Semaglutide Reduces the Risk of Adult-onset Epilepsy in Type 2 Diabetes: A Target Trial Emulation and Mediation Analysis
Yong Eun1, Suhwan Bong3, Hyun Yong Koh4, Rhonda Trousdale2, Young Min Cho5, Yoonhyuk Jang6, Soon-Tae Lee6
1Medicine, 2Endocrinology Diabetes and Metabolism, Columbia University/NYC Health + Hospitals, 3Biostatistics, Harvard T.H. Chan School of Public Health, 4Neurology, Baylor College of Medicine/Texas Children's Hospital, 5Endocrinology and Metabolism, 6Neurology, Seoul National University Hospital
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.

10.1212/WNL.0000000000216020
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