July 24, 2008— -- The tens of millions of Americans who take statin drugs to control their cholesterol levels are also taking a calculated risk -- the small chance that they might experience muscle weakness, the most common side effect of the drugs.
Now, British researchers say a screening test that could predict which patients will suffer these side effects may one day be a reality, thanks to their discovery of a gene linked to their occurrence.
But, whether the cost of this potential advance in personalized medicine can justify the returns is still a matter of contention among doctors.
"My first impression is that this is the first time that genomics can be useful in day-to-day clinical medicine," said Dr. Christopher Cannon, a heart researcher at Brigham and Women's Hospital, and an associate professor of medicine at Harvard Medical School, who was not involved with the study. "It seems to be a useful test, and could be one that patients would want to know when they are starting therapy."
Dr. Eric Topol, the chief academic officer of Scripps Health, calls the study a "fantastic jump forward" and says that it is the first to provide strong evidence of a gene that can show potential side effects that will result from a drug.
"It's an exceptionally important one, it's a real major discovery," said Topol. "[It's] not a first, but it's the most impressive one to date."
But, citing cost, not all researchers are so sure about the study's usefulness.
"It is difficult to advocate for an expensive test to determine susceptibility to an adverse effect that occurs in only 1 in 1,000 to 1 in 10,000 patients who take the drug," said Dr. Steve Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic, and former president of the American College of Cardiology. "It's nice science, but not a practical screening tool."
Nissen added that since most patients who develop the muscle weakness, known as myopathy, recover completely, any screening test that may be developed in the future may be largely unnecessary.
"The test is designed to determine susceptibility to a non-lethal adverse effect," Nissen said. "If used for all patients starting statin therapy, the costs would be prohibitive."
An estimated 12 to 25 million Americans take some dosage of statins. Researchers found that, among patients who took a more aggressive dose of the drug, roughly 1 in 1,000 were likely to suffer from myopathy, and a common reason why patients stop taking statins -- and most of those cases could be explained by the gene variant.
To find the gene, researchers used a study of 12,000 patients taking an 80-milligram daily dose of statins (the standard dose is 40 milligrams), and looked at the genetic profiles of 85 patients of European descent who were suffering from myopathy. They compared this to the genetic profiles of 90 additional patients, who were similar to the 85, but did not report the side effect.
What the researchers found was that one particular gene variation accounted for 60 percent of the myopathy cases. Similar links between this gene and muscle weakness were seen in patients taking a standard dose of the drug.
The findings are published in this week's issue of the New England Journal of Medicine.
In addition to being a good predictor of the side effect, a test for this gene could cost less than $1 per patient, said Rory Collins, co-director of the Clinical Trial Services Unit at Oxford University, and the study coordinator from the SEARCH team that ran the study and published the results.
"For patients ... at a particularly high risk of a heart attack ... these results provide the opportunity to test for this gene variant, and in those individuals who've got it, you might be a bit more cautious," Collins said. "It allows doctors and their patients to use statin therapy more effectively, particularly use high doses more effectively and safely."
Still, the balance between potential cost and possible benefits remains a point of contention among doctors.
Topol noted that the cost of the test would depend on licensing, rather than lab fees. He said that while the test itself would cost pennies, that cost could escalate quickly, depending on the amount needed to cover licensing costs from the patent.
And while the side effect is uncomfortable, it is rarely fatal.
"If the cost were very high, we might continue to do what we do now," said Dr. Gordon Ewy, chief of cardiology at the University of Arizona. "So many patients have muscle aches and pains, especially as they (we) get older, that what we do is have them stop the drug to see if the aches go away, and then restart the drug."
In the most severe cases, however, the side effect can lead to a rare condition known as rhabdomyolysis, where the skeletal muscle breaks off and goes into the blood. The result can be kidney failure, though the discomfort generally leads the patient and doctor to take action before that point. Plus, the condition generally stops when the statin doses do.
Still, "the problem of statin-induced myopathy, although not extremely common, is the most common problem leading to discontinuation of the drugs," according to Dr. Mason Freeman, director of the lipid metabolism unit at Massachusetts General Hospital.
Freeman maintains that myopathy can be a major obstacle for treating a potentially fatal condition. "The problems can prevent people with terrible lipids and coronary disease from getting a treatment we know would improve their health outcomes."
Regardless of how they see the possibility of testing statin patients for a myopathy gene, several doctors hailed this study as a new development in applying genetics to clinical practice -- an area with many exciting developments, but relatively few clinical uses so far.
While he feels this particular gene is not a significant enough finding, "the concept of using the genome to guide pharmacotherapy is an important one, and will be the subject of several future reports, I'm sure," said Dr. Daniel Edmundowicz, the director of preventive cardiology at the University of Pittsburgh School of Medicine.
Meanwhile, others feel the test is useful when the patient does not have the gene.
"Perceived myalgias (muscle aches) in patients taking statins is a big issue and many patients quit taking them," said Dr. Peter McCullough, chief of the division of nutrition and preventive medicine at William Beaumont Hospital in Royal Oak, Mich. "If we could use a genetic test to find out who really is at risk for them, we could provide considerable reassurance to the many individuals who have common aches and pains, and have them stay on the medication."
But, even for those who feel this particular gene will have significant value in the clinic, they feel more testing will be needed, particularly in non-European populations, before it can be widely used. And cost may be too big an obstacle.
"It is a high quality study, but until we have everyone's genome sequenced and the data is at the fingertips of the physician, without requiring a new blood test to be done, this genetic test is unlikely to be widely used except under the unusual circumstances I outlined," said Freeman.