Genes Play Role In Who Benefits From Statin
In Boost to 'Personalized Medicine,' Study Links Patient Genetics With Efficacy of Cholesterol Drug
By a WALL STREET JOURNAL Staff Reporter
June 16, 2004; Page D1
In a finding with potentially significant implications for the millions of people taking cholesterol-lowering statins, researchers have discovered that patients with a certain genetic makeup get less benefit from a commonly prescribed drug.
Currently, doctors take a scattershot approach and put most patients with high cholesterol on statins, even though they can't be sure the drugs will be effective for a given individual. Homing in on who is less likely to benefit could help doctors better tailor a drug regimen. The study is the largest look to date at the role of genetics in the effectiveness of statins.
The results, published in this week's Journal of the American Medical Association, could eventually lead to a simple genetic test to determine what drug is best for patients at risk of heart ailments. The study also provides a boost to the concept of so-called personalized medicine -- the hope that genetic testing will help doctors identify which drugs work best for their individual patients.
The discovery threatens to shake up the lucrative $26 billion market for statins -- the big-selling products that help lower cholesterol in the blood and reduce the risk of heart attacks and strokes. Statins are the biggest source of revenue for many drug companies. But researchers say further investigation is needed before genetic testing could be routinely recommended in prescribing drugs.
All of the 1,500 patients in the study were taking Pravachol, a Bristol-Myers Squibb Co. product with sales of $2.83 billion last year. Patients with a certain common genetic variant had a 22% smaller drop in total cholesterol and a 19% smaller drop in LDL or "bad" cholesterol than those patients without the variant.
Bristol-Myers, in a statement, called for further study of all statin drugs, saying "it will be critically important to confirm these results and determine whether the same or similar markers may apply to other members of the statin class."
In the study, researchers from Brigham and Women's Hospital in Boston and Harvard Medical School examined 10 genes in the DNA of study participants. The relevant genetic variant was found in 7% of the patients studied.
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STATIN FACTORS
Some issues to consider when deciding whether to take statins:
A family history of heart disease
Hypertension: blood pressure of 140/90 or higher
HDL (good) cholesterol lower than 40 mg/dL
Age: 45 or older for men; 55 or older for women
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Paul M. Ridker, a study author and director of the hospital's Center for Cardiovascular Disease Prevention, cautioned that the results shouldn't lead to changes in current prescription practices, saying more study is needed. But, he said, the study "suggests there may be a future for this idea of using genetic testing to figure out who really benefits more than others."
The Brigham and Women's investigators are now testing another statin -- the world's top-selling drug, Lipitor, from Pfizer Inc. -- to see if its effectiveness is influenced by the same genetic variant. The researchers are also seeking to confirm the results of their most recent study by testing a different group of patients on Pravachol.
In addition, they are looking at both Lipitor and Pravachol to see if patients with the genetic variance suffer more heart attacks while on the drugs than those without it. There are also plans to examine whether increasing the dose received by those with the variant improves the effectiveness of the drug.
Proponents of personalized medicine -- also often called pharmacogenetics -- argue that not only could genetic testing better identify the patients most likely to respond to a particular drug therapy, it could also spare patients from suffering dangerous or painful side effects by taking drugs that are not likely to help them. In the case of some statins, severe side effects such as liver function abnormalities and muscle breakdown resulting in kidney damage have been reported in a small number of cases.
Much of the work in pharmacogenetics has occurred in the study of cancers. Last year, the Food and Drug Administration approved a label change for the drug thioguanine, used to treat patients with leukemia, alerting doctors to the availability of a genetic test to screen for an inherited enzyme deficiency linked to a potentially fatal reaction to the drug.
The field of pharmacogenetics has been slow to attract research dollars, in part because drug companies are reluctant to spend money on research that may cut into their bottom line. At the same time, government regulators have imposed few rules requiring genetic-based research as part of the drug approval process.
The Brigham and Women's study was initially a joint project with Variagenics Inc., a Cambridge, Mass., company created to explore the possibility of matching medications to individual genetic profiles. Variagenics, however, had difficulty generating business and was dissolved in 2002.
"No one has succeeded in commercializing pharmacogenetics," said Daniel I. Chasman, the lead Variagenics researcher on the study who was hired by the hospital after the company ceased operations.
Some drug companies, however, are looking at the issue internally. GlaxoSmithKline PLC, for instance, has a genetics-research unit headed by a former Duke University researcher considered a pioneer in the field. Bristol-Myers Squibb is also doing in-house research in this area, a spokeswoman said.
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