Abstract Details

Title Semaglutide Reduces the Risk of Adult-onset Epilepsy in Type 2 Diabetes: A Target Trial Emulation and Mediation Analysis

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S5 - Clinical Epilepsy (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

Objective

To determine whether semaglutide reduces the risk of incident adult-onset epilepsy or seizures in adults with type 2 diabetes compared with sodium–glucose cotransporter-2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs).

Background

Adult-onset epilepsy and seizures are increasingly recognized in individuals with T2DM, potentially through neuroinflammatory pathways. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide have shown neuroprotective benefits beyond glycemic control. Whether semaglutide use lowers the risk of new-onset epilepsy remains unclear.

Design/Methods

We conducted a retrospective active-comparator, new-user target trial emulation using the NIH All of Us Controlled Tier Dataset v8. Adults (≥18 years) with T2DM initiating semaglutide, SGLT2i, or GLDs between Dec. 2018 and Dec. 2021 were followed through Dec. 2023. Outcomes (incident epilepsy/seizures) were identified via ICD-9/10 and SNOMED CT. Inverse probability of treatment weighting (IPTW) balanced baseline demographics, comorbidities, medications, HbA1c, and BMI. Cox proportional hazards estimated hazard ratios (HRs), while targeted maximum likelihood estimation (TMLE) estimated risk differences (RD) and numbers needed to treat (NNT). Counterfactual mediation evaluated HbA1c and BMI as mediators (12-month windows over 48 months).

Results

Among 393,596 adults, 8,533 met criteria for the semaglutide vs GLD comparison (2,397 vs 6,136), and 7,455 for semaglutide vs SGLT2i (1,650 vs 3,725). After IPTW adjustment, semaglutide was associated with significantly lower risk of adult-onset epilepsy/seizures compared with GLDs (HR 0.46, 95% CI 0.25–0.83; P=0.010) and SGLT2i (HR 0.44, 95% CI 0.22–0.86; P=0.017). TMLE findings were consistent (GLDs: RD −0.014; NNT 69; P<0.001; SGLT2i: RD −0.008; NNT 129; P<0.001). Mediation by HbA1c and BMI was minimal (HbA1c: 1.1% [GLDs], 3.6% [SGLT2i]; BMI: ≤0.3%). Effects remained stable across 12–48 months of follow-up.

Conclusions

Semaglutide was associated with a lower risk of adult-onset epilepsy or seizures compared with SGLT2i and GLDs. The effect appeared largely independent of glycemic or weight changes, supporting possible non-glycemic neuroprotective mechanisms of GLP-1 receptor agonists.

Authors/Disclosures
Hyunyong Koh, MD, PhD PRESENTER	Dr. Koh has nothing to disclose.
Yong Eun, MD	Dr. Eun has nothing to disclose.
Suhwan Bong	Mr. Bong has nothing to disclose.
Rhonda Trousdale, MD	The institution of Dr. Trousdale has received research support from NIH.
Nathaniel Cho, BS	Mr. Cho has nothing to disclose.
Yoonhyuk Jang, MD, PhD	Mr. Jang has nothing to disclose.
Soon-Tae Lee, MD, PhD (Department of Neurology, Seoul National University Hospital)	Prof. Lee has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Advanced Neural Technologies. Prof. Lee has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Piehealthcare. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Salted. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for argenx. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arialys. The institution of Prof. Lee has received research support from Roche. Prof. Lee has received intellectual property interests from a discovery or technology relating to health care.

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