DAY 1: Incretin-Based Therapies Mark a Significant Shift in the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

A meta-analysis presented at the 2025 Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Arizona showed that incretin-based dual and triple agonists have the potential to elevate the level of care for patients with metabolic dysfunction-associated steatohepatitis (MASH) by delivering significant improvements in hepatic and metabolic outcomes.

MASH is a progressive liver disease with deep connections to diabetes, insulin resistance, and obesity. By targeting these metabolic drivers, incretin-based therapies can inhibit the underlying mechanisms of MASH rather than just the associated symptoms. While recent studies have hinted that incretin-based therapies may benefit patients with MASH, there is little information about their effect on long-term hepatic outcomes.

“Weight loss improves outcomes, but long-term maintenance is difficult, prompting investigation of metabolic agents that target hepatic steatosis,” lead author Amanda Rigdon, MD, an internal medicine specialist at the Lakeland Regional Health Medical Center in Lakeland, Florida, said in a poster presentation. “Incretin-based therapies, particularly dual and triple receptor agonists, targeting glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon, have shown promising effects on weight loss, metabolic function, and liver fat reduction.” 

Rigdon and colleagues conducted a systematic review and meta-analysis to compare the efficacy of GLP-1 agonist monotherapy with dual and triple incretin agonists in reducing liver fat and improving other hepatic and metabolic outcomes, such as lipid levels and liver enzymes, in individuals with MASH. The final analysis, which included data from six randomized controlled trials, showed that incretin-based therapies significantly reduced liver fat in patients with MASH. Triple agonist retatrutide achieved the greatest reduction (up to 83%), followed by dual GLP-1/glucagon agonists pemvidutide (64%) and survodutide (60%) and GLP-1/GIP agonist tirzepatide (47%). GLP-1 monotherapy with semaglutide also reduced liver fat, but to a lesser extent (39%). 

Although gastrointestinal side effects were common, all therapies were generally well tolerated. The authors cautioned that longer follow-up periods and standardized endpoints are necessary to paint a more complete picture of the long-term clinical benefits of these therapies. 

“This meta-analysis provides compelling evidence that dual and triple incretin agonists lead to significant liver fat reduction in patients with MASH, with a clear dose-response effect observed across all agents,” the authors concluded. “Triple agonists like retatrutide demonstrated the most profound effects, achieving up to an 83% reduction in liver fat at higher doses. Among the dual agonists, pemvidutide and survodutide showed superior efficacy compared to tirzepatide, likely due to glucagon’s direct hepatic lipolytic effects. GLP-1 monotherapy, such as semaglutide, achieved a meaningful but lesser reduction, reinforcing the enhanced efficacy of multi-receptor agonists in reducing liver fat in MASH. These findings support the potential of incretin-based therapies as a cornerstone in the management of MASH.”