Weighing the Benefits of High-Dose Simvastatin Against the Risk of Myopathy

Perspective:

The following are five points to remember about this perspective:

1. Findings of a disproportionate increase in the risk of myopathy with high-dose simvastatin resulted in Food and Drug Administration (FDA) recommendations for restricting the 80 mg dose. This was also based on the finding in the SEARCH post–myocardial infarction trial in which the cardiovascular event rate was approximately 25% in both the 80 mg and 20 mg groups. The latter may have been explained in part by greater use of low-density lipoprotein cholesterol (LDL-C)–lowering agents in the 20 mg group and the prevalence of statin use prior to the trial.

2. A serum creatine kinase (CK) level more than 10x the upper limit of normal (ULN) with unexplained muscle weakness or pain developed in 0.9% on 80 mg and 0.02% on 20 mg. Rhabdomyolysis with a serum CK level more than 40x ULN developed in 4/1,000 of the 80 mg group and none on 20 mg. The increased risk with high-dose simvastatin was only 1/1,000 after the first 12 months.

3. Simvastatin is particularly prone to drug–drug interactions, in part because it is extensively metabolized by the CYP3A4 enzyme system. Much of the increase in risk for myopathy on 80 mg simvastatin was associated with concomitant use of medications such as amiodarone, diltiazem, and amlodipine. Simvastatin dose should not exceed 20 mg when used with amlodipine; 10 mg with amiodarone, verapamil, and diltiazem; and should not be used with antifungals, gemfibrozil, cyclosporine, and the macrolide antibiotics.

4. In clinical trials, the incidence of CK >10x ULN is very low for all statins, but approximately 3x as high with simvastatin than the more effective (reduction in LDL-C) rosuvastatin and atorvastatin. And the rates of reported fatal rhabdomyolysis is higher with 80 mg of simvastatin than with 80 mg of atorvastatin or with 20 mg and 40 mg of rosuvastatin.

5. The FDA recommends that the 80 mg dose of simvastatin be used only in patients who have been taking this dose for 12 months or more without signs or symptoms of clinically significant muscle toxicity. For these patients, the agency suggests that the cardiovascular benefits of high-dose simvastatin outweigh the low absolute risk of myopathy. In those who require a greater reduction in LDL-C than can be achieved with 40 mg of simvastatin, consideration should be given to atorvastatin or rosuvastatin.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Statins

Keywords: Fluorobenzenes, Risk, Myocardial Infarction, Lipoproteins, Pyrimidines, Muscle Weakness, Heptanoic Acids, Simvastatin, Rhabdomyolysis, Drug Interactions, Pyrroles, Prevalence, Incidence, Cholesterol, United States Food and Drug Administration, Cardiology, Cardiovascular Diseases, Muscular Diseases, United States, Sulfonamides


< Back to Listings