The Effect of GLP-1 Receptor Agonists on Epilepsy: No Appetite for Seizures

Association Between GLP-1 Receptor Agonist Use and Epilepsy Risk in Type 2 Diabetes Cheng CY, Lo SC, Huang CN, Yang YS, Wang YH, Kornelius E. Neurology . 2026;106(1):e214509. doi:10.1212/WNL.0000000000214509. Epub 2025 Dec 10. PMID: 41370744. Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of developing epilepsy, particularly in later life. While preclinical studies suggest neuroprotective properties of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), real-world comparative effectiveness data remain limited. We aimed to evaluate whether GLP-1 RA use is associated with a lower risk of incident epilepsy compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) use in adults with T2DM. Methods: We conducted a retrospective cohort study using the TriNetX network from 2015 to 2023, including adults aged 18 years or older with T2DM who were new users of either GLP-1 RAs or DPP-4is. Patients with a previous diagnosis of epilepsy or seizure, or those using antiepileptic drugs, were excluded. The primary outcome was incident epilepsy, identified using ICD-10-CM codes. Propensity score matching (1:1) was performed based on demographics, socioeconomic status, body mass index, comorbidities, and baseline medications. Cox proportional hazard models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). We also conducted prespecified subgroup and sensitivity analyses to assess the robustness of the findings. Results: After matching, 452 766 patients were included (226 383 in each group; mean age 60.5 years; 47.1% female). During follow-up, 1670 individuals in the GLP-1 RA group and 1886 in the DPP-4i group developed epilepsy, corresponding to cumulative incidences of 2.35% versus 2.41%. Glucagon-like peptide-1 receptor agonists use was associated with a significantly lower risk of epilepsy (HR 0.84, 95% CI 0.78-0.90), with protective associations evident at 1 year (HR 0.71, 95% CI 0.62-0.80), 3 years (HR 0.81, 95% CI 0.74-0.88), and 5 years (HR 0.82, 95% CI 0.76-0.88). Among individual agents, semaglutide showed the strongest association (HR 0.68, 95% CI 0.60-0.77). The results were consistent across major subgroups, including both age and sex. Sensitivity analyses excluding patients with overlapping or switching exposure yielded similar findings (HR 0.71, 95% CI 0.64-0.78). Discussion: Glucagon-like peptide-1 receptor agonists therapy was associated with a significantly lower epilepsy risk compared with DPP-4i use in adults with T2DM. These results support the hypothesis that GLP-1 RAs may exert neurologic benefits beyond glycemic control. Limitations include the observational design and potential residual confounding. Seizure Recurrence after GLP-1 Receptor Agonist Initiation in Adults with Epilepsy AbuAlrob MA, Hussein A, Abdellatif R, Itbaisha A, Zammar K, Mesraoua B. Epilepsia . 2025. doi:10.1111/epi.70022. Epub ahead of print. PMID: 41251033. Objective: To examine whether initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with seizure recurrence and related outcomes in adults with epilepsy and type 2 diabetes. Methods: We conducted a retrospective cohort study using de-identified electronic health records from the TriNetX Research Network (January 2003-August 2025), including adults ≥18 years with ≥3 epilepsy or recurrent seizure diagnoses. Patients initiating a GLP-1 RA (exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, or tirzepatide) without prior comparator therapy were compared with those initiating other glucose-lowering agents (sodium–glucose cotransporter 2 inhibitors, dipeptidyl peptidase 4 inhibitors, sulfonylureas, or insulin) without GLP-1 RA exposure. Propensity score matching (1:1) was performed on 82 covariates, yielding 8688 matched pairs. Outcomes were assessed using Cox proportional hazards models. Results: After matching, the mean age was 52.6 years, and 67.6% were female. Median follow-up was 514 days (interquartile range IQR 671) for GLP-1 RA initiators and 415 days (IQR 769) for comparators. Glucagon-like peptide-1 receptor agonists initiation was associated with lower risk of seizure recurrence (HR 0.82, 95% confidence interval CI 0.78-0.86; RD −2.1%), hospitalization (HR 0.35, 95% CI 0.29-0.43; RD −2.6%), and all-cause mortality (HR 0.40, 95% CI 0.34-0.47; RD −4.8%). Associations with status epilepticus (HR 0.75, 95% CI 0.66-0.85; RD −0.7%) and ICU admission (HR 0.82, 95% CI 0.69-0.96; RD −0.3%) were smaller; the latter was not statistically significant. Significance: In this large multinational cohort, GLP-1 RA initiation was associated with reduced risks of seizure recurrence, hospitalization, and mortality compared with other glucose-lowering therapies. These hypothesis-generating findings warrant confirmation in prospective studies before translation into clinical practice.