New Cholesterol Drug Fails Human Trial

Poor results may doom once-promising line of research, experts say

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By Ed Edelson
HealthDay Reporter

WEDNESDAY, March 22, 2006 (HealthDay News) -- A promising theory, focused on a drug that experts hoped would help prevent heart disease, has been proven wrong in a real-world trial.

The idea was to prevent the formation of the fatty plaques that clog arteries by blocking an enzyme that steers cholesterol into those plaques.

However, pactimibe, a drug designed to interfere with the enzyme, did nothing to stop plaque formation, researchers report in the March 23 issue of the New England Journal of Medicine. In fact, it seems to have increased the danger.

"This approach has proven to be too risky, and it should not be pursued further," said Dr. Sergio Fazio, a professor of medicine at Vanderbilt University Medical Center, and the author of an accompanying editorial in the journal.

The report was rushed into print by the journal, according to lead researcher Dr. Steven E. Nissen, who is interim chairman of cardiovascular medicine at the Cleveland Clinic. Preliminary results from the trial had already been presented earlier this year at an American Heart Association meeting.

Nissen applauded the journal's decision to publish the study results, even though things didn't pan out as hoped.

"Things have really changed in the last few years," he said. "Negative trials used to get buried. In my view, it is very important to publish these negative results because other drugs in this class are in development, and the trial seemed to show an increasing rate of atherosclerosis [hardening of the arteries]."

The class of drugs in question block the effect of an enzyme known by its abbreviated name of ACAT. ACAT inhibitors act in a completely different way from statins, the widely used cholesterol-lowering medications that include blockbusters like Lipitor and Pravachol. While statins prevent the body from producing cholesterol, ACAT inhibitors, in theory, were supposed to prevent cholesterol from forming plaques and also keep it out of cells.

That idea was good on paper, Fazio said. However, he added that the trial's poor results were predictable, based on similar results in a prior clinical trial using a different ACAT inhibitor, and from Fazio's own research using an animal model.

In theory, the way to prevent cholesterol from forming plaque and get cholesterol out of the cell is to make sure it is in a form called "free cholesterol," Fazio said. An ACAT inhibitor does increase the amount of free cholesterol, but there's a catch: animal studies have shown that "too much free cholesterol is toxic to the cell," he said.

For that reason, this line of research may be a dead end, Fazio said. "Instead of telling the cell to make more free cholesterol, we have to think of ways to get cholesterol out of the cell, to open the doors and let cholesterol out."

A number of researchers are working on different methods of "opening the doors and windows of the cell" so that cholesterol can exit, Fazio said. One promising method is to increase the number of cholesterol receptors that would grab hold of the molecule outside the cell, he said.

The pactimibe trial did have one positive result, according to Nissen. The researchers used a technique called intravascular ultrasonography to measure the formation of plaque in the 408 people with coronary disease who took part in the trial. The technique provided good information on plaque formation and can be used in other studies, he said.

Another report on cholesterol and heart disease in the same issue of the journal focused on the role of genetics.

Researchers at the University of Texas Southwestern Medical Center in Dallas report that people who carry one of three variants of genes involved maintaining blood cholesterol levels are at substantially reduced risk of heart disease. Two of the gene variants are found predominantly in blacks, one in whites. One of the gene variants reduced blood levels of LDL cholesterol by 28 percent and the risk of coronary heart disease by 88 percent, the researchers reported.

More information

For more on cholesterol and heart disease, head to the American Heart Association.

SOURCES: Steven E. Nissen, M.D., interim chairman, cardiovascular medicine, Cleveland Clinic; Sergio Fazio, M.D., Ph.D., professor, medicine, and co-director, Atherosclerosis Research Unit, division of cardiovascular medicine, Vanderbilt University, Nashville, Tenn.; March 23, 2006, New England Journal of Medicine

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