Digestion. 2026 Sep 9:1. doi: 10.1159/dig/acmag014. Online ahead of print.
ABSTRACT
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly prevalent conditions closely linked to obesity, insulin resistance, and cardiometabolic diseases. Although lifestyle modification remains the cornerstone of management, it frequently fails to achieve sustained histologic improvement, suggesting that patients require effective pharmacologic therapies.
SUMMARY: Incretin-based treatments, including glucagon-like peptide-1 (GLP-1) receptor agonists and newer dual agonists additionally targeting glucose-dependent insulinotropic polypeptide (GIP), have emerged as promising disease-modifying options. These agents improve hepatic steatosis primarily through weight reduction and enhanced insulin sensitivity, while also exerting pleiotropic effects on inflammation, and lipid metabolism. Phase 2 clinical trials consistently demonstrate improvement in steatohepatitis with GLP-1 receptor agonists, with encouraging signals of fibrosis improvement observed with dual agonists such as tirzepatide. Interim data from a phase 3 clinical trial with semaglutide show clinically meaningful benefits in both MASH resolution and fibrosis regression. These findings have led to accelerated regulatory approval of semaglutide for the treatment of non-cirrhotic MASH with stage F2-F3 fibrosis. In addition to hepatic effects, incretin-based therapies provide substantial cardiometabolic benefits, reinforcing their relevance in a disease strongly associated with cardiovascular risk.
KEY MESSAGES: Overall, mono- and dual-incretin agonist therapies represent a significant advance in the treatment landscape of MASLD/MASH, although long-term outcome data are required to confirm durability, safety, and impact on major adverse liver-related outcomes.
PMID:42715139 | DOI:10.1159/dig/acmag014