S2339 Semaglutide Reduces Incident Cirrhosis, Complications, and Mortality in MASLD Patients With Diabetes: A Retrospective Cohort Study

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to type 2 diabetes (T2DM), cirrhosis and mortality. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has demonstrated histologic benefit in a recent phase-3 trial. Whether these gains translate into improved clinical outcomes in MASLD and T2DM remains unknown. We evaluated semaglutide association with cirrhosis, decompensation, and mortality in a real-world cohort. Methods: We used TriNetX (2015-2025), a large-scale database comprising electronic health records from 104 U.S. healthcare organizations to compare outcomes among adults ≥18 years with MASLD (International Classification of Diseases, Tenth Revision (ICD-10) K76.0 or K75.81, excluding other liver diseases) and T2DM (E11.x) by semaglutide user status, stratified by cirrhosis status. Baseline was the first encounter with both codes, and persons with any study outcome on or before baseline were excluded. Semaglutide exposure required a first prescription ≥90 days after baseline without prior exposure. Propensity score matching (1:1) balancing 15 demographic/metabolic covariates was used with follow-up ascertained up to 3 years. In persons without cirrhosis, outcomes included progression to cirrhosis and incident cirrhosis complications. In cirrhosis, outcomes were composite and individual cirrhosis complications, hepatocellular carcinoma, and liver transplantation. Binary outcomes were analyzed with logistic regression, and time-to-event outcomes with Cox proportional-hazards models. Results: Baseline characteristics and median follow-up were well balanced after matching. Mean age was 57 (SD 13.5) and 60 (SD 13.2) years, 52.7% and 59.6% women for the non-cirrhosis and cirrhosis cohorts, respectively. In persons without cirrhosis, non-semaglutide users had roughly twice the odds of incident cirrhosis and 2.4 times higher odds of decompensation. In the cirrhosis cohort, non-semaglutide use was associated with 60% higher decompensation risk. All-cause mortality was ∼4-fold higher in non-users, regardless of cirrhosis status. Conclusion: In this propensity-matched, real-world cohort of >100,000 U.S. adults with MASLD and T2DM, semaglutide use was associated with significantly lower odds of cirrhosis, fewer cirrhosis-related complications, and improved survival. These findings extend the histologic efficacy observed in recent clinical trials to clinically meaningful endpoints and support semaglutide’s potential role as a disease-modifying agent in MASLD.