GLP-1 Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Hepatic and...

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.