Glucagon-Like Peptide-1 Receptor Agonist Use and Liver-Related Outcomes in Metabolic Dysfunction-Associated Steatotic Liver Disease and Type 2 Diabetes in the All of Us Research Program

INTRODUCTION: Randomized clinical trials indicate that glucagon-like peptide-1 receptor agonist (GLP-1 RA) treatment improves histologic endpoints in steatotic liver disease, but its effects on long-term clinical outcomes remain uncertain. We examined the association between GLP-1 RA use and hepatic complications in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM). METHODS: We conducted a retrospective, new-user cohort study emulating sequential monthly target trials using All of Us Research Program data from 2010 to 2023 to compare GLP-1 RA users with propensity score-matched controls. Eligible participants had MASLD and T2DM. We excluded participants with previous hepatic complications or other chronic liver diseases. The primary outcome was a composite of incident cirrhosis, hepatic decompensation, hepatocellular carcinoma, or liver transplantation. We performed intention-to-treat and per-protocol analyses. RESULTS: A total of 2,110 GLP-1 RA users were matched to 2,110 nonusers. Over a median follow-up of 2.7 years, 187 hepatic complication events occurred: 74 among GLP-1 RA users (13.5 per 1,000 person-years) and 113 among nonusers (21.9 per 1,000 person-years). GLP-1 RA use was associated with a 38% lower risk in the intention-to-treat analysis (hazard ratio, 0.62; 95% confidence interval, 0.46-0.83; P = 0.003) and a 42% lower risk in the per-protocol analysis (hazard ratio, 0.58; 95% confidence interval, 0.42-0.80; P = 0.001). Subgroup analyses by baseline fibrosis-4 and body mass index demonstrated consistent directional trends. Landmark analyses at 6 months were consistent with the primary findings. A negative control outcome, incident fracture, showed no association. DISCUSSION: In a nationwide, diverse cohort of individuals with MASLD and T2DM, GLP-1 RA use was associated with a reduction in hepatic complication events, supporting a potential hepatoprotective effect in real-world clinical practice.