S2327 Comparative Efficacy of Tirzepatide vs Semaglutide on Liver and Cardiovascular Related Outcomes in Patients With MASLD/MASH, Obesity, and Type 2 Diabetes Mellitus: A Real-World Cohort Study

Introduction: Metabolic-associated steatotic liver disease (MASLD) and metabolic-associated steatohepatitis (MASH) commonly coexist with obesity and type 2 diabetes mellitus (T2DM). Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 receptor agonist, have emerged as effective treatments addressing various metabolic derangements. This study compares real-world liver and cardiovascular outcomes of tirzepatide and semaglutide in patients with MASLD/MASH, obesity, and T2DM. Methods: Using the TriNetX global health research network, a retrospective, propensity score-matched analysis was conducted involving patients ≥18 years old with MASLD/MASH, obesity (body mass index ≥30 kg/m²), and T2DM treated with tirzepatide or semaglutide (n = 15,453 in each arm after propensity score matching). Matching included demographics, clinical characteristics, medications, and laboratory parameters. Outcomes assessed over 3 years included cirrhosis, hepatocellular carcinoma (HCC), major adverse cardiovascular events (MACE), all-cause mortality (ACM), and all-cause hospitalizations (ACH) with reported risk ratios (RR). Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Kaplan Mayer curves. Results: Compared to semaglutide, tirzepatide was significantly associated with a lower risk of several outcomes: a 17% reduction in MACE (RR 0.83; 95% CI, 0.77–0.90), a 29% reduction in ACM (RR 0.71; 95% CI, 0.57–0.90), a 23% reduction in ACH (RR 0.77; 95% CI, 0.73–0.82), a 25% reduction in myocardial infarction (RR 0.75; 95% CI, 0.64–0.89), an 11% reduction in heart failure (RR 0.89; 95% CI, 0.83–0.95), and a 29% reduction in heart failure exacerbations (RR 0.71; 95% CI, 0.59–0.84). There were no statistically significant differences between Tirzepatide and Semaglutide in the risk of progression to cirrhosis (RR 0.94; 95% CI, 0.86–1.02) or the incidence of HCC (RR 1.16; 95% CI, 0.81–1.65). Conclusion: In this large, propensity score-matched real-world cohort, Tirzepatide treatment was associated with lower risks of cardiovascular-related outcomes, all-cause mortality, and all-cause hospitalizations compared to Semaglutide in patients with MASLD/MASH, obesity, and T2DM. These findings highlight potential clinical advantages associated with dual GIP/GLP-1 agonism in managing complex metabolic conditions.