Effects of lipid-lowering drugs on epilepsy and its subtypes: A drug-target Mendelian randomization study

Statins, commonly used lipid-lowering drugs to reduce cardiovascular risk, have also been suggested to have protective effects against epilepsy. However, whether this association is causal remains unclear. We conducted a drug-target Mendelian randomization study to examine the effects of genetically predicted inhibition of 3 established lipid-lowering targets (3-hydroxy-3-methylglutaryl coenzyme A reductase [statins], Niemann-Pick C1-Like 1 [ezetimibe], and proprotein convertase subtilisin/kexin type 9 [PCSK9 inhibitors]) on epilepsy and its subtypes. The inverse-variance weighted approach served as the primary analysis, supplemented with multiple sensitivity tests to ensure robustness. Genetically proxied 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition was associated with decreased risks of epilepsy (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.82-0.92; P = 1.4 × 10-6) and focal epilepsy (OR = 0.83; 95% CI: 0.76-0.92; P = 1.5 × 10-4). Inhibition of Niemann-Pick C1-Like 1 corresponded to a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.98; 95% CI: 0.97-0.98; P = 1.2 × 10-34) but increased risks of focal epilepsy (lesion negative, OR = 1.08; 95% CI: 1.06-1.09; P = 5.9 × 10-31), childhood absence epilepsy (OR = 1.06; 95% CI: 1.05-1.07; P = 1.8 × 10-21), and juvenile absence epilepsy (OR = 1.03; 95% CI: 1.01-1.05; P = 9.7 × 10-3). PCSK9 inhibition was linked to reduced risks of generalized epilepsy with tonic-clonic seizures (OR = 0.99; 95% CI: 0.98-1.00; P = 1.4 × 10-2), juvenile absence epilepsy (OR = 0.96; 95% CI: 0.93-1.00; P = 2.7 × 10-2), and juvenile myoclonic epilepsy (OR = 0.96; 95% CI: 0.93-1.00; P = 2.9 × 10-2). The effects of lipid-lowering drug targets on epilepsy risk vary by target and exhibit pleiotropy. Statins and PCSK9 inhibitors appear protective against epilepsy and several subtypes, whereas ezetimibe may increase susceptibility to certain subtypes. These results underscore the importance of considering target-specific effects when choosing lipid-lowering therapies for patients with or at risk of epilepsy.