Safety and Efficacy of GLP ‐1 Receptor Agonists in Adults With Epilepsy, Obesity, and Type 2 Diabetes

Objective Managing obesity in patients with epilepsy is complicated by the weight‐gaining properties of essential antiseizure medications (ASMs) such as valproate and pregabalin. We evaluated the safety and efficacy of initiating glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) in this population. Methods We conducted a retrospective cohort study using the NIH All of Us Research Program database, identifying adults with comorbid epilepsy, type 2 diabetes, and obesity. New initiators of GLP‐1 RAs were compared with matched controls using 1:1 propensity score matching that included baseline weight‐gaining ASM use. The primary safety outcome was a composite of seizure‐related hospitalization or new ASM addition. Secondary efficacy endpoints (weight and HbA1c change at 12 months) were stratified by concomitant weight‐gaining ASM use. Results The propensity‐matched cohort included 610 patients with well‐balanced baseline characteristics. GLP‐1 RA initiation was not associated with failure to control seizure compared with standard care (hazard ratio 0.92, 95% CI 0.68–1.23; p = 0.57); given the observed events, the study could detect a hazard ratio of 1.53 or greater. GLP‐1 RA users achieved a mean adjusted weight loss of −5.73% ( p = 0.001) and an HbA1c reduction of −0.71% ( p = 0.018). Significant weight reduction was achieved even among patients concomitantly treated with weight‐gaining ASMs (adjusted difference −4.15%, p = 0.003). Interpretation GLP‐1 RAs showed no evidence of seizure worsening and remained effective for weight loss even among patients receiving weight‐gaining ASMs, supporting their use for metabolic benefit in patients with epilepsy.