Bad News for 'Good' Cholesterol Drug

Dec. 5, 2006 — -- It was supposed to be the next cholesterol wonder drug.

Many hoped its impact would be revolutionary, on par with cholesterol-busting statins in its lifesaving potential.

Now, the nation's top heart experts wonder whether hopes for HDL-boosting medicines can ever be revived following a trial exposing the risks of one such drug.

Drug giant Pfizer halted trials of Torcetrapib on Saturday after independent safety monitors discovered an unexpectedly high number of deaths with its use.

The drug is designed to raise levels of HDL -- commonly known as "good" cholesterol. Researchers believed this approach would complement that of drugs like statins, which lower LDL, or "bad" cholesterol.

The drug, which had been in development for almost 15 years, was in the midst of its largest, and final, clinical test when monitors noticed an increased death rate in those taking the drug.

Out of 15,000 volunteers in the study, 82 people taking Torcetrapib died, compared to only 51 people in the group not taking the drug.

"The higher mortality rate may be small in numbers of patients," said Dr. Christopher Cannon of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital.

"But when we think about the tens of millions of people with heart disease who could potentially be treated by this drug. … That turns into a large number of patients who could be at risk," Cannon said.

Because the exact cause of the patient deaths in the trial is still unclear, it is too soon to tell whether other HDL-raising medications will be affected by Torcetrapib's failure.

The findings, however, represent a major blow to researchers who had high hopes for drugs designed to raise levels of HDL.

Experts now wonder whether the HDL-raising strategy can be salvaged.

"This is a very sad outcome considering Torcetrapib's potential," said Dr. Melvyn Rubenfire, professor of internal medicine at the University of Michigan in Ann Arbor, Mich.

He added the approach "was the next major potential opportunity to reduce heart attacks, strokes and atherosclerosis."

"It's a huge setback," said Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation in Cleveland.

"For patients already taking a statin, what can we offer them if they continue to have cardiovascular events? Not much," Nissen said.

Some experts were quick to point out, though, that despite Torcetrapib's failure, finding ways to raise HDL levels was still a promising area of research to combat cholesterol.

"I think it is terribly important to emphasize that this development says nothing about the overall strategy of targeting HDL therapeutically," said Dr. Daniel Rader, director of the Preventive Cardiovascular Medicine and Lipid Clinic at the University of Pennsylvania School of Medicine in Philadelphia.

Others said the failed trial might hint at problems to come if other similar drugs showed the same results.

"This marks a huge shift in the anticipated next step in the treatment of atherosclerosis," said Dr. Kevin Graham, director of preventive cardiology at the Minneapolis Heart Institute in Minneapolis, Minn. "The initial questions will focus on the mechanisms, whether this applies to all drugs of this class or whether it is particular to this drug. It is too early to say."

Finding the Problem

Nissen says additional tests may determine what it was, specifically, that caused the increase in patient death.

The key thing to determine, he says, is whether Torcetrapib increased or decreased the formation of cholesterol-containing plaques on the inside of the arteries.

"If the HDL produced by giving a CETP inhibitor is 'pro-atherogenic' -- that is, if it promotes plaque development -- then it is reasonable to expect every CETP inhibitor to do the same," Nissen said. "They all work by the same mechanism."

If the mechanism was at fault, researchers hoping to develop similar drugs may be back to square one.

"I think we all fear that it might be the mechanism," Cannon said. "The increased mortality and cardiovascular events speak to a broad-based problem, rather than one occurring in patients who develop hypertension from the drug."

Another possibility is that the drug changed the effects of HDL cholesterol in the bloodstream -- perhaps making "good" cholesterol not so good after all.

"The HDL particles observed in patients on Torcetrapib were larger and had different chemical properties than those seen under normal biological conditions," said Dr. James Stein, division of cardiovascular medicine at the University of Wisconsin in Madison, Wis. "We can't simply assume that high HDL cholesterol is good. Indeed, it is conceivable that these particles are harmful."

Likewise, some say raising HDL levels may simply be of little, if any, help in the first place.

"Just because higher HDL levels are associated with decreased coronary events … doesn't guarantee that raising HDL pharmacologically will show the same benefit," said Dr. Daniel Edmundowicz, director of preventive cardiology at the University of Pittsburgh Medical Center's Cardiovascular Institute in Pittsburgh.

Still Hope for HDL Therapy

Most experts we talked to, however, were optimistic that future HDL-raising drugs might not carry the same adverse effects as Torcetrapib.

"Torcetrapib itself raises blood pressure, a property of the drug," Rader said. "And we still don't know how much this may have contributed to adverse outcomes."

"Based on studies using other drugs that raise HDL, such as niacin, that have been previously shown to reduce heart attacks, it is more likely that the problem occurred due to the side effects of this drug, rather than the result of raising HDL," said Dr. Michael Miller, director of the Center for Preventive Cardiology at the University of Maryland in Baltimore.

"This does not mean that other medicines under investigation to raise HDL are not going to be beneficial -- they raise different types of HDL and work by different mechanisms in the body," said Dr. Patrick McBride, associate director of the preventive cardiology program at the University of Wisconsin. "There is still great potential for treatments in the future to raise HDL cholesterol."

For now, however, doctors and experts in the field will have to readjust their expectations of what was supposed to be the next big breakthrough in cholesterol treatment.

"They were pretty enthusiastic about this," says ABC News medical editor Dr. Timothy Johnson. "Everyone was betting that this was going to be the next big thing. They did something dramatic before with LDL cholesterol with statins, and I think that everyone was hoping to see something similarly dramatic with HDL."

"There may be other drugs that act on HDL. We do know that niacin is very effective in increasing HDL, and there are other products coming down the pipe," Johnson said.