Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction-associated Steatohepatitis: A Systematic Review and Meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 40489581 · doi:10.1210/clinem/dgaf336
What was done
Authors systematically reviewed PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) evaluating GLP-1 receptor agonists (liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, retatrutide) against placebo or active comparators in MASLD/MASH. Outcomes evaluated included imaging-based liver fat content (LFC), liver histology (steatosis, ballooning, lobular inflammation, fibrosis), serum liver enzymes (ALT, AST, GGT), and noninvasive fibrosis markers/liver stiffness. Pooled mean differences and risk ratios with 95% confidence intervals were calculated using random-effects models.
What was found
Twenty-five RCTs with 2,600 patients were analyzed (median treatment duration: 24 weeks). GLP-1-based therapies significantly reduced LFC by 5.21%, with retatrutide showing the largest effect. On histology, treatments induced significant improvements in steatosis, hepatocellular ballooning, and lobular inflammation, but showed nonsignificant improvement in fibrosis (with tirzepatide demonstrating more robust evidence than semaglutide or liraglutide). Serum ALT, AST, and GGT were significantly decreased. Liver stiffness also significantly improved, with semaglutide showing the most prominent effect. No drug-related hepatic adverse events were observed.
Why it matters
This meta-analysis demonstrates that GLP-1-based and multi-incretin therapies consistently improve hepatic steatosis, inflammation, and liver enzymes in MASLD/MASH, though definitive histological fibrosis regression remains unproven at short-to-medium follow-up.
Limits
Exact numerical effect sizes and confidence intervals for histological, enzymatic, and stiffness outcomes were omitted in the abstract. Interventions pooled single GLP-1RAs alongside dual and triple co-agonists. A median duration of 24 weeks is likely insufficient to capture histological reversal of liver fibrosis or long-term clinical liver-related outcomes.
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- supports Retatrutide's glucagon receptor activation combined with GLP-1 and GIP agonism leads to significant weight reduction and marked improvements in liver fat and NASH.