Abstracts

Rationale: Several studies have shown that certain AEDs affect the metabolism of cholesterol in the liver by interacting with the cytochrome P450 (CYP450) system. In addition, HMG-CoA reductase inhibitors (statins), one of the major therapies for hypercholesterolemia, are also metabolized in CYP450. Many anti-epileptic drugs (AEDs) induce the metabolism of CYP450, thus creating a potential significant drug interaction. We hypothesize that patients on enzyme inducing AEDs (EIAEDs) would have higher cholesterol, LDL and HDL levels compared to those on non-enzyme inducing AEDs (NEIAEDs). In addition, when comparing EIAEDs with NEIAEDs in patients on statins, we proposed that the EIAED group would have higher dose utilization when compared to patients on NEIAEDs. Methods: This study is a retrospective analysis of men and women Veteran patients who attend an out-patient seizure clinic at the Audie L Murphy VAMC in San Antonio, TX. The study consisted of two arms: patients on AEDs and patients on AEDs plus simvastatin. Simvastatin was chosen as it is the first line cholesterol lowering agent at the VA. The patients were on at least one AED and simvastatin for 6 months at a steady dose prior to cholesterol levels being examined. Patients taking other classes of cholesterol lowering medications were excluded. Also, patients taking valproate, an inhibitor of 3A4, were excluded. Medication dosing and type were reviewed and cholesterol levels were analyzed. Comparisons in simvastatin dose and cholesterol levels were made between patients taking EIAEDs and NEIAEDs and were analyzed using the standard t test with unequal variance. Results: The retrospective analysis consisted of 167 consecutive patients who were taking simvastatin (10 mg - 80mg daily) and an AED, and 222 patients taking only an AED. These groups were further divided into patients on at least one EIAED and those on only NEIAEDs. When comparing total cholesterol (TC) and LDL in patients on statin therapy and patients not on statin therapy, the EIAED group had significantly higher levels. Furthermore, in both groups (with statin therapy and without statin therapy), patients on EIAEDs had higher levels of TC and LDL. Finally, the average daily dose of simvastatin was significantly higher (p<0.05) in the EIAED group at 45.12 ( 2.7) mg compared to 37.87 ( 0.35) mg in the NEIAED group. Conclusions: This retrospective cohort study demonstrates that EIAEDs do have a significant effect on metabolism of cholesterol, leading to higher levels of both TC and LDL. In addition, the higher simvastatin dose utilization in the EIAED group shows that induction of the CYP450 system also affects simvastatin metabolism. In all, EIAEDs not only inherently increase the levels of TC and LDL, but also induce the metabolism of simvastatin, making it less efficacious and thus contributing to higher cholesterol levels. More studies are needed to assess whether the risk for cardiovascular morbidity and mortality is increased in this patient population as a result of choosing a particular class of AED.