GLP-1 Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Hepatic and Cardiovascular Outcomes.
This review synthesizes evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), with particular attention to the liver-heart connection. The authors draw on mechanistic studies, biopsy-based randomized trials, real-world data, and cardiovascular outcome trials. Key trial findings highlighted include: liraglutide (LEAN trial) achieving steatohepatitis resolution in 39% vs. 9% of placebo recipients; semaglutide showing dose-dependent histologic resolution (up to 59% vs. 17% in Phase 2) and meeting dual histologic endpoints in F2–F3 MASH at interim analysis; and tirzepatide (SYNERGY-NASH) demonstrating MASH resolution in 44–62% vs. 10% with fibrosis improvement signals. Cardiovascular outcome benefits were observed across LEADER, SUSTAIN-6, SELECT, and REWIND trials. Mechanistically, GLP-1RAs are described as reducing hepatic lipogenesis, inflammation, and insulin resistance while improving systemic cardiometabolic risk factors. The review concludes that semaglutide and tirzepatide may serve as foundational therapies for high-risk MASLD patients, while noting gaps in long-term durability data, optimal treatment duration, and evidence in cirrhosis.
Why this grade: This is a narrative review synthesizing findings from multiple trial types; it does not generate new primary data and its conclusions depend entirely on the quality and scope of the studies it synthesizes.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults worldwide and represents a systemic cardiometabolic disorder in which cardiovascular disease is the leading cause of death. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are uniquely positioned to address this liver-heart axis by combining hepatic disease-modifying signals with proven cardiovascular risk reduction. This review synthesizes mechanistic, randomized trial, real-world, and cardiovascular outcome evidence for GLP-1RAs in MASLD and metabolic dysfunction-associated steatohepatitis (MASH). In biopsy-based trials, liraglutide (LEAN) increased steatohepatitis resolution without fibrosis worsening (39% vs. 9% with placebo), while semaglutide demonstrated dose-dependent resolution (up to 59% vs. 17% in Phase 2). More recently, semaglutide 2.4 mg weekly met both histologic endpoints at interim analysis in F2-F3 MASH (resolution without fibrosis worsening 62.9% vs. 34.3%; fibrosis improvement ≥ 1 stage 36.8% vs. 22.4%), and tirzepatide (SYNERGY-NASH) achieved high rates of MASH resolution (44%-62% vs. 10%) with concomitant fibrosis improvement signals (up to 51% vs. 30%). Cardiovascular outcome trials demonstrate consistent reductions in major adverse cardiovascular events with GLP-1RAs, including liraglutide (LEADER), semaglutide (SUSTAIN-6 and SELECT), and dulaglutide (REWIND). Mechanistically, GLP-1RAs reduce hepatic lipogenesis and lipotoxicity, attenuate inflammation, improve insulin sensitivity, and modulate gut-brain-liver signaling, with systemic benefits on weight, blood pressure, and atherogenic lipoproteins. Collectively, the evidence supports GLP-1RAs, particularly semaglutide and tirzepatide, as foundational therapies for MASLD patients with obesity, type 2 diabetes, advanced fibrosis, or heart failure phenotypes. Key gaps include treatment duration, durability of fibrosis benefit, and effectiveness in cirrhosis, requiring long-term follow-up.
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