Sex-specific risk factors for genital infections associated with SGLT2 inhibitors in type 2 diabetes: a retrospective cohort study and disproportionality analysis using JADER

Background: Genital infections are notable adverse events that may lead to nonadherence to or discontinuation of sodium-glucose cotransporter 2 (SGLT2) inhibitors, essential agents in the management of type 2 diabetes (T2D). Although sex differences in incidence rates have been reported, the risk factors for each sex remain poorly understood. Objective: To identify sex-specific risk factors for genital infections associated with SGLT2 inhibitors, with the aim of optimising prevention and intervention strategies. Design: (i) Retrospective cohort study based on real-world clinical data and (ii) disproportionality analysis using the Japanese Adverse Drug Event Report database. Methods: (i) We investigated sex-specific risk factors for genital infections attributable to SGLT2 inhibitors using logistic regression, and further evaluated the discriminatory ability of sex–risk-factor combinations using a Cox proportional hazards model. (ii) As a supplementary analysis, a disproportionality analysis using reporting odds ratios (RORs) was performed for genital infection associated with SGLT2 inhibitors, stratified by the risk factors identified in (i). Results: (i) Among 2202 patients with T2D, 36 (1.6%) individuals developed genital infections after initiation of SGLT2 inhibitors (median 596.5 days). Females had a higher incidence than males (3.6% vs 0.8%, p < 0.001). In females, the combination of older age (⩾65 years) and three or more concomitant antidiabetic medications was identified as a significant contributor to infection risk, whereas elevated body mass index (BMI) was implicated in males. The Cox model demonstrated excellent discrimination (concordance index, 0.83; p < 0.001). (ii) A total of 228,261 cases submitted by diabetes patients were examined. The RORs were higher in older individuals and in those taking a greater number of diabetic medications, only in females. The effects of the combination of these factors and BMI could not be evaluated. Conclusion: Older age and polypharmacy of antidiabetic agents in females were identified as risk factors for SGLT2 inhibitor-associated genital infections.