Dual GLP-1/glucagon receptor agonists in metabolic dysfunction–associated steatotic liver disease: a meta-analysis of randomized controlled trials

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) affects approximately one-third of the global population. We aimed to evaluate the efficacy and safety of dual glucagon-like peptide-1 and glucagon receptor agonists (GLP-1/Gcg RAs) in patients with MASLD. PubMed, Web of Science, Scopus, and Cochrane Library were searched for randomized controlled trials (RCTs) comparing GLP-1/Gcg RAs with placebo or active comparators in patients with MASLD. Data were pooled using a random-effects model. The primary endpoint was relative change in liver fat content (LFC). Six RCTs (885 patients) were included. Compared with control, dual GLP-1/Gcg RAs significantly reduced relative LFC (mean difference [MD], -45.94%; 95% CI, -54.40 to -37.49), alanine aminotransferase (ALT) (MD, -16.97; 95% CI, -24.84 to -9.11), and aspartate aminotransferase (AST) (MD, -10.91; 95% CI, -17.15 to -4.68). Regarding safety, treatment increased the risk of gastrointestinal adverse events, including vomiting (RR: 4.08, 95% CI: 1.28–12.93), nausea (RR: 2.41, 95% CI: 1.43–4.03), decreased appetite (RR: 2.42, 95% CI: 1.24–4.71), constipation (RR: 1.73, 95% CI: 1.16–2.58), and diarrhea (RR: 1.62, 95% CI: 1.12–2.35), while serious adverse events were not significantly increased. In patients with MASLD, dual GLP-1/Gcg RAs showed promising hepatic benefits in Phase 2 trials. Further large, long-term RCTs are needed to establish their effects on fibrosis progression and clinically meaningful hepatic outcomes. Not applicable.