Genetic Variants Associated With Risk of Statin-Induced Myopathy

July 24, 2008

July 24, 2008 — A new genomewide-association study has identified a genetic risk factor for myopathy in patients who are being treated with statins to lower LDL-cholesterol levels [1]. Investigators observed a strong association between statin-induced myopathy and two tightly linked variants in SLCO1B1, a gene that encodes for a protein involved in the transport of statins and other drugs from the blood into the liver.

"A lot of the emphasis in pharmacogenomics has been on identifying drugs that produce a particular efficacy, but I think these findings suggest that much greater emphasis on safety could be more fruitful," senior investigator Dr Rory Collins (Clinical Trials Service Unit, Oxford, UK) told heartwire . "It might well be that there are just a few pathways that result in these big increases in rare but serious side effects in particular individuals."

In an editorial accompanying the study [2], Dr Yusuke Nakamura (University of Tokyo, Japan) echoes this sentiment, writing that, among potential causes of adverse drug reactions, underlying genetic susceptibility plays a large role. "The identification of such variants is expected to improve the management of patient care by determining which patients should take a specific drug and which patients should take a modified dose of the drug," writes Nakamura. "This strategy could potentially reduce medical costs and improve the process of drug development."

The study, from the ongoing Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and editorial are published online July 23, 2008 in the New England Journal of Medicine.

Myopathy Observed in Patients Treated With 80 mg Simvastatin

SEARCH is a study conducted by the Oxford investigators involving 12 000 patients with prior MI and is designed to determine whether the 80-mg dose of simvastatin is more effective than simvastatin 20 mg in reducing cardiovascular events. Speaking with heartwire , Collins said the SEARCH group began to see more myopathy cases in this ongoing trial, mostly in patients treated with the 80-mg dose, than was observed in previous simvastatin studies, including one that tested simvastatin 40 mg against placebo.

"The dose where we start to see myopathy varies from statin to statin, but with simvastatin 40 mg per day, the rate of myopathy is around 1/10 000 per annum," said Collins. "But if you push the dose up from 40 mg to 80 mg, the rate increases to about 1/1000 per annum, about a 10-fold increase. With the other statins, there will be a point in which doubling of the dose will produce be a big increase in myopathy."

Interim analyses also revealed a strong association with myopathy among patients treated concomitantly with amiodarone, which resulted in an adjustment of the study protocol but led investigators to believe there might be a few important pathways responsible for large differences in myopathy risk. With this in mind, the group performed a large genomewide study using approximately 300 000 markers in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking simvastatin 80 mg in the study.

The genome scan turned up a strong association of myopathy with a single nucleotide polymorphism (SNP) located within SLCO1B1. In addition to this marker, there was a linked variant within the gene, one that has been associated previously with statin metabolism. The prevalence of the genetic variant in the population was 15% and was shown to be strongly associated with the risk of myopathy. Compared with those without the genetic variant, those with one copy of variant had a fourfold greater risk of myopathy, while those with both copies had a 16-fold increase in risk. The association of the SNP with myopathy was replicated in another trial of patients taking 40-mg simvastatin daily.

Using the Information in Clinical Practice

Asked about the clinical implications, Collins said this is a common variant, and there are hopes that a simple test for it could be developed sooner rather than later, something that is particularly important as more and more patients are aggressively treated to lower LDL-cholesterol targets.

"I think if your myopathy risk is low, say with a standard dose of a statin, there probably isn't much point in screening," said Collins. "But for a patient where a doctor is thinking about a higher dose of a statin because the patient is at higher risk of heart attack or stroke, and they are trying to lower their LDL cholesterol as much as possible to lower that risk, then it might be worthwhile genotyping to be reassured the myopathy risk would not be particularly high or to be aware that the patient might be at risk. If they were homozygous for the variant, you might decide not to use a high-dose statin but instead go with a combination of different lipid-lowering agents."

In his editorial, Nakamura writes that the usefulness of identifying those with a high risk of adverse drug reactions in response to drug therapy is slowly being performed in clinical practice, but studies identifying those at genetic risk have been less than comprehensive, mainly because the genetic loci screened is limited and the number of patients with specific types of adverse reactions is small.

"The result is that many studies have lacked sufficient statistical power," he writes.

The study by the SEARCH investigators showed that 60% of the cases of statin-induced myopathy were attributed to SLCO1B1, which suggests that avoiding prescribing high-dose simvastatin to those heterozygous or homozygous for the variant allele could reduce the incidence by about 60%. Avoiding high-dose simvastatin in those homozygous for the risky allele could reduce the risk by 25%, and these patients could be treated with combination therapy. Further investigations into the optimal prescribing approach are required, as are studies investigating the association between the SLCO1B1 variants and statin-induced rhabdomyolysis, which results in severe muscle damage accompanied by toxic effects on various organs such as the kidney, writes Nakamura.

Merck sponsors the SEARCH trial.

  1. The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; DOI:10.1056/NEJM0a0801936. Available at: www.nejm.org.

  2. Nakamura Y. Pharmacogenomics and drug toxicity. N Engl J Med 2008; DOI:10.1056/NEJMe0805136. Available at: www.nejm.org.



The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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