Sweetening the Odds: Can Newer Glucose-Lowering Drugs Bend the Arc of Epileptogenesis?

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Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Late Onset Epilepsy: A Real-World Cohort Study Lin BH, Huang HM, Lin HA, Lin SF. Epilepsia . 2026;67(7):3444–3456. doi:10.1002/epi.70239. Objective: Late onset epilepsy (LOE) is associated with substantial morbidity. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may exert neuroprotective effects. This study evaluated the association between SGLT2i and risk of LOE among older adults with type 2 diabetes mellitus. Methods: This retrospective cohort study was conducted between 2013 and 2025 with a 3-year follow-up using the TriNetX global network. Patients ≥ 60 years old with type 2 diabetes mellitus were classified into two cohorts—new SGLT2i users and new dipeptidyl peptidase-4 inhibitors users—following a 6-month washout of other antihyperglycemic agents except metformin. Patients with major neurological diseases or contraindications to SGLT2i were excluded. Propensity score matching was used to balance baseline characteristics between two cohorts. The primary outcomes were incident LOE, status epilepticus, and initiation of antiseizure medications. Unadjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence interval (CIs). Results: A total of 1435648 patients were identified. After matching, 60203 patients were included in the SGLT2i cohort (mean age = 67.7 years, 42.3% female) and 60203 in the control cohort (mean age = 67.7 years, 41.7% female). SGLT2i use was associated with lower risk of LOE (HR = .55, 95% CI = .44–.68), status epilepticus (HR = .38, 95% CI = .21–.69), and antiseizure medication initiation (HR = .63, 95% CI = .58–.69). SGLT2i reduced LOE risk in patients with stroke (HR = .69, 95% CI = .42–.88) and dementia (HR = .44, 95% CI = .25–.78) but not in those with traumatic brain injury or brain tumors. Significance: SGLT2i use was associated with reduced risk of LOE among selected patients, supporting its role in an etiology-specific therapeutic approach for older adults at risk of epilepsy. Semaglutide and Risk of Adult-Onset Seizure: A Target Trial Emulation Eun Y, Bong S, Koh HY, Trousdale RK, Cho YM, Jang Y, Lee ST. Neurology. 2026 Jul 14;107(1):e218174. doi: 10.1212/WNL.0000000000218174. Epub 2026 Jun 17. PMID: 42308439; PMCID: PMC13278381. Background and objectives: Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes. Methods: Using the All of Us Research Program, we emulated a population-based target trial in new-user, active-comparator cohorts from January 2018 to October 2023. We compared semaglutide vs other GLDs and semaglutide vs SGLT2i. Incident epilepsy or seizure was identified from diagnostic codes. Effects were estimated using inverse probability of treatment weighting with weighted Cox models and targeted maximum likelihood estimation (TMLE). Subgroup and sensitivity analyses with multiple outcome definitions and analytic approaches were conducted to assess the robustness of findings. We evaluated mediation through hemoglobin A1c (HbA1c) and body mass index (BMI) using the longitudinal Vansteelandt framework. Results: We analyzed 10,213 patients in the semaglutide (n = 2,586, mean age, 60.1 years; 56.8% female) vs other GLDs cohort (n = 7,627, mean age, 63.7 years; 54.2% female) and 8,605 patients in the semaglutide (n = 2,814, mean age, 60.5 years; 66.2% female) vs SGLT2i cohort (n = 5,791, mean age, 64.4 years; 47.3% female). Semaglutide was associated with a lower risk of adult-onset seizure compared with other GLDs (weighted HR 0.44 [95% CI 0.25-0.79]; 4-year risk difference -1.78% [95% CI -2.58 to -0.98]) and SGLT2i (weighted HR 0.48 [95% CI 0.27-0.85]; 4-year risk difference -1.46% [95% CI -2.41 to -0.51]). TMLE estimated risk differences per 1,000 persons of -14.20 (95% CI -18.33 to -10.07) vs other GLDs and -7.62 (95% CI -11.65 to -3.60) vs SGLT2i, corresponding to numbers needed to treat of 70 and 131, respectively. Mediation was minimal for HbA1c (2.4% vs other GLDs; 6.5% vs SGLT2i) and BMI (0% vs other GLDs; 0.7% vs SGLT2i). Discussion: Semaglutide initiation was associated with a lower risk of adult-onset seizure compared with SGLT2i and other GLDs in patients with type 2 diabetes, independent of glycemic and weight effects. Residual confounding, low event counts, and shorter follow-up limit causal interpretation. Classification of evidence: This study provides Class II evidence that semaglutide use was associated with a lower risk of adult-onset seizures compared with other GLDs and SGLT2i.

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