Gene mutations linked to statin resistance

22 December 2008

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Scientists at Duke University Medical Center have identified genetic mutations that may help explain why some people don't respond very well to statins, drugs taken by millions of Americans to fight high cholesterol and prevent coronary artery disease.

The findings, published in the Dec. 17 issue of Circulation: Cardiovascular Genetics, suggest that some patients may fail to see lower LDL cholesterol levels from taking the drugs -- no matter what the dose -- because of their genetic makeup.

Statins are generally effective in lowering low-density lipoprotein cholesterol, or LDL (the so-called "bad" cholesterol) -- even slashing LDL levels in half, in some cases. But in about 20 percent of patients, statins fail to bring LDL into target range, a phenomenon known as "statin resistance."

Geoffrey Ginsburg, MD, PhD, director of the Center for Genomic Medicine in Duke's Institute for Genome Science & Policy, says race, age and smoking status may exert modest influence on statin response, but he believes genetic variation may play a more powerful role.

To find out, Duke researchers randomly assigned 509 patients with high cholesterol to receive the lowest dose of one of three statins for eight weeks. Afterward, participants took the highest recommended dose of the same drug for a second, 8-week period. The statins tested included atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol).

Researchers wanted to study statins at two dose levels because the results could help answer an important clinical question: If a low or moderate dose of a statin isn't lowering LDL to target levels - the definition of statin resistance - could more of the drug overcome that?

"This is the first study we know of that looked at the value of dose escalation among statin resistant patients," says Deepak Voora, MD, a cardiologist at Duke and the lead author of the study. "What the research told us, among other things, is that dose escalation is not the best choice for statin resistant patients. The better option would be to simply switch them to the most potent statin available."

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