Seizure recurrence after GLP ‐1 receptor agonist initiation in adults with epilepsy

Abstract 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. GLP‐1 RA initiation was associated with lower risk of seizure recurrence (HR .82, 95% confidence interval [CI] .78–.86; RD −2.1%), hospitalization (HR .35, 95% CI .29–.43; RD −2.6%), and all‐cause mortality (HR .40, 95% CI .34–.47; RD −4.8%). Associations with status epilepticus (HR .75, 95% CI .66–.85; RD −.7%) and ICU admission (HR .82, 95% CI .69–.96; RD −.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.