WEDNESDAY, July 23, 2008 — Cholesterol-lowering drugs like simvastatin (Zocor) and atorvastatin (Lipitor) are one of the great health breakthroughs of the 20th century—they’re safe and can dramatically lower LDL, the bad cholesterol. But they’re not risk-free: Some people experience muscle pains, known as myopathy, which can make taking the drugs unpleasant and, in rare cases, lead to a life-threatening condition.
Now a new study suggests that 15% of the population may have a specific genetic variant that increases their risk of experiencing statin-related muscle aches.
In the new research, a University of Oxford team sequenced the genes of 85 people who developed myopathy after taking high-dose simvastatin (80 mg) in a larger trial of 12,000 people. They compared the DNA of those subjects with 90 people in the same study who did not develop myopathy.
What they discovered was that one small change in a gene that is responsible for transporting drugs in the liver was associated with myopathy.
People who inherit a single copy of the genetic variant from a parent were 4.5 times as likely to develop myopathy, and those with two copies (one from each parent) were almost 17 times as likely to develop the condition when taking a high-dose statin compared with those without a copy, according to the study in The New England Journal of Medicine.
It’s a common problem
About 1 in 10,000 people per year who take regular doses of statin drugsdevelop myopathy, according to the study, though the risk goes up with higher doses. According to Merck spokesperson Ronald Rogers, the incidence can be as high as half of 1% (roughly 1 in 200) for those taking large, 80 mg doses of Zocor for at least four years.
However, Leslie Cho, MD, director of the Women’s Cardiovascular Center at the Cleveland Clinic in Ohio, says a higher percentage of patients in the real world may complain of muscle aches.
“Muscle aches on statins is rarely reported in [clinical] trials because drug companies don’t want to look for that, but it’s a very common thing that clinicians hear every day,” she says. “It’s especially common in the elderly and we are always trying to look for ways to make that better. If there is a predisposing genetic thing for it, that would be a good thing.”
Gene test could be used in the clinic, but not likely
If further research confirms the findings, and a cheap enough gene test is developed, doctors could one day use it to help determine if a patient who is a candidate for a statin might be at risk for developing myopathy.
However, those are some big “ifs,” and such a test may not be cost-effective for every patient, according to experts.
“Now would I use this on every patient before I started statins? I don’t think I would,” says Dr. Cho, who was not involved in the new research. “To get this test on every single patient before they start statins would not be cost-effective unless it is incredibly cheap.”
Donna Arnett, PhD, a spokesperson for the American Heart Association, confirmed that the findings are important, but a long way from being used routinely in doctors’ offices.
“There are a lot of steps until we get to that clinical testing in your doctor's office,” says Arnett, a chair and professor of epidemiology at the University of Alabama at Birmingham who does research in genetic epidemiology. The new findings need to be replicated in other patients and with other statins, but if it holds true, it could result in a useful test, according to Arnett.
How serious is myopathy?
Dr. Cho says that many statin-taking patients who experience some pain think they have myopathy, but the condition is more than minor aches and pains. Doctors look for pain and weakness in large muscle groups on both sides of the body, such as the buttocks, upper arms, and upper legs.
And many people don’t know that a host of other things can increase their chances of myopathy in combination with statins—including excessive alcohol intake and drugs such as cyclosporine (an anti-rejection drug), fibrates (a cholesterol-lowering drug), macrolide antibiotics (such as erythromycin), antifungals (like fluconazole), protease inhibitors (used to treat HIV), and colchicine (used to treat gout).
Patients can often reduce their risk by talking with their doctor about possible drug interactions.
Gene’s link to more serious side effect is unknown
While myopathy is a relatively common side effect, it can progress to a rare and potentially life-threatening side effect called rhabdomyolysis, which occurs when muscle actually breaks down and leads to kidney failure.
“The thing we worry about the absolute most is rhabdomyolysis, which is life-threatening,” says Dr. Cho. In contrast, myopathy is “very benign but it's obviously lifestyle-limiting for patients.”
The incidence of rhabdomyolysis is estimated to be 44 events per 1 million statin users per year, according to an editorial accompanying the study. It’s not clear if the gene variant is linked to rhabdomyolysis, but testing for a link should begin “as soon as possible,” writes Yasuke Nakamura, MD, of the University of Tokyo.
While more research is needed, Dr. Cho says she could see a gene test being useful in patients who develop myopathy after taking the drugs.
“But I think that to have a carte-blanche statement that every patient that gets started on statins should have this test is kind of overkill.”
The study was funded by a research grant from Merck to the University of Oxford.
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