Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction-associated Steatohepatitis: A Systematic Review and Meta-analysis.
This systematic review and meta-analysis pooled data from 25 randomized controlled trials (RCTs) involving approximately 2,600 patients to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide — on metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Across a median treatment period of 24 weeks, the authors reported that GLP-1RAs were associated with a statistically significant mean reduction in liver fat content of 5.21%, with retatrutide showing the largest effect. Histological analyses suggested significant improvements in steatosis, hepatocellular ballooning, and lobular inflammation, though improvements in fibrosis did not reach statistical significance. Liver enzymes (ALT, AST, γ-GT) and liver stiffness also improved significantly, with semaglutide showing the most pronounced effect on stiffness. No liver-related adverse drug effects were identified. Limitations include heterogeneity across trials, variable treatment durations, and the relatively short median follow-up, which may be insufficient to capture fibrosis outcomes. The evidence base is derived entirely from RCTs in human populations.
Why this grade: The conclusions are drawn from a pooled analysis of 25 RCTs in approximately 2,600 human patients, representing the highest tier of clinical study design for evaluating therapeutic efficacy.
Objective 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. Methods We searched PubMed, Embase, and Cochrane Library databases 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, nonalcoholic fatty liver disease fibrosis score, cytokeratin 18, procollagen III, and liver stiffness) were evaluated. Mean differences and risk ratios with 95% confidence intervals were pooled using a random-effect model. Results Twenty-five RCTs involving 2600 patients who 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 retatrutide displaying the most obvious treatment effects. GLP-1RAs treatment induced significant histological improvements in steatosis, hepatocellular ballooning, and lobular inflammation but nonsignificantly improved fibrosis, with the evidence for tirzepatide more robust than that for semaglutide and liraglutide. GLP-1RAs treatment significantly decreased serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase 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 were observed. Conclusion GLP-1RAs decreased liver fat deposition and improved histological steatosis, hepatocellular ballooning, and lobular inflammation, without worsening of fibrosis in MASLD and MASH.
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