Comparative effectiveness of tirzepatide versus GLP-1 receptor agonists on the risk of venous thromboembolism in patients with obesity: a real-world cohort study.

BACKGROUND: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a major cause of morbidity and mortality in patients with obesity. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been associated with weight loss and potential reductions in VTE risk, evidence regarding tirzepatide remains limited. This study aimed to evaluate the comparative effectiveness of tirzepatide versus GLP-1 RAs in reducing the risk of VTE in patients with obesity. METHODS: We conducted a retrospective cohort study using the TriNetX global federated health research network. Adults with obesity (body mass index ≥30 kg/m or ICD-10-CM diagnosis codes) who initiated tirzepatide or GLP-1 RAs between January 2022 and August 2025 were identified. An active-comparator, new-user design was applied. Propensity score matching (1:1) was used to balance baseline demographics, comorbidities, and laboratory parameters. The primary outcome was 1-year incidence of VTE; secondary outcomes included PE, DVT, and all-cause mortality. Negative control outcomes and E-values were used to assess residual confounding. RESULTS: After matching, 701,374 patients were included. Tirzepatide initiation was associated with a significantly lower risk of VTE compared with GLP-1 RAs (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.83-0.98;  = 0.011). The benefit was driven by reductions in PE (HR, 0.88; 95% CI, 0.79-0.98;  = 0.021) and all-cause mortality (HR, 0.90; 95% CI, 0.82-0.99;  = 0.024), whereas no significant difference was observed for DVT (HR, 0.96; 95% CI, 0.86-1.07;  = 0.410). CONCLUSION: In this large real-world cohort, tirzepatide use was associated with a significantly lower 1-year incidence of VTE compared with GLP-1 RAs in patients with obesity, particularly through reductions in PE and all-cause mortality. These findings suggest an association between tirzepatide use and a lower risk of VTE compared with GLP-1 receptor agonists. However, given the observational nature of this study, causality cannot be established, and the results should be considered hypothesis-generating.