Semaglutide in metabolic dysfunction–associated steatohepatitis (MASH)

Metabolic dysfunction–associated steatohepatitis (MASH)

• was formerly called non–alcohol-related steatohepatitis, is a severe form of metabolic dysfunction–associated steatotic liver disease (MASLD; formerly, nonalcoholic fatty liver disease), characterized by steatosis, hepatocyte damage, and inflammation
• steatohepatitis promotes liver fibrosis, progression to cirrhosis, and hepatocellular carcinoma
• advanced fibrosis (stage 3 or higher) significantly increases liver-related and all-cause mortality

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the management of obesity and type 2 diabetes:

• in an interim analysis of ESSENCE study (n=800), semaglutide associated with higher steatohepatitis resolution without worsening of liver fibrosis (difference vs placebo: 28.7% [95% CI 21.1-36.2]) & reduction in liver fibrosis without worsening steatohepatitis (14.4% [7.5-21.3%] (1)
  • the study authors concluded that in patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results

A review notes that athough weight loss accounted for a major part of histological improvement of MASH with semaglutide, particularly for improvements in disease activity, observed improvement in fibrosis was mediated by weight loss to a lesser extent (2).

Reference:

1. Sanyal AJ et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. NEJM April 30th 2025.
2. Jara M et al. Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis. Nat Med 2025;31:3128–3140.