Semaglutide and Risk of Adult-Onset Seizure: A Target Trial Emulation

Area of Science:

• Neurology
• Endocrinology
• Pharmacology

Background:

• Adult-onset seizures pose a significant health burden, often stemming from acquired brain injuries.
• Preventive strategies for adult-onset seizures remain limited, highlighting the need for novel therapeutic approaches.
• Type 2 diabetes is associated with an increased risk of neurological complications, including seizures.

Purpose of the Study:

• To investigate whether initiating semaglutide is linked to a reduced incidence of adult-onset seizures in adults with type 2 diabetes.
• To compare the risk of adult-onset seizures between semaglutide users and those taking sodium-glucose cotransporter 2 inhibitors (SGLT2i) or other glucose-lowering drugs (GLDs).

Main Methods:

• A target trial emulation using the 'All of Us' Research Program database (January 2018 - October 2023).
• Comparison of new-user, active-comparator cohorts: semaglutide vs. other GLDs and semaglutide vs. SGLT2i.
• Statistical analysis using inverse probability of treatment weighting (IPTW) with Cox models and targeted maximum likelihood estimation (TMLE).

Main Results:

• Semaglutide use was associated with a significantly lower risk of adult-onset seizure compared to both other GLDs (weighted HR 0.44) and SGLT2i (weighted HR 0.48).
• The 4-year risk difference indicated a reduction of 1.78% compared to other GLDs and 1.46% compared to SGLT2i.
• Mediation analyses showed minimal contribution from changes in hemoglobin A1c (HbA1c) or body mass index (BMI) to this effect.

Conclusions:

• Semaglutide initiation appears to be associated with a reduced risk of adult-onset seizures in patients with type 2 diabetes.
• The observed association was independent of glycemic control and weight reduction.
• Further research is needed to confirm causality due to potential residual confounding and limited event counts.