SGLT2 Inhibitors and Risk of Postmenopausal Bleeding in Women: An Active‐Comparator, New‐User Cohort Study

Aims A recent case report and pharmacovigilance reports have suggested a possible association between sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and postmenopausal bleeding (PMB), but population‐level evidence is lacking. We evaluated the risk of PMB among women aged 55–90 years initiating SGLT2 inhibitors versus dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Materials and Methods We conducted an active‐comparator, new‐user cohort study using data from the All of Us Research Program. Women aged 55–90 years who newly initiated either an SGLT2 inhibitor or a DPP‐4 inhibitor were included. The primary outcome was the first recorded PMB during follow‐up. Propensity score (PS) matching, with exact matching on calendar period, was used to control for confounding. Hazard ratios (HRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were estimated using Cox and Poisson regression models. Results Among 2603 women, 1328 initiated SGLT2 inhibitors and 1275 initiated DPP‐4 inhibitors. After 1:1 PS matching, 650 pairs achieved good covariate balance. In the matched cohort, 37 and 34 PMB events occurred over 2248.2 and 2374.2 person‐years, respectively. SGLT2 inhibitor initiation was not associated with increased PMB risk (HR 1.14, 95% CI 0.70–1.84; IRR 1.15, 95% CI 0.71–1.87). Sensitivity analyses were consistent with the primary findings. Conclusions SGLT2 inhibitor initiation was not associated with a significantly increased PMB risk compared with DPP‐4 inhibitor initiation. These findings did not provide evidence of increased PMB risk with SGLT2 inhibitor therapy, although wide confidence intervals and limited outcome events warrant confirmation in larger studies.