GLP-1 Receptor Agonists Consistently Resolve MASH and Improve Fibrosis While Reducing Cardiovascular Events in MASLD Patients

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, representing a systemic cardiometabolic disorder where cardiovascular disease is the leading cause of death. Current treatments often fall short in addressing both hepatic pathology and cardiovascular risk simultaneously. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are uniquely positioned to target this critical liver-heart axis by combining direct hepatic disease-modifying signals with their established benefits in cardiovascular risk reduction, offering a comprehensive therapeutic approach.

This comprehensive review synthesized mechanistic, randomized trial, and real-world evidence for GLP-1RAs in MASLD and metabolic dysfunction-associated steatohepatitis (MASH). The authors analyzed data from key biopsy-based trials, including LEAN (liraglutide), Phase 2 and SELECT (semaglutide), and SYNERGY-NASH (tirzepatide), alongside major cardiovascular outcome trials (LEADER, SUSTAIN-6, REWIND, SELECT). The synthesis focused on hepatic histological endpoints, such as MASH resolution and fibrosis improvement, as well as major adverse cardiovascular events (MACE) across various GLP-1RA agents.

GLP-1RAs demonstrated significant efficacy in MASH resolution and fibrosis improvement. In the LEAN trial, liraglutide increased steatohepatitis resolution without fibrosis worsening by 39% compared to 9% with placebo. Semaglutide showed dose-dependent resolution in Phase 2 trials, reaching up to 59% versus 17% in the placebo group. More recently, semaglutide 2.4 mg weekly met both histologic endpoints at interim analysis in F2-F3 MASH, achieving resolution without fibrosis worsening in 62.9% of patients versus 34.3% in the placebo group, and fibrosis improvement by at least 1 stage in 36.8% versus 22.4%. Tirzepatide (SYNERGY-NASH) achieved high rates of MASH resolution, ranging from 44% to 62% compared to 10% with placebo, with concomitant fibrosis improvement signals up to 51% versus 30%. Cardiovascular outcome trials consistently demonstrated significant reductions in major adverse cardiovascular events with GLP-1RAs. Mechanistically, GLP-1RAs reduce hepatic lipogenesis and lipotoxicity, attenuate inflammation, improve insulin sensitivity, and modulate gut-brain-liver signaling, leading to systemic benefits on weight, blood pressure, and atherogenic lipoproteins.

The evidence strongly supports GLP-1RAs, particularly semaglutide and tirzepatide, as foundational therapies for MASLD patients with obesity, type 2 diabetes, advanced fibrosis, or heart failure phenotypes.