Major Adverse Liver Outcomes With Tirzepatide and Injectable Semaglutide in Adults With Overweight or Obesity and Type 2 Diabetes

Objective This study aimed to compare the effectiveness of tirzepatide versus injectable semaglutide in preventing major adverse liver outcomes (MALO) among adults with overweight or obesity and type 2 diabetes. Methods This retrospective target trial emulation utilized the TriNetX global network to analyze new users of tirzepatide and semaglutide. The primary outcome was time‐to‐first MALO (a composite of cirrhosis, decompensated events, and hepatocellular carcinoma). Propensity score matching balanced baseline covariates. Results Over a median follow‐up of ~17 months, no significant difference in MALO risk was observed between tirzepatide and semaglutide initiators (estimated incidence rate [IR] 4.05 vs. 4.04 per 1000 person‐years [PY]; hazard ratio [HR] 1.04, 95% CI 0.88–1.23). This comparable risk profile was maintained across sensitivity analyses, including people with MASLD (IR 9.97 vs. 10.03 per 1000 PY; HR 1.03, 95% CI: 0.75–1.42) and “as treated” analysis (HR 0.98, 95% CI: 0.80–1.21). Tirzepatide achieved greater BMI reduction (mean difference ~1.1 kg/m 2 , p < 0.001). Internal validation confirmed both agents significantly outperformed sitagliptin. Conclusions In this high‐risk population with type 2 diabetes, tirzepatide and injectable semaglutide offered comparable effectiveness in mitigating liver disease progression and MALO in the short‐ to medium‐term follow‐up.