Impact of Glucagon-Like Peptide-1 Receptor Agonists on Liver-Related Outcomes, Laboratory and Physiologic Parameters in Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis.

Background Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease globally, with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show potential for MASH due to their metabolic benefits, but evidence on histological outcomes remains inconclusive.

Methods We conducted a PRISMA 2020-compliant systematic review and meta-analysis, including 25 randomized controlled trials (RCTs, n=2481). Primary outcomes were resolution of MASH without fibrosis worsening and fibrosis improvement without steatohepatitis worsening. Secondary outcomes included anthropometric and biochemical parameters. Risk of bias was assessed via ROB 2, and evidence certainty via GRADE. Trial sequential analysis (TSA) addressed random errors.

Results GLP-1 RAs significantly increased MASH resolution without fibrosis worsening (OR=4.04; 95% CI [2.69-6.05]; P<0.00001; 7 RCTs, n=1456). No significant improvement in fibrosis was observed (OR=1.54; 95% CI [0.95-2.48]; P=0.08; 5 RCTs, n=1277). Secondary outcomes showed reduced BMI (MD=-0.52 kg/m2; P=0.05) but no significant changes in weight, waist circumference, liver enzymes, or lipids. TSA confirmed sufficient evidence for MASH resolution (RIS=197) but not fibrosis improvement (RIS=1693). GRADE indicated high certainty for primary outcomes.

Conclusion GLP-1 RAs promote MASH resolution but do not significantly improve fibrosis. Their benefits appear to be driven by metabolic mechanisms rather than direct antifibrotic effects. Larger RCTs targeting fibrosis endpoints are warranted.

Trial Registration The protocol for our meta-analysis and systematic review was registered and recorded in PROSPERO (registration no. CRD420251090801).