Tirzepatide use and the risk of endometrial cancer in women with overweight or obesity: a retrospective cohort study

Endometrial cancer (EC) is strongly associated with obesity, and tirzepatide produces substantial weight loss with preclinical evidence of direct antitumor activity. We aimed to evaluate the association between tirzepatide use and incident EC risk in women with overweight or obesity. Using the TriNetX US Collaborative Network, we identified women with overweight or obesity who initiated tirzepatide (study group) or lifestyle modification interventions (control group) between January 1, 2022, and December 31, 2025. After 1:1 propensity score matching (PSM), the risk of incident EC over two years was compared using Cox proportional hazards regression. After matching, 176,981 patients were included in each group. The mean age was 49.3 ± 13.8 years in the study group and 49.1 ± 16.1 years in the control group. The estimated cumulative follow-up was approximately 202,632 person-years in the tirzepatide group and 194,447 person-years in the lifestyle modification group. During a maximum follow-up window of two years, tirzepatide use was associated with a lower hazard of newly recorded EC diagnoses compared with the comparator cohort (HR, 0.717; 95% CI, 0.593–0.867), a finding that was consistent across most subgroups, including women aged ≥ 50 years, White women, and those with type 2 diabetes (T2D), hypertension, hyperlipidemia, or obstructive sleep apnea. Tirzepatide use was associated with a lower short-term hazard of newly recorded EC diagnoses among women with overweight or obesity. These observational findings do not establish a preventive effect, and longer-term studies are needed to assess whether the association persists.