Cenobamate beyond Epilepsy: exploring associations with vascular risk factors through serological markers

Anti-seizure medications (ASM) variably affect cardiovascular and cerebrovascular risk factors, as evidenced by changes in associated serological biomarkers. While enzyme-inducing ASM vascular effects are well studied, those of cenobamate (CNB) remain unknown. We examined CNB's impact on vascular risk by analyzing longitudinal changes in these biomarkers, addressing an important knowledge gap as CNB use expands in epilepsy management.

We conducted a retrospective analysis of adults (≥18 years) receiving CNB with ≥ 3 serial biomarker measurements (either 2 pre-/1 post-CNB or 1 pre-/2 post-CNB). Analyzed biomarkers comprised glycosylated hemoglobin (HbA1c), international normalized ratio (INR), and the lipid profile consisting of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), and total cholesterol (TC).

Among 413 patients receiving CNB, 96 patients met inclusion criteria (56 HbA1c, 50 lipid profile analysis, 21 INR). HbA1c increased significantly by 0.24 % post-CNB (p = 0.017), with greater increases in patients with diabetes mellitus (DM) (0.48 % vs. 0.09 % in non-diabetics, p < 0.001). Insulin use was associated with a further HbA1c rise (0.61 %increase, p=<0.001). Lipid profile changes showed an overall non-significant increase (HDL-c + 0.44 mg/dL, LDL-c + 6.99 mg/dL, TC + 8.84 mg/dL, and TG + 7.68 mg/dL), though statins attenuated these effects. Significant dose-dependent changes were observed for LDL-c and TC (p(Dose) = 0.007-0.012; p(statin) = 0.008-0.009). HDL-c increased non-significantly by 0.96 mg/dL per 100 mg of CNB without statins but decreased by 0.35 mg/dL per 100 mg of CNB with statins. TG levels rose modestly regardless of statin use. INR increased non-significantly (+0.05-point, p = 0.609) post-CNB, without any dose-dependent effect within the anticoagulant (AntiCOAG) users and non-users. Anticoagulant use was barely significantly associated with higher post-CNB INR values(p (AntiCOAG) = 0.043).

While this retrospective study has inherent limitations, our results indicate potential CNB-associated changes in metabolic biomarkers. Definitive evaluation of CNB's vascular effects will require prospective, controlled, multicenter studies that integrate serial biomarker monitoring with clinical endpoints and adjusting for concomitant ASM use, particularly enzyme-inducing agents.