Scope and Efficacy of Semaglutide in Metabolic Dysfunction-associated Steatohepatitis: A Critical Review of Recent Evidences

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH), formerly termed nonalcoholic steatohepatitis (NASH), is a progressive hepatic manifestation of systemic metabolic dysfunction and a growing cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. Semaglutide, a glucagon-like peptide-1 receptor agonist licensed for type 2 diabetes and obesity, has emerged as a leading pharmacological candidate for MASH, culminating in a completed phase 2 programme and an interim phase 3 histological analysis. This review critically appraises the trajectory of evidence for subcutaneous semaglutide across the fibrosis spectrum, from early-stage disease to compensated cirrhosis, situating the drug within the wider landscape of glucagon-like peptide-1 receptor agonism, dual and triple incretin agonism, and the first liver-directed approval, resmetirom. Randomised, placebo-controlled trials demonstrate that semaglutide 2.4 mg weekly produces dose-dependent, weight-loss-associated resolution of steatohepatitis without worsening of fibrosis in a majority of treated patients with stage 2 or 3 fibrosis, together with favourable effects on cardiovascular and renal outcomes in overlapping populations. Fibrosis-stage improvement, however, has been inconsistent across trials, and efficacy appears substantially blunted or absent in established cirrhosis. Mechanistic evidence indicates that hepatic benefit is mediated predominantly indirectly, through weight reduction, improved insulin sensitivity, and reduced adipose-derived lipotoxic flux, rather than through direct hepatocellular glucagon-like peptide-1 receptor signalling, a point that remains contested. Gastrointestinal adverse effects are common, and a meaningfully elevated risk of biliary disease has been documented. The evidence base is characterised by industry sponsorship of all pivotal trials, short observation windows relative to the natural history of fibrosis progression, uncertain durability of histological gains after discontinuation, and unresolved questions regarding optimal patient selection, combination strategies, and comparative effectiveness against resmetirom and emerging multi-receptor agonists. This review concludes that semaglutide is a clinically meaningful but incompletely characterised addition to MASH pharmacotherapy, with fibrosis-modifying efficacy that remains less robust and less consistent than its effect on steatohepatitis activity, and identifies methodological priorities for the confirmatory phase of the ESSENCE programme and related outcome trials.