Statin-Induced Myopathy and SNP Polymorphisms

With the media fixation on the cholesterol-lowering combo Vytorin (ezetimibe/simvastatin)—namely, the negative results of the ENHANCE study and the SEAS trial—it's easy to forget that statins alone have their drawbacks. Case in point is the well-known risk of myopathy with the drug class, which is reported to occur approximately once per 10,000 patients who take lower-dose therapy.

This incidence rate may seem inconsequential, until you remember that about 13 million Americans take statins—some at high dosages and with drugs that can inhibit statin metabolism (thereby increasing the risk of drug-associated myopathy).

In this week's issue of the NEJM, UK investigators report a "single strong association" of simvastatin-related myopathy* with the presence of the rs436657 single-nucleotide polymorphism (SNP) on the gene SLCO1B1 (chromosome 12). The SLCO1B1 gene encodes for an organic anion-transporting polypeptide that has been shown to regulate the hepatic uptake of statins—suggesting that the SNP dictates a class effect for the risk of myopathy. The odds ratio for myopathy was 16.9 (95% CI: 4.7, 61.1) in individuals homozygous for the C (cytosine) allele, versus individuals homozygous for the T (thymidine) allele.

Genetic data were collected and analyzed from 85 subjects who developed myopathy while taking simvastatin 80 mg/d in the Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) (N = 12,064) and compared with data from 90 subjects who did not develop myopathy while taking high-dose simvastatin. The SNP association with myopathy in SEARCH was corroborated by data from the Heart Protection Study of simvastatin 40 mg/d; although the relative risk with a C allele was less robust in this lower-dose study.

Other relative risks for baseline patient characteristics from SEARCH reveal a markedly elevated risk of simvastatin-associated myopathy with the concomitant use of amiodarone.

The authors conclude that genotyping of SLCO1B1 polymorphisms may enable safer statin treatment, and Yusuke Nakamura, MD, PhD, advises in an accompanying editorial that SLCO1B1 variants must be tested for an association with a more severe myopathic event, statin-induced rhabomyolosis, as soon as possible.

* Reversible.