Semaglutide use is associated with a lower risk of adult-onset seizures

A new study published in the journal Neurology suggests that adults with type 2 diabetes who take the medication semaglutide might have a lower risk of developing seizures later in life. The research indicates that this protective association is not entirely explained by weight loss or improved blood sugar control. The findings provide evidence that semaglutide might offer unique benefits for brain health beyond its primary metabolic uses.

Adult-onset seizures, which begin after the age of 18, often point to underlying brain damage. These neurological events tend to arise from conditions like head trauma, strokes, or neurodegenerative diseases. “Most previous neurological research on GLP-1 receptor agonists has focused on neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Adult-onset seizure is different,” said Yoonhyuk Jang, a research professor in the Department of Neurology at Seoul National University Hospital and a postdoctoral research fellow in the Department of Immunology at Harvard Medical School.

“It is often a neurological manifestation of accumulated brain insults associated with aging, including cerebrovascular disease, neurodegeneration, traumatic brain injury, and other acquired conditions,” Jang explained. As people age, the accumulation of these brain insults increases the likelihood of developing seizures, which directly impacts overall brain health and quality of life.

“We were interested in whether semaglutide might also influence this broader aspect of brain health,” Jang said. “In that sense, we viewed adult-onset seizure not only as a clinical outcome, but also as a marker of brain vulnerability in an aging society.”

Currently, doctors rely heavily on anti-seizure medications to manage symptoms after they start. Preventive treatments that can stop or slow the development of these seizures remain limited. Semaglutide is a medication originally designed to treat type 2 diabetes by enhancing insulin production and regulating blood sugar.

The medication belongs to a class of drugs called glucagon-like peptide 1 (GLP-1) receptor agonists, which mimic a natural hormone in the body to help control metabolism. Beyond managing diabetes and assisting with weight loss, emerging evidence suggests that semaglutide might protect the nervous system. “Semaglutide has demonstrated impressive benefits across a wide range of systemic diseases, including cardiovascular and kidney disease,” Jang said. “This led us to ask a broader question: could these benefits also extend to brain health?”

The researchers designed the study to look beyond isolated symptoms and focus on the connections between metabolic regulation and the nervous system. “Our study was not simply about testing whether semaglutide lowers seizure risk,” Jang explained. “More broadly, it was an attempt to explore the brain-body axis, the concept that systemic health and brain health are deeply interconnected.”

The scientists evaluated whether semaglutide use is associated with a lower incidence of newly developed seizures in adults. They compared its effects against other common diabetes medications, such as sodium-glucose cotransporter-2 inhibitors, which help the kidneys remove sugar from the body through urine. The team analyzed data from the All of Us Research Program, a large health database tracking diverse populations in the United States.

They focused on adults with type 2 diabetes who had just started a new prescription for a diabetes medication between January 2018 and October 2023. To simulate a randomized clinical trial, the authors matched patients based on 46 different baseline characteristics. These variables included age, sex, race, income, existing medical conditions, and other medications being taken.

The study constructed two primary comparison groups, tracking patients over an average of one and a half to nearly three years using medical diagnostic codes. The first group matched 2,586 patients starting semaglutide against 7,627 patients starting other general diabetes medications. The second group matched 2,814 patients starting semaglutide against 5,791 patients starting sodium-glucose cotransporter-2 inhibitors.

The primary measure was the first occurrence of an adult-onset seizure, excluding seizures caused by dangerously low blood sugar. In the comparison between semaglutide and other general diabetes medications, the researchers found that semaglutide was associated with a lower risk of developing adult-onset seizures. Over a four-year period, the cumulative incidence of seizures in the semaglutide group was 1.01 percent, compared to 2.79 percent in the other medications group. This translates to an absolute risk reduction of 1.78 percentage points.

The analysis produced a hazard ratio of 0.44 for this comparison. A hazard ratio below 1.0 suggests a lower risk, meaning patients taking semaglutide had roughly 56 percent less hazard of developing a seizure over the study period. In practical terms, treating 70 patients with semaglutide instead of other diabetes medications was associated with one fewer patient developing seizures.

Similar patterns emerged when comparing semaglutide to sodium-glucose cotransporter-2 inhibitors. The four-year cumulative incidence of seizures was 1.07 percent for semaglutide users, compared to 2.53 percent for those on the alternative medication. The hazard ratio was 0.48, and the researchers calculated that 131 patients would need to be treated with semaglutide to observe one fewer case of adult-onset seizure.

The researchers conducted specific statistical analyses to understand if this association was driven by patients losing weight or lowering their blood sugar. They measured this by tracking changes in body mass index (BMI) and hemoglobin A1c (HbA1c). They found that these metabolic improvements accounted for very little of the observed reduction in seizure risk.

“One of the most surprising findings came from our longitudinal mediation analyses,” Jang told PsyPost. “We expected that improved glycemic control or weight loss would explain at least a substantial portion of the observed association. Instead, changes in HbA1c and BMI accounted for only a very small fraction of the effect.”

Specifically, blood sugar changes explained only 2.4 to 6.5 percent of the association, and body mass index changes explained almost none of it. “This suggests that semaglutide may influence seizure risk through mechanisms beyond its metabolic benefits,” Jang continued. “Whether these mechanisms involve neuroinflammation, direct central nervous system effects, or other biological pathways remains unknown, and answering that question will require further experimental and clinical research.”

Despite these patterns, the researchers caution against applying the findings too broadly. “The most important point is that this study should not be interpreted as evidence that semaglutide should currently be prescribed to prevent seizures,” Jang said. “Our study identifies an association, not a causal treatment recommendation.”

Observational data of this nature cannot determine that a medication directly prevents a condition. “Another important point is that our study focused specifically on adult-onset seizure in people with type 2 diabetes, not on patients with established epilepsy,” Jang noted. “These are related but distinct clinical conditions, and the findings should not automatically be generalized to all neurological diseases or all patient populations.”

The researchers also urge a measured reading of the statistical results. “This was a large population-based study involving approximately 18,000 patients with type 2 diabetes,” Jang explained. “The observed association was relatively strong, with hazard ratios that were even larger than those reported in some randomized cardiovascular outcome trials of semaglutide. Whenever an observational study finds an effect of this magnitude, it is important to interpret the results cautiously.”

While the team performed multiple tests to verify the findings, unmeasured lifestyle variables or health behaviors could still influence the results. “As larger real-world datasets become available or randomized trials are conducted, the estimated effect size may become smaller,” Jang said. “Our study should therefore be viewed as evidence supporting the possibility of a protective effect rather than definitive proof of one.”

The reliance on electronic health records presents another limitation, as medical codes can sometimes capture single seizures provoked by temporary illnesses. Additionally, the average follow-up time was somewhat short, creating a situation where many patients started the drug during the COVID-19 pandemic, a period that severely disrupted regular health care patterns.

Tracking patients over a longer period would help clarify if the protective association lasts over a lifetime. “Our long-term goal is to better understand whether GLP-1 receptor agonists can modify the biological processes that increase seizure susceptibility and influence epileptogenesis—the process by which a normal brain becomes epileptic,” Jang said. “We hope our findings encourage future research into how improving systemic health may help preserve brain health throughout aging.”

The study, “Association of Semaglutide With Lower Risk of Adult-Onset Seizure in Type 2 Diabetes,” was authored by Yong Eun, Suhwan Bong, Hyun Yong Koh, Rhonda K. Trousdale, Young Min Cho, Yoonhyuk Jang, and Soon-Tae Lee.