TOPLINE

Semaglutide initiation was associated with more than half the risk for adult-onset seizure compared with other glucose-lowering drugs (GLDs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in adults with type 2 diabetes in a target trial emulation using the All of Us Research Program. The protective association appeared independent of glycemic control or weight loss, with minimal mediation through A1c or body mass index (BMI).

METHODOLOGY

• Researchers emulated a population-based target trial using All of Us Research Program data from January 2018 to October 2023.
• A total of 10,213 patients were included in the semaglutide (n=2586; mean age 60.1 years; 56.8% women) vs other GLDs cohort (n=7627; mean age 63.7 years, 54.2% women).
• A total of 8605 patients were included in the semaglutide vs SGLT2 inhibitor cohort: 2814 on semaglutide (mean age 60.5 years; 66.2% women) and 5791 on SGLT2 inhibitors (mean age 64.4 years; 47.3% women).
• Study outcome was incident epilepsy or seizure, with effects estimated using inverse probability of treatment weighting with weighted Cox models and targeted maximum likelihood estimation (TMLE).
• Mediation analysis evaluated whether A1c and BMI explained the observed associations using the longitudinal Vansteelandt framework.

TAKEAWAY

• Semaglutide was associated with a lower risk for adult-onset seizure than other GLDs (weighted hazard ratio [HR], 0.44; 95% CI, 0.25-0.79).
• Compared with SGLT2 inhibitors, semaglutide was associated with a lower risk for adult-onset seizure (weighted HR, 0.48; 95% CI, 0.27-0.85).
• TMLE showed absolute risk reductions of 14.2 and 7.6 seizures per 1000 persons vs other GLDs and SGLT2 inhibitors, corresponding to numbers needed to treat of 70 and 131, respectively.
• Mediation through A1c was minimal (2.4% vs other GLDs; 6.5% vs SGLT2 inhibitors), as was mediation through BMI (0% vs other GLDs; 0.7% vs SGLT2 inhibitors).

IN PRACTICE

"Semaglutide initiation was associated with a lower risk of adult-onset seizure compared to SGLT2i and other GLDs in patients with type 2 diabetes, independent of glycemic and weight effects," the authors wrote.

SOURCE

The study was led by Yong Eun, MD, NYC Health + Hospitals/Harlem, New York and was was published online on June 17 in Neurology.

LIMITATIONS

Follow-up was shorter in semaglutide users than in comparator groups. The modest number of outcome events limited precision. The study did not directly measure biological mechanisms.

DISCLOSURES

The study was supported by grants from the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, the Korea Health Technology R&D Project, and the National Research Foundation of Korea. The authors received consultation fees, research grants, and advisory fess from LG Chemical and Hanmi, Sanofi, AstraZeneca, Daewoong Pharmaceuticals, Roche/Genentech, Advanced Neural Technologies, argenx, Arialys, Piehealthcare, and Salted, outside the submitted work. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.