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Mutation Puts Statin-Users At Higher Risk for Myopathy

ARTICLE IN BRIEF

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A particular variant of the gene — SCLO1B1 — was associated with 60 percent of the cases of myopathy in a new study.

Scientists have discovered a mutation that puts statin users at higher risk for muscle weakness or pain, a side effect that has triggered alarm among physicians and patients.

The gene regulates substances that filter through the liver and a particular variant of the gene — SCLO1B1 — is associated with 60 percent of the cases of myopathy identified during the study. The SNP, or single nucleotide polymorphism, located within the SCLO1B1 gene encodes a polypeptide that regulates hepatic uptake of statins. About 15 percent of the general population has one copy of this C allele and two percent have two copies.

The findings were reported online July 23 in advance of the print edition of The New England Journal of Medicine (NEJM). The scientists, led by Rory Collins, MBBS, of the University of Oxford, suggested that genetic testing to identify those people with the variant “may be useful in the future for tailoring both the statin dose and safety monitoring.”

STUDY PROTOCOLS

The British investigators tapped into the findings from the SEARCH study, a randomized trial of 12,064 people with a history of myocardial infarction that was designed to test whether an 80 mg dose of simvastatin provided more benefit in lowering cholesterol and homocysteine than a 20 mg dose.

The patients were followed for an average of six years, by which time SEARCH investigators had discovered 98 cases of definite or incipient myopathy among those 6,031 patients on the 80 mg dose. Half of these cases appeared during the first year of treatment and all recovered once the medication was discontinued.

With previous evidence that genes may play a role in how statins work in the body, Dr. Collins and his team took advantage of this large pool of patients who had myopathy (and an equally large number of people who did not) to see whether they could identify a genetic variant that put people at risk for muscle symptoms.

They conducted a sweep of the genome using more than 300,000 SNPs and found a strong association with the SCLO1B1 gene. Those with two copies of the C allele who were taking 80 mg doses of simvastatin (Zocor) were 17 times more at risk for myopathy than patients with two copies of the more common T variant. Having one copy of the C allele increased the odds of muscle damage four-fold in those taking high doses of simvastatin.

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DR. HARLAN KRUMHOLZ said that the study is important because it demonstrates that a persons genetic profile can characterize a persons risk of an adverse drug reaction. But he questioned whether all statin-users should be screened since the side effect is a rare and reversible complication.

The myopathy was rare among those taking the 20 mg dose, with only two definite and six incipient cases in 6,033 study patients. (The incidence at 20–40 mg doses is 1 case per 10,000 patients per year.)

On the heels of these findings the scientists reviewed the cases of statin-induced myopathy in the Heart Protection Study that was carried out on 20,536 patients in the UK between July 1994 and May of 1997. These patients had diabetes or pre-existing occlusive vascular disease and were randomly assigned to take a 40 mg dose of simvastatin or placebo. They were followed for five years, after which the investigators identified 24 cases of definite or incipient myopathy among the 10,269 patients taking the 40 mg dose. (The myopathy was picked up in all but one while they were taking the statin.) By contrast, 12 cases of myalgia or weakness were observed in those taking placebo.

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DR. RORY COLLINS suggested that genetic testing to identify those people with the variant “may be useful in the future for tailoring both the statin dose and safety monitoring.”

DNA analysis also captured the risk genetic variant associated with myopathy, but it was much smaller (two-fold) because they were taking the lower dose of statin.

The scientists said that the genetic risk is not limited to simvastatin but includes the whole class of statin drugs. “These findings are likely to apply to other statins because myopathy is a class effect,” they wrote.

EXPERTS COMMENT

In an accompanying editorial in the NEJM, Yusuke Nakamura, MD, PhD, of the University of Tokyo said: “The study by the SEARCH Collaborative Group shows an unequivocal association.” He suggested that screening the population of patients taking cholesterol-lowering statins “could reduce the incidence of myopathy by nearly 60 percent.”

Harlan Krumholz, MD, a professor of cardiology, epidemiology, and public health at Yale University School of Medicine and director of the Yale-New Haven Hospital Center for Outcomes Research and Evaluation, said that the study is important because it demonstrates that a person's genetic profile can characterize a person's risk of an adverse drug reaction. But Dr. Krumholz noted that the genotype demonstrated an increased risk for a rare and reversible complication of statins.

Also, although the CC homozygotes had an increased risk, 82 percent of them never developed myopathy, he noted. Thus, “the clinical application of this study is far from clear even if such a screening test were widely available,” said Dr. Krumholz. He posed this question: “Would it really be worth screening all of these people if the condition is reversed once the medicine is stopped?”

REFERENCE

• The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy — A genomewide study. N Engl J Med 2008;359:789–799.