Trial halted on drug shown to increase HDL cholesterol

Torcetrapib is out, but the pursuit continues for a means to raise good cholesterol without causing harm.

By Victoria Stagg Elliott — Posted Jan. 15, 2007

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The abrupt shutdown of a large study of a medication that raises high density lipoprotein is being viewed as a significant letdown. Experts agree, though, that this recent action is by no means the end of the story when it comes to interest in this heart disease risk reduction strategy.

"Ultimately, the HDL approach will work, but this is a huge setback," said Steven Nissen, MD, president of the American College of Cardiology, who has been involved in the research. "We have to go back and figure out what happened and what we can learn from it."

On Dec. 2, 2006, Pfizer Inc. ended its 15,000-subject study assessing the safety and efficacy of torcetrapib, a cholesteryl ester transfer protein inhibitor, along with all other research related to this drug. The action was taken because the project's independent data safety monitoring board detected an increased rate of cardiovascular events and deaths among participants who took it.

It was definitely a shock; positive results from smaller trials were published as recently as a month earlier. According to a pair of papers published in the Nov. 7, 2006, Journal of the American College of Cardiology, torcetrapib -- either alone or in combination with atorvastatin -- raised HDL by as much as 54%. It was also well tolerated, although some patients did experience a small rise in blood pressure.

"This was somewhat of a spectacular failure," said Christie Ballantyne, MD, director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center and the atherosclerosis clinical research laboratory at Baylor College of Medicine in Houston. He was one of the drug's researchers.

Cardiovascular experts say this incident is a significant reversal because raising levels of HDL cholesterol is viewed as the most likely possibility for making further inroads against cardiovascular disease. Several drugs currently on the market do raise HDL, but their effect is relatively small. Those that have shown a more dramatic impact have unpleasant side effects. Among those being studied to make a greater impact, torcetrapib was the furthest along the clinical trial process.

"HDL-raising was going to be one of the great new advances within the next five to 10 years, but this has pushed the field at least three if not five years back," said Richard Krasuski, MD, director of adult congenital heart disease services at the Cleveland Clinic.

Sorting through findings for insights

While this study is closed, experts say research into pharmaceuticals and lifestyle interventions that will raise HDL is far from over.

"We have gone as far as we can with LDL lowering alone," said Greg Brown, MD, PhD, professor of cardiology at the University of Washington, Seattle. "The future of cardiovascular medicine is very much still LDL lowering plus HDL raising."

He is researching combining niacin with simvastatin to impact HDL and cardiovascular risk.

With regard to the torcetrapib trial, scientists want far more information than has been released by the company, and this step is expected to happen soon. For example, Dr. Nissen, who is also the chair of the cardiovascular medicine department at the Cleveland Clinic, is in the process of analyzing data from his imaging studies of trial participants.

Dr. Nissen expects to present findings at the March meeting of the American College of Cardiology.

The central question bedeviling scientists is why this drug failed.

The possible reasons are many. Something in the drug itself could have been toxic. It could also be an effect of this medication class. In addition, interfering with the cholesteryl ester transfer protein may not be the right way to raise HDL without causing harm. Finally, the resulting HDL might not be of high enough quality.

"It could be that it's a problem with the concept, or it could be a problem with the drug," said Paul D. Thompson, MD, director of cardiology at Hartford Hospital in Connecticut who also studied this drug. "We don't know what. It just didn't work."

Raising HDL may not even be the right way to further reduce cardiovascular risk, although many experts suspect it will be. Low HDL is a confirmed risk factor for heart disease, but whether raising HDL reduces this risk, without affecting other factors, remains murky.

"Maybe it's true that we should raise HDL levels, but we don't know that yet," said Andrew Lockman, MD, associate professor of clinical family medicine at the University of Virginia in Charlottesville.

"This shows that changing someone's numbers doesn't necessarily mean that you're doing them good," Dr. Lockman said.

Those pursuing this line of research say answering these questions is particularly crucial because this information may affect other related projects.

Several companies are investigating compounds that interfere with this protein or approach HDL-raising from alternate angles.

But even without the extensive analysis to understand why this drug had the effect that it did, for many researchers the take-home message is that affecting HDL is far more complicated than LDL.

"It makes us realize that this is not going to be quite as easy as we first thought," Dr. Krasuski said.

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Seeking the answers

Pfizer Inc. ended research into torcetrapib, a cholesteryl ester transfer protein inhibitor that raised high density lipoprotein cholesterol, because of an increase in cardiovascular events and deaths among patients who took it in a large phase III trial. More detailed analyses are expected in the next few months that may shed light on why this drug did not work as well as hoped. Possibilities include:

  • Toxicity might be limited to this one drug.
  • The adverse events could be caused by this drug class.
  • Inhibiting the cholesteryl ester transfer protein may not be a safe way to raise HDL levels.
  • The HDL created by this strategy may not be of good quality.
  • Raising HDL might not reduce cardiovascular risk.

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External links

"Third Report of the Expert Panel: Detection, Evaluation and Treatment of High Blood Cholesterol in Adults," National Heart, Lung and Blood Institute's National Cholesterol Education Program (link)

"Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels," abstract, Journal of the American College of Cardiology, Nov. 7, 2006 (link)

"Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels on a Background of Atorvastatin," abstract, Journal of the American College of Cardiology, Nov. 7, 2006 (link)

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