S2340 Semaglutide and Tirzepatide Show Comparable Hepatic Outcomes in MASLD: A Propensity-Matched Analysis of a Multi-Institutional EHR Database

Introduction: MASLD is a leading cause of cirrhosis and mortality. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has demonstrated histologic benefit in a recent phase-3 trial. Likewise, tirzepatide, a dual gastric inhibitory peptide (GIP)/GLP-1 RA, is being investigated for MASLD, yet comparative evidence on clinical outcomes is limited. 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). Baseline was first MASLD encounter; persons with other liver disease or any study endpoint on/before baseline were excluded. Separate analyses were conducted for those with and without cirrhosis at baseline. We created 2 cohorts: semaglutide ≥90 d after baseline with no exposure to tirzepatide and tirzepatide ≥90 d after baseline with no exposure to semaglutide. Propensity score matching (1:1) balanced 12 covariates. Outcomes were ascertained for up to 3 years. In persons without cirrhosis, outcomes were progression to cirrhosis and incident composite cirrhosis complications. In cirrhosis, outcomes were composite and individual cirrhosis complications (variceal bleeding, ascites, jaundice, hepatic encephalopathy), hepatocellular carcinoma (HCC), and liver transplantation (LT). Logistic and Cox models (HR) compared semaglutide to tirzepatide (reference), as appropriate. Results: Baseline characteristics and median follow-up were well balanced after matching. The odds of developing cirrhosis did not differ between persons prescribed semaglutide (0.25%) vs tirzepatide (0.24%) (OR 1.1, 95% CI 0.7-1.7, P = 0.74). Similarly, the odds of composite cirrhosis complications did not differ between semaglutide and tirzepatide users with (OR 1.0, 95% CI 0.8-1.3, P = 1.00) or without cirrhosis (OR 0.9, 95% CI 0.7-1.3, P = 0.72). Risks of individual complications, HCC, and LT were also similar between treatment groups. Cox regression showed no survival difference between semaglutide and tirzepatide users in those with (HR 0.55, 95% CI 0.27–1.12) and without (HR 1.04, 95% CI 0.72–1.50) cirrhosis. Conclusion: In this large, propensity-matched real-world cohort of persons with MASLD, semaglutide and tirzepatide users had no differences in risk of cirrhosis progression, complications, or survival, suggesting potential therapeutic equivalence for hepatic outcomes. Prospective head-to-head trials are needed to guide optimal agent selection.