Association Between Use of Sodium–Glucose Cotransporter 2 Inhibitors and Epilepsy: A Population-Based Study Using Target Trial Emulation

OBJECTIVE: Preclinical studies in animals have suggested potential neuroprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), but no epidemiological study has investigated the potential effects of SGLT-2is on epilepsy risk. We aimed to assess the association between use of SGLT-2is and epilepsy incidence. RESEARCH DESIGN AND METHODS: We emulated a target trial comparing SGLT-2is and dipeptidyl peptidase 4 inhibitors (DPP-4is) based on the Yinzhou Regional Health Care Database. Cohorts of patients with type 2 diabetes mellitus who were new users of an SGLT-2i or a DPP-4i were assembled. Inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression modeling were applied to estimate the hazard ratio (HR) and 95% CI of the association between use of SGLT-2is and incidence of epilepsy. RESULTS: The final cohort included 24,930 new users of SGLT-2is and 28,924 initiators of DPP-4is. A total of 243 patients with incident epilepsy were found during a median follow-up of 2.0 (interquartile range 0.8-3.3) years, with the incidence of epilepsy being 174.2 and 231.5 per 100,000 person-years in users of SGLT-2is and DPP-4is, respectively. After controlling for potential confounding using IPTW, SGLT-2i use was associated with a lower incidence of epilepsy, with an HR of 0.71 (95% CI 0.52-0.97). Various subgroup analyses and sensitivity analyses supported the results in primary analyses. CONCLUSIONS: SGLT-2is were associated with a reduced incidence of epilepsy in the study population. More studies are needed to confirm and replicate the study results.