SGLT2i Use Associated with Reduced Risk of Late-Onset Epilepsy: Study

In order to determine the possible antiepileptogenic properties of SGLT2i, a retrospective cohort analysis was performed using the TriNetX database, which is a worldwide health research network. This particular analysis was carried out between 2013 and 2025, with an obligatory three-year follow-up period. The analysis involved an extremely large number of patients, namely 1,435,648, at the very beginning. It should be noted that only patients 60 years old and above, suffering from type 2 diabetes, participated in this study. These patients were randomly divided into two groups according to the administration of new medications: those who took SGLT2i or DPP-4 inhibitors.

It should be mentioned that the study used a 6-month washout period of any glucose lowering agents except metformin and excluded patients with previous neurological disorders and SGLT2i contraindicated conditions. In addition, there was a need to use propensity score matching in order to balance the clinical characteristics of the participants in these two groups. Thus, a perfectly matched sample of two equally sized groups (60,203 patients in each group) was created.

Key findings:

• For SGLT2i initiators, there was a 45% lower risk of incidence of late-onset epilepsy in comparison with patients under DPP-4 inhibitors, which was calculated as a hazard ratio (HR) of 0.55 (95% CI = 0.44–0.68).
• The hazard ratio for developing status epilepticus, a condition characterized by an extended period of seizure episodes, was calculated as 0.38 (95% CI = 0.21–0.69) in SGLT2i initiators compared with DPP-4 inhibitor group; hence, it was 62% lower.
• In SGLT2i initiators, the risk of initiation of antiseizure medication was 37% lower, resulting in HR of 0.63 (95% CI = 0.58–0.69).
• In subgroup analysis, SGLT2i use lowered the probability of LOE occurrence in patients with stroke (HR = 0.69, 95% CI = 0.42–0.88) and dementia (HR = 0.44, 95%CI = 0.25–0.78), though no significant protective effect was observed in patients with traumatic brain injury or brain tumors.

It can be concluded that the results obtained in this pivotal retrospective cohort study show the relationship between the use of SGLT2i drugs and the decreased risk of late-onset seizures, status epilepticus, and anticonvulsants' requirement in elderly patients with type 2 diabetes. The evidence of the stronger protective action in patients with stroke and/or dementia will guide treatment approaches based on disease etiology. Physicians treating elderly patients suffering from type 2 diabetes mellitus with a high probability of developing brain disorders will have two beneficial choices of pharmacotherapy: lowering blood glucose levels and preventing seizures.

Reference:

Lin B-H, Huang H-M, Lin H-A, Lin S-F. Sodium-glucose cotransporter 2 inhibitors and the risk of late onset epilepsy: A real-world cohort study. Epilepsia. 2026;00:1–13. https://doi.org/10.1002/epi.70239