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/m2, 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.