MONDAY, March 26, 2007 (HealthDay News) -- A once-promising experimental heart drug does not slow the progression of plaque build-up in coronary arteries, even though it increases HDL or "good" cholesterol and lowers LDL or "bad" cholesterol, researchers report.
"Something very strange is going on with this drug [torcetrapib], where none of these fantastic changes translate into benefit for the arterial walls," said Dr. John J.P. Kastelein of the Academic Medical Center in Amsterdam, the Netherlands, and lead author of two studies of the drug.
Pfizer Inc. pulled the plug on a major clinical trial of torcetrapib in December due to an increased risk of death and other adverse outcomes. At the time, there were still questions as to whether the drug actually worked.
At stake now is the future of this class of medications that would lower heart disease risk by raising HDL levels.
"This needs more extensive research. That's very, very important for us, because raising HDL is the next holy grail," Kastelein said. "We have already attained the first holy grail by reducing LDL. But this drug is a dirty drug. We need more research with compounds that are clean."
Kastelein and others presented their study results Monday at the annual meeting of the American College of Cardiology, in New Orleans.
LDL cholesterol is worrisome, because if too much circulates in the blood, it can help to form plaque -- a thick, hard deposit that can clog arteries. This can lead to the creation of clots that can cause heart attacks or strokes. HDL cholesterol is beneficial, because it carries cholesterol away from arteries and to the liver, where it's passed from the body.
Kastelein presided over two studies involving patients with high levels of cholesterol, either familial or other causes. The participants were randomly selected to take torcetrapib plus a statin (a drug that lowers LDL cholesterol) or the statin alone.
There were unparalleled increases in HDL levels along with decreases in LDL, but no benefit on the progression of atherosclerosis -- plaque buildup in the arteries. One measure even indicated a progression of the disease, the research found.
"The results were like a Dutch pancake," Kastelein deadpanned.
Another study of torcetrapib turned up similar "robust" HDL increases along with LDL decreases that resulted in an unprecedented LDL-HDL ratio of less than 1. But, the drug resulted in increased blood pressure and had no effect on plaque.
"We did not see a slowing of the progression of coronary atherosclerosis," said study lead author Dr. Steven Nissen, chairman of the Cleveland Clinic's Department of Cardiovascular Medicine, and president of the American College of Cardiology.
The study is also expected to be published in the March 29 issue of the New England Journal of Medicine.
Still, Nissen seemed optimistic about prospects for medications that could raise levels of HDL cholesterol. "When you have a drug that isn't clean, that has this unusual toxicity, you don't have the answer definitely as to whether this class will or will not work," he said. "If we had stopped after removing the first statin from the market, we would have made a terrible mistake."
Nissen also co-authored a study being presented at the conference that suggested that an experimental drug dubbed LY518674 also raised HDL levels but also produced some safety concerns. That study is to be published in the March 28 issue of the Journal of the American Medical Association.
Other research presented at the conference found that CSL-111, a drug that mimics HDL, did not significantly reduce plaque in coronary arteries in patients who had experienced acute coronary syndrome. However, there were improvements in two other measures that pointed to beneficial changes in the blood vessels. This study is also expected to be published in the March 28 issue of JAMA.
"We think that when we take both the primary and secondary endpoints together, this really is suggestive of a favorable, rapid treatment effect of CSL-111," said study lead author Dr. Claude Tardif, of the Montreal Heart Institute.
The high-dose component of the CSL-111 trial was discontinued due to abnormalities in liver function tests. The remainder of the trial involved a lower dose of the drug.
A final study found that a combination of aliskiren and valsartan, two drugs that work against the enzyme rennin, were more effective in lowering blood pressure than either of the compounds alone.
This was the first study to assess the drugs together. "These two agents act at both ends of the same general pathway and give an additive effect," said lead author Dr. Suzanne Oparil, of the University of Alabama at Birmingham School of Medicine.
More information
For more on cholesterol and heart disease, visit the American Heart Association.
