A large U.S. study finds that drugs acting on the GLP-1 receptor may be linked to a lower likelihood of developing epilepsy among adults with type 2 diabetes. In comparisons with DPP-4 inhibitors, GLP-1 receptor agonists were associated with a 16% reduction in epilepsy risk. The strongest signal came from semaglutide, which showed the most pronounced risk decrease, while liraglutide and dulaglutide did not show significant effects. This suggests epilepsy—a condition that often goes unrecognized in people with type 2 diabetes—may be less common among those using GLP-1 receptor agonists.
In the study, Edy Kornelius, MD, PhD, and colleagues analyzed U.S. electronic health records from 2015 to 2023 through the TriNetX network. They identified 226,383 adults with type 2 diabetes who newly started GLP-1 receptor agonists and matched them to an equal-sized group initiating DPP-4 inhibitors. The average participant age was about 60.5 years, with roughly 47% women. Both groups had similar baseline diabetes control (HbA1c around 8.5%).
Over a median follow-up of five years, epilepsy developed in 2.35% of GLP-1 receptor agonist users compared with 2.41% of DPP-4 inhibitor users. The overall 16% lower risk translates to a hazard ratio of 0.84 (95% CI, 0.78 to 0.90). When broken down by time, protective associations appeared at one year (HR 0.71), three years (HR 0.81), and five years (HR 0.82). Sensitivity analyses that excluded patients with changing or overlapping medications yielded similar results (HR 0.71).
Among specific drugs, semaglutide (marketed as Ozempic and Rybelsus) showed the strongest link to reduced epilepsy risk (HR 0.68; 95% CI, 0.60 to 0.77). Other GLP-1 agents, such as liraglutide (Victoza) and dulaglutide (Trulicity), did not demonstrate significant associations. The dual GLP-1/GIP agonist tirzepatide (Mounjaro) was not evaluated in this analysis because it entered the market after the study window.
This study came as GLP-1 therapies have faced mixed results in neurology. Notably, semaglutide recently failed to show cognitive benefits in early Alzheimer’s disease trials. Still, the researchers emphasize that a negative trial in one neurological domain does not rule out possible advantages in other conditions with different disease mechanisms. GLP-1 receptor agonists influence several pathways—metabolic inflammation, vascular health, oxidative stress, and insulin signaling—that could affect neurological disorders, including epilepsy.
To interpret these findings, the authors caution that this is observational data. They highlight the need for mechanistic studies to understand how GLP-1 signaling might alter neuronal excitability, inflammation, or neuroprotection. More detailed information from biomarkers and imaging would help clarify the mechanisms. Ideally, randomized trials or prospective cohorts could determine whether GLP-1 receptor agonists causally reduce epilepsy risk and whether certain agents have distinct neurological effects.
Potential limitations include residual confounding from unmeasured factors such as genetics, sleep quality, alcohol use, or medication costs and preferences. Misclassification could arise from reliance on diagnostic codes, and incomplete data on medication adherence might have influenced the results.
Bottom line: GLP-1 receptor agonists are associated with a lower incidence of epilepsy among adults with type 2 diabetes in this large observational study, with semaglutide showing the strongest signal. Whether these drugs causally reduce epilepsy risk remains to be proven, but the finding invites further research into how metabolic therapies might impact neurological health. How do you interpret these results, and should epilepsy risk be a consideration when choosing glucose-lowering therapies? Share your thoughts in the comments.
