Semaglutide, a GLP-1 receptor agonist (RA), was associated with a significantly lower risk for adult-onset epilepsy in patients with diabetes than other glucose-lowering drugs (GLDs). Notably, this risk reduction appeared largely independent of improvements in glycemic control or weight.

Approved for type 2 diabetes and obesity management, semaglutide has shown neuroprotective effects in stroke and dementia, but these new findings suggest it may also have a unique neuroprotective mechanism specific to seizure prevention.

“If a patient has type two diabetes and a high risk or likelihood of a seizure disorder, it would be beneficial to consider using semaglutide with overall brain health in mind, not just for stroke prevention and cardiovascular health,” Yong Eun, MD, primary care attending, Department of Medicine, NYC Health, Columbia University, New York City, told Medscape Medical News.

The findings were presented on December 7 at the American Epilepsy Society (AES) 79th Annual Meeting 2025.

Novel Trial Design

Patients with type two diabetes have a 25% increased risk for a seizure disorder compared with the general population, said Eun, whose research focuses on metabolic syndrome and uses data-driven insights to address health disparities.

For the study, Eun and his team used data from the National Institutes of Health All of Us Research Program, an open-access, population-based cohort of 393,596 adults with electronic health records.

They conducted a “target trial emulation” analysis, which uses observational data to simulate a clinical trial, complete with balanced baseline covariates such as demographics, comorbidities, and medication use.

The researchers identified patients with diabetes mellitus with no prior diagnosis of epilepsy or seizures. They then constructed retrospective cohorts of new users of different medication classes. These included semaglutide, SGLT2 inhibitors, and other GLDs, including sulfonylureas, thiazolinediones, or DPP-4 inhibitors.

Of the total cohort, 10,140 individuals were eligible for the comparison of semaglutide (n = 2548) with other GLDs (n = 7592), and 8510 for the comparison of semaglutide (n = 2785) with SGLT2 inhibitors (n = 5725). The mean age was 63.5 years, and the mean follow-up was 2.6 years.

Using inverse probability of treatment weighted statistical methodology, the analysis showed that semaglutide significantly reduced epilepsy or seizure risk compared with GLDs (hazard ratio [HR], 0.40; 95% CI, 0.22-0.73; P = .003) and compared with SGLT2 inhibitors (HR, 0.45; 95% CI, 0.25-0.81; P = .008).

Investigators found that semaglutide use was linked to more than a 50% reduction in seizure disorder risk. Further analyses showed that this relationship was essentially independent of improvements in glucose control or weight loss. Changes in hemoglobin A1c and BMI accounted for less than 5% of the association across all comparisons, suggesting that semaglutide’s apparent effect on epilepsy risk is driven by other mechanisms. “We found that using semaglutide was associated with more than halving the risk of a seizure disorder in our population.”

Unclear Mechanism

The exact neuroprotective mechanism by which semaglutide reduces epilepsy risk in patients with diabetes is unknown, although it could involve reduced inflammation or epigenetics, he said. Further research is needed to understand why these effects are particularly pronounced with semaglutide but not with other classes, Eun noted.

He indicated that additional analyses underway by his group suggest semaglutide may outperform other agents in its class — as well as drugs from other glucose-lowering classes — in lowering epilepsy risk.

The results are relevant beyond the neurology field, said Eun. “I think this is more of a discussion about brain health, which is critical for healthy aging in a modern society with increasing life expectancy.”

Commenting for Medscape Medical News, Daniel M. Goldenholz, MD, PhD, assistant professor in the Division of Epilepsy at Beth Israel Deaconess Medical Center in Boston, said he was struck by the study’s methodological rigor and the scale of the dataset underpinning its findings.

The ability of semaglutide to reduce the incidence of epilepsy in patients with diabetes is “an important possibility,” he said. “This study could be pointing toward an important neuroprotective pathway.”

However, he raised concerns about the extent to which the analysis accounted for established risk factors for developing epilepsy and emphasized the need for follow-up research, including mechanistic and prospective studies. He also pointed out that the relatively high number needed to treat suggests the signal may have greater relevance at a population level than as a potent protective effect for individual patients.

The study reported receiving no outside funding. The investigators and Goldenholz reported having no relevant financial disclosures.