"In a healthy heart, shown here, HDL cholesterol helps prevent accumulation of plaque in the arteries. (Custom Medical Stock)"

" For nearly two decades, the mantra of cardiologists has been "Reduce bad cholesterol and increase good cholesterol.""

"Low-density lipoprotein, or LDL, the bad cholesterol, is a major contributor to the buildup of deadly plaque in coronary arteries, and it is now well established that the family of drugs called statins lowers it, reducing the risk of heart attacks and stroke by about a third."

" High-density lipoprotein, or HDL, the good cholesterol, works exactly the opposite ? breaking down plaque and disposing of its bad components. Studies in animals show that raising levels of good cholesterol also decreases the risk of heart attack, and humans with a naturally elevated level of HDL have less plaque than other people."

"The holy grail of pharmaceutical companies thus has been to produce a drug that raises HDL, and several companies have compounds in development."

"But results presented last week at a New Orleans meeting of the American College of Cardiology suggest that this approach may have a limited future. Studies show that at least some of these drugs do not lower plaque even though they raise HDL levels significantly, and at least one, called torcetrapib, has been shown to raise the risk of heart attacks and death."

""Whether this failure represents a problem unique to torcetrapib or suggests a lack of efficacy for the entire class of similar drugs remains to be defined," said Dr. Steven Nissen of the Cleveland Clinic. "We may yet be able to salvage the class, but we face an extremely difficult uphill battle.""

"Torcetrapib is the first of a class of drugs called CETP inhibitors. CETP, or cholesteryl ester transfer protein, is an enzyme that plays a major role in recycling cholesterol, breaking down and reforming individual components. Researchers became interested in it when they observed that Japanese families with unusually low levels of CETP had extraordinarily high levels of HDL ? two to 2 1/2 times the normal level ? and a low incidence of heart disease."

"Pfizer began a clinical trial involving more than 15,000 patients, comparing a combination of torcetrapib and the statin atorvastatin with atorvastatin alone. That trial was abruptly halted last December after three years when it became clear that those taking the torcetrapib combination had a 60% higher death rate."

"Nissen and others presented the first detailed analysis of the trial at the cardiology meeting and in a series of papers published online by the New England Journal of Medicine. The results were disappointing, at best."

"Nissen and his colleagues found that the drug increased levels of HDL by 61% ? an "unparalleled amount" ? and lowered LDL by 21% compared with the group receiving only atorvastatin. Despite those changes, the volume of plaque in the coronary arteries, as measured by ultrasound, was unchanged."

""Our findings demonstrate the great difficulty in developing strategies to interrupt the atherosclerosis process," Nissen said."

"Dr. John J.P. Kastelein of the University of Amsterdam and his colleagues studied the carotid arteries of the neck in a separate subgroup of patients. Their findings were presented in two additional reports at the meeting and in the
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