PracticeUpdate Neurology February 2019

EDITOR’S PICKS 8

Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid-Lowering Agents in the Elderly Epilepsia

Take-home message • Through this study, the authors wanted to examine the change in effectiveness of statins caused by carbamazepine interaction. Among the 194 participants of the STEP-ONE trial, the authors examined lipid fractions, lipoprotein (a), and C-reactive protein (CRP) and found that, in patients not taking statins, those treated with carbamazepine had a higher level of total cholesterol than those treated with levetiracetam (+16.6 mg/dL; P = .053), and lipoprotein(a) was significantly lower in patients taking lamotrigine than in the patients taking carbamazepine and leveti- racetam, with CRP higher in patients on carbamazepine than in other patients. • The authors concluded that carbamazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Contrary to what has been reported by some previous studies, they also noted that other lipid markers yielded drug– gender interactions without a consistent pattern. Omar Khan MD COMMENT By William H. Theodore MD M intzer et al analyzed a data subset from a clinical trial of antiepileptic drugs (AEDs) in the elderly. 1 Patients not taking statins treated with carbamazepine (CBZ) had higher total cholesterol than those treated with levetiracetam (LEV). Lipoprotein(a) was significantly lower in patients taking lamotrigine (LTG) than CBZ or LEV. C-reactive protein was higher in people on CBZ. When differences in lipid levels between patients taking statins or not were compared, lipid-lowering effects seemed to be reduced in patients on CBZ. Interpretation of the results needs to consider difficulties of post hoc subset analysis. Only 194 of 361 patients randomized in the underlying study, not designed to meas- ure effects on lipids, were included and not all had full data available. The original randomization did not take lipids or C-reactive protein into account. Baseline BMI was significantly higher in the CBZ group. The study was supported by UCB, maker of levetiracetam. Previous studies suggested hepatic enzyme-inducing AEDs may alter lipid profiles, even in patients not taking statins. In addition, because these drugs are metabolized via cytochrome P450, it is reasonable that CBZ, a hepatic enzyme inducer, might vitiate their effects. Interactions of hepatic enzyme-inducing AEDs with many other therapeutic drugs are well-known. Some data suggest that CBZ may be more effective for seizure control, but less well-tolerated than LTG or LEV. Both CBZ and LTG have mood-stabilizing properties, whereas LEV can have adverse psychiatric effects. Choosing the best AED requires careful balancing of antiseizure and adverse effects, and depends on a full evalua- tion of each patient, particularly including concurrent systemic disease. Reference 1. Werhahn KJ, Trinka E, Dobesberger J, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 2015;56(3):450-459.

Abstract OBJECTIVE To examine serologic markers of vas- cular risk under treatment with commonly used antiepileptic drugs (AEDs) in the elderly in a randomized setting, and to determine whether the reduced exposure to hydroxymethylglutar- yl-CoA reductase inhibitors (“statins”) caused by carbamazepine reduces the effectiveness of the drugs as lipid-lowering agents. METHODS Standard lipid fractions, lipoprotein(a), and C-reactive protein (CRP) were examined in a subset of those participating in the STEP- ONE trial, in which elderly patients with new epilepsy were randomized to treatment with carbamazepine, lamotrigine, or levetiracetam. Separate comparisons were made by individ- ual AED, among those treated with statins, and, for CRP, among those treated with anti-inflam- matory drugs. RESULTS One hundred ninety-four patients had the aforementioned serologic measurements. In patients not taking statins, those treated with carbamazepine had higher total cholesterol than those treated with levetiracetam (+16.6 mg/dL, P = 0.053), with values from patients on lamotrig- ine intermediate, whereas cholesterol fractions were subject to drug-gender interactions which did not show a consistent pattern. Lipoprotein(a) was significantly lower in lamotrigine patients than in the carbamazepine and levetiracetam groups. After accounting for the effects of ster- oids, CRP was higher in carbamazepine patients than in other patients. Patients taking a statin had lower lipid levels than those not taking a statin regardless of AED, but the differences between statin-treated and non-statin-treated patients were much larger (50%-100% or more) in the lamotrigine and levetiracetam groups than in the carbamazepine group (P = 0.035 for interaction effect of statin use and AED on total cholesterol). SIGNIFICANCE Here, we demonstrate that carba- mazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Native AED effects on lipids were inconsistent and sub- ject to drug-gender interaction, in contrast with other studies; further investigation is necessary to determine if these latter findings are genu- ine or spurious. Impact of Carbamazepine, Lamotrigine, and Levetiracetam on Vascular Risk Markers and Lipid-Lowering Agents in the Elderly. Epilepsia 2018 Oct 01;59(10)1899-1907, S Mintzer, E Trinka, G Kraemer, et al. www.practiceupdate.com/c/74819

Dr. Theodore is Chief of the Clinical Epilepsy Section at the National Institute of Neurological Disorders and Stroke, National Institutes of Health in Bethesda, Maryland.

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