Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis

New therapies are urgently needed for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We conducted this systematic review and meta-analysis to evaluate the therapeutic effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on MASLD/MASH. We searched PubMed, Embase and Cochrane Library database to identify randomized controlled trials (RCTs) that compared GLP-1RAs with placebo or active agents with respect to the efficacy in patients with MASLD/MASH. The effects of GLP-1RAs on liver fat content (LFC) by imaging, liver histology, serum liver enzymes, and noninvasive fibrosis indexes (fibrosis-4, NFS, CK-18, procollagen III and liver stiffness) were evaluated. Mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effect model. 25 RCTs involving 2600 patients that used GLP-1RAs including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide and retatrutide were included. Overall, GLP-1RAs treatment for a median of 24 weeks demonstrated a significant reduction in LFC by 5.21%, with the retatrutide displaying the most obvious treatment effects. GLP-1RAs treatment induced significant histological improvements in steatosis, hepatocellular ballooning and lobular inflammation, but non-significantly improved fibrosis, with the evidence for tirzepatide more robust than that for semaglutide and liraglutide. GLP-1RAs treatment significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT) compared with control. GLP-1RAs also significantly improved liver stiffness, with semaglutide displaying the most obvious treatment effect. No drug-related adverse effects involving the liver was observed. GLP-1RAs decreased liver fat deposition and improved histological steatosis, hepatocellular ballooning and lobular inflammation, without worsening of fibrosis in MASLD and MASH.