Statin snag

Gene variant places some people at risk of side effect from statins

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Cholesterol-reducing drugs called statins do their job with remarkable efficiency, but in rare individuals they can cause a painful muscle side effect called myopathy. Researchers report in an upcoming issue of the New England Journal of Medicine the discovery of a gene variant that places people at risk of this complication.

The gene, called SLCO1B1, encodes a protein that shuttles compounds from the blood stream into the liver for processing. This cargo includes statins.

Properly deposited, these drugs then go on to decrease the levels of LDL, the bad cholesterol.

But people with the variant form of the gene make a version of this protein that transports statins poorly, leaving an excess amount in the blood stream, says study coauthor Rory Collins, a physician and epidemiologist at the University of Oxford in England.

From there the story gets rather mysterious. “It’s still not clear how statins cause myopathy,” he says. But left to linger in the blood, statins seem to have that effect. “The mechanism is unknown.”

Collins and his colleagues suspected that statins were involved because a trial had shown that people getting high doses of a statin were 10 times as likely to develop the side effect as people receiving a low dose, Collins says. But since not everyone gets myopathy on high-dose statins, the scientists guessed that a gene — or a rogue form of one — might explain some of the risk.

Blood samples were collected from 192 of the trial volunteers between 1998 and 2001. Half the volunteers had myopathy, half did not. The statin used in the trial was simvastatin, marketed as Zocor. The scientists screened thousands of genes in these blood samples, and the one that stood out was SLCO1B1.

Genes often come in a variety of forms, resulting in the assemblage of slightly different proteins. The researchers found that among people taking high-dose simvastatin, those who carried one particular variant of the SLCO1B1 gene had four times the risk of myopathy compared with people carrying other forms of SLCO1B1. If a person carried two copies of this variant — one inherited from each parent — the risk shot up 17-fold, the researchers report.

“We’ve always suspected there are genetic differences,” says endocrinologist Robert Hegele of the University of Western Ontario in London, Ontario “It’s great that they did this study.” 

Hegele estimates that roughly five to 10 percent of patients on statins report some muscle aches and pains at some point.

Collins and his team calculated that 18 percent of people with two copies of the gene variant who take a high does of statins would develop myopathy, while three percent of people who harbor only one copy and take the high drug dose would get myopathy.

Severe myopathy can damage muscles and even the kidneys. The researchers calculated that nearly two-thirds of the cases of myopathy in patients taking high-dose statins are attributable to the variant.

Doctors might avoid giving statins to people who have two copies of the variant and prescribe only low-dose statins for people carrying one copy, reasons physician Yusuke Nakamura of the University of Tokyo, writing in the same NEJM issue.

As an alternative, doctors might use the anti-cholesterol drug ezetimibe, sold as Zetia, which lowers LDL via a mechanism different from that employed by statins, Hegele says. Statins reduce cholesterol production in the liver, whereas Zetia inhibits cholesterol absorption in the intestines.

While doctors’ offices aren’t equipped to test for the gene, Collins says, the actual lab test for the variant is inexpensive. “The technology is straightforward. It would cost less than a dollar in a standard genetics lab,” he says.

The number of people in the United States taking statins nearly doubled from 2000 to 2005, rising from 15.8 million to 29.7 million, according to the Medical Expenditure Panel Survey conducted by the federal government.

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