S2765 Beyond Diabetes: The Role of Glucagon-Like Peptide-1 Receptor Agonists in Non-Diabetic NASH

Introduction: Nonalcoholic steatohepatitis (NASH) is associated with metabolic syndrome, a component of which is type 2 diabetes. However, emerging evidence suggests that NASH also affects non-diabetics, for whom therapeutic choices are limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which are frequently prescribed for metabolic conditions like type 2 diabetes and obesity, have proven to improve liver function. This study assesses the efficacy and safety of GLP-1 RAs in non-diabetic adults with NASH or NAFLD. Methods: A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science was executed through November 2024. Randomized controlled trials (RCTs), meta-analyses, and systematic reviews of GLP-1RA treatment in people with NASH or NAFLD were included, with a focus on the non-diabetic subpopulation. The primary outcomes were histological NASH resolution, hepatic fat reduction, changes in liver enzymes and metabolic parameters. Results: Thirty RCTs and multiple meta-analyses (over 2,000 patients) were appraised. These studies concluded that liraglutide and semaglutide markedly enhanced NASH resolution. In the LEAN trial, 39% on liraglutide attained resolution vs 9% on placebo (∼39% non-diabetics). A phase 2 study of semaglutide indicated 59% resolution compared to 17% placebo in both diabetic and non-diabetic groups. Meta-analyses verified a significant decrease in visceral adiposity and a reduction in hepatic fat (weighted mean difference ∼–3.1%). Improvements in alanine aminotransferase, aspartate aminotransferase, and insulin resistance were consistently seen. Despite the remarkable safety, the common adverse effects observed were gastrointestinal symptoms. However, results on the regression of fibrosis were inconsistent, and the majority of trials included mixed groups, making it difficult to draw inferences about people without diabetes. Conclusion: GLP-1RAs are a promising therapeutic breakthrough for non-diabetic patients with NASH because they reduce hepatic steatosis, inflammation, and metabolic markers. However, dedicated large-scale RCTs in non-diabetic groups are required to validate these findings and inform clinical guidelines.