and dual agonists are associated with significant improvements in hepatic fibrosis, whereas their effect is limited in those with <10% weight loss. However, a significant reduction in LDL-C was observed only among patients achieving substantial (≥10%) weight loss. This finding suggests that for patients requiring comprehensive cardiovascular risk management, additional lipid-lowering strategies may be needed to optimize the effectiveness of the intervention. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42025640318.