Statins don't always lower cholesterol

Therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) lowers total and low-density lipoprotein (LDL) cholesterol and has proven to be highly effective for cardiovascular risk reduction, according to background information in the article. However, there is wide variation in interindividual response to statin therapy, and it has been hypothesized that genetic differences may contribute to this variation.

Daniel I. Chasman, Ph.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues conducted a study to determine whether common genetic variants influence the degree of lipid level reduction during pravastatin therapy. The study included 1,536 individuals treated with pravastatin, 40 mg/per day. Their DNA in blood samples was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period.

"In this analysis of 148 SNPs across 10 genes known to be involved in cholesterol synthesis and statin metabolism, we found 2 common and closely linked polymorphisms in the HMG-CoA reductase gene that were significantly associated with a 22 percent smaller reduction in total cholesterol and a 19 percent smaller reduction in LDL cholesterol following 24 weeks of pravastatin therapy," the authors write. "For total cholesterol, these effects remained significant after adjustment for all SNPs evaluated and were consistent in magnitude and direction among men and women and among whites as well as the total cohort."

"We recognize that these data have considerable pathophysiologic interest and provide strong clinical evidence that there may be promise in the concept of 'personalized medicine' and the use of genetic screening to target certain therapies. The absolute difference in total cholesterol reduction associated with the HMG-CoA reductase genotype in our data was 9 mg/dL (0.23 mmol/L), an effect large enough to affect health on a population basis. Future studies must determine whether this difference can be offset by dose adjustment or the choice of an alternative nonstatin lipid-lowering therapy. In the meantime, clinical reminders to take treatment daily and to titrate dose as necessary to achieve National Cholesterol Education Program goals remain critical issues for practice," the authors conclude.

JAMA: The Journal of the American Medical Association