GLP-1 receptor agonists have been linked to a reduced risk for epilepsy in patients with type 2 diabetes.

Results of an observational study showed that patients taking GLP-1s were 16% less likely to develop epilepsy compared to those on DPP-4 inhibitors. Among the GLP-1s studied, semaglutide showed the strongest association with a lower risk for epilepsy.

“More research is needed, but these findings support the theory that GLP-1 drugs may have neurological benefits beyond controlling blood sugar,” principal investigator Edy Kornelius, MD, PhD, at Chung Shan Medical University in Taichung, Taiwan, said in a news release.

The study was published online on December 10th in Neurology.

Mounting Evidence

People with diabetes are significantly more likely than those without the disease to develop epilepsy.

As previously reported by Medscape Medical News, semaglutide was associated with a 50% reduction in the risk for epilepsy in people with diabetes. Another recent study also showed that starting GLP-1s was associated with a lower risk for seizure recurrence among adults with epilepsy and diabetes.

Findings from preclinical studies point to GLP-1 drugs reducing oxidative stress and inflammation, which are contributing factors to the development of epilepsy. Yet, real-world evidence linking GLP-1s to epilepsy risk is lacking, the investigators noted.

For the retrospective cohort study, the researchers used the TriNetX database, which included data from 452,766 patients with type 2 diabetes (mean age, 60.5 years; 47.1% women) from 2015 to 2023.

Within this cohort, they analyzed new users of GLP-1s and compared them to new users of DPP-4s, a second-line treatment for type 2 diabetes.

The primary outcome was incident epilepsy, identified by ICD-10 codes. The GLP-1 drugs evaluated were dulaglutide, liraglutide, and semaglutide.

The investigators used propensity score matching (1:1) to balance the GLP-1 and DPP-4 inhibitor groups for demographic and socioeconomic covariates as well as body mass index, comorbidities, and drugs used at baseline. Cox proportional hazard models were employed to estimate the hazard ratio (HR) for incident epilepsy associated with either group of drugs.

Potential Neuroprotective Effects

After matching, 2.41% of patients using DPP-4 inhibitors developed epilepsy, compared to 2.35% taking GLP-1s.

GLP-1 use was associated with a lower risk for epilepsy than DPP-4 inhibitor use (HR, 0.84; 95% CI, 0.78-0.90). This association held up across subgroups, including age, sex, high blood pressure, and cardiovascular disease.

Among the GLP1s studied, semaglutide showed the strongest association with a reduced risk for epilepsy (HR, 0.68; 95% CI, 0.60-0.77), suggesting that “semaglutide primarily drove the overall protective association,” the investigators wrote.

In a sensitivity analysis, they excluded patients who had used both drugs and found a consistent association between GLP-1 use and lower epilepsy risk (HR, 0.71; 95% CI, 0.64-0.78).

“Additional randomized, controlled trials that follow people over time are needed to confirm these findings, but these results are promising, since people with diabetes are at increased risk of developing epilepsy later in life,” Kornelius said. 

He also noted that the findings don’t imply that DPP-4 inhibitors are harmful or that GLP-1s are definitively beneficial for brain health.

Limitations of the study included its observational design and potential residual bias from unmeasured variables.

The authors reported no relevant disclosures. The study was supported by grants from Chung Shan Medical University Hospital (CSH-2022-A-022).