New biological target identified for cholesterol-lowering drugs

July 19, 1999

DALLAS, July 20 -- Cholesterol-lowering drugs may have anti-inflammatory effects that increase their potential to reduce a person's risk of heart disease, according to a report in today's Circulation: Journal of the American Heart Association.

High blood cholesterol levels and inflammation both may contribute to the fundamental process driving atherosclerosis, fatty deposits that may block blood vessels. Atherosclerosis is the underlying cause of heart attacks or stroke.

The study's lead author, Paul Ridker, M.D., associate professor of medicine at Harvard Medical School and a cardiologist at Brigham and Women's Hospital, says, "Our data support an important new biological target for reducing heart attack risk."

In their study, researchers tested pravastatin, a cholesterol-lowering drug, for its ability to reduce C-reactive protein (CRP), which is elevated during inflammation.

"We have known for some time that elevated C-reactive protein, a chemical marker for inflammation, is associated with an increased risk of heart attack and stroke. What we didn't know was CRP could be lowered with cholesterol-lowering drugs."

The study followed 472 heart attack patients randomly chosen to receive either a cholesterol-lowering drug or a placebo (a dummy pill with no effect.) The researchers used a high sensitivity test to measure blood levels of CRP at baseline and after five years.

While CRP levels tended to increase in the placebo group, the drug-treated group had significant reductions in CRP levels. After five years, CRP levels among those taking the drug were almost 38 percent lower than the placebo group's, the researchers report.

The changes seem unrelated to any decline in cholesterol levels. Even when patients in the placebo group were able to lower their low-density lipoprotein -- the so-called 'bad' component of total cholesterol -- through diet and exercise, CRP increased over time.

"This drug appears to have an effect beyond lowering the bad cholesterol," Ridker says. More research is needed to learn if the anti-inflammatory effect extends to other cholesterol-lowering drugs. All of the patients in this study were able to continue taking the drug with few side effects during the five-year period.

Ridker says many studies make it clear that measuring an inflammatory marker can improve the ability to predict cardiovascular risk in both apparently healthy individuals and those who have had a heart attack.

"Commercially available, high-sensitivity tests for CRP are now in development and are likely to be on the market by the end of the year," he says. "It's important to recognize that the standard test for CRP, which has been available for years, is just not sensitive enough to provide information for cardiovascular risk prediction."

No one knows the source of the inflammation, although "atherosclerosis may ultimately prove to be an inflammatory disease in the same way that we currently consider rheumatoid arthritis to be an inflammatory condition," Ridker says.

"Atherosclerosis is a life-long process, and we've learned that the long-term use of statins or other cholesterol-lowering drugs can greatly reduce cardiovascular risk," he says. "Our data suggest that their long-term use may be working on two aspects of this process: cholesterol levels and inflammation."

For example, in an article published in the New England Journal of Medicine in 1997, Ridker's group reported that healthy individuals with the highest levels of CRP were three times more likely to suffer a first heart attack and two times more likely to suffer a first stroke in an eight-year period than those with the lowest CRP levels.

"Our study is the first to investigate how the long-term use of a statin drug affects this inflammatory process, and it adds to the growing body of evidence that inflammation -- the body's reaction to injury -- plays an important role in the development of heart disease," says Eugene Braunwald, M.D., professor of medicine at Harvard University and co-author of the study conducted at Brigham and Women's Hospital and Harvard Medical School.

"One of the greatest advances in cardiology in the last 25 years has been the development of the statin drugs," Braunwald adds. "They've been shown in numerous trials to lower cholesterol and decrease the risk of heart attack. This article suggests that statins may have an important effect that is totally different from cholesterol-lowering. It's a twofer."

Researchers say the next step will be to determine if lowering CRP levels leads to fewer heart attacks.

Co-authors include: Nader Rifai, Ph.D., Marc A. Pfeffer, M.D.; and Frank Sacks, M.D.

American Heart Association

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