Genetically Proxied SGLT2 Inhibition and Risk of Epilepsy: A Mediation Mendelian Randomization Study of Circulating Metabolites

Background: Epilepsy is a chronic neurological disorder that can significantly impair quality of life. Previous studies have demonstrated the positive effects of sodium–glucose co-transporter 2 (SGLT2) inhibitors on various systems, including the nervous system. SGLT2 inhibitors have been shown to reduce seizure activity in pentylenetetrazol-induced epilepsy models in rats. Recent study results showed that glucose-lowering drugs including SGLT2 inhibitors reduced risk of seizures and epilepsy. Methods: Genetic variants of SGLT2 inhibition were selected as exposure instrumental variables (IVs) and used type 2 diabetes (T2DM) as validation. Two-sample Mendelian Randomization (MR) analysis was conducted to explore the causal relationship between SGLT2 inhibition and epilepsy. In addition, we performed a two-step MR to evaluate whether possible circulating metabolites mediate the effects of SGLT2 inhibition on epilepsy. Results: The two-sample MR analysis showed that genetically proxied SGLT2 inhibition was associated with lower odds of epilepsy under MR assumptions [IVW: OR = 0.30 (95% CI: 0.13, 0.71), p = 0.0064]. Exploratory two-step analyses identified 3-methylglutaconate and N-acetylleucine as candidate metabolic signals; however, neither signal remained statistically significant after Benjamini–Hochberg correction. Conclusion: Our study suggests that SGLT2 is associated with a reduced risk of epilepsy, and the underlying mechanism may be the potential antioxidant and anti-inflammatory effects of SGLT2. In addition, circulating 3-methylglutaconate and N-acetylleucine should therefore be regarded as candidate metabolic signals rather than established mediators.