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.