Research into raising HDL cholesterol presses on despite setbacks

Many still view this strategy as offering the best chance for the next big breakthrough in cardiovascular health.

By Victoria Stagg Elliott — Posted April 16, 2007

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Filling in the blanks regarding the fall of torcetrapib, the once-promising cardiovascular drug for which Pfizer Inc. pulled the clinical trials plug in December 2006, has become a hot topic in the ongoing pursuit of a new and better way to address cholesterol problems.

For instance, new research indicates that the drug raised high-density lipoprotein cholesterol but did not impact coronary atherosclerosis. This finding is most likely because it did not create well-functioning cholesterol molecules, according to a pair of studies presented at the American College of Cardiology meeting in New Orleans and published last month in the New England Journal of Medicine.

"Our findings demonstrate the great difficulty in developing therapies to interrupt the atherosclerosis process," said Steven Nissen, MD, one of the study's lead authors and ACC's immediate past president.

Pfizer ended research into this drug because of an increased rate of cardiovascular events and deaths among study participants who took it. But although this recent round of data confirms that the drug didn't work and also provides some insight into why, those involved say there are still many questions that need answering. Much work also is needed if a drug is to be developed that does safely raise HDL -- the strategy many view as most likely to produce the next big cardiovascular health breakthrough.

"It's been about 20 years since the statin drugs were introduced," said Dr. Nissen, who is also chair of Cleveland Clinic's Cardiovascular Medicine Dept. "Statins are great, but we need more. We have to figure out how to raise HDL."

For instance, while torcetrapib provides no benefits in the population as a whole or any subgroup studied, it's unclear if the adverse effects are limited to this drug or could be caused by any in the cholesteryl ester transfer protein class. Experts say this information is important because several companies are researching other compounds that act on the same mechanism. None of the others seem to raise blood pressure as torcetrapib did, one of the earliest signs that this drug would not work as hoped.

"Whether the CETP class is the right way of raising HDL is still very much up in the air," said Antonio Gotto, MD, a cardiologist and dean of Weill Medical College of Cornell University in New York.

Not giving up

Other HDL-raising strategies also recently failed to live up to their promise. Dr. Nissen presented information on LY518674 at the ACC meeting and published it in the Journal of the American Medical Association. This drug is a selective PPAR-alpha agonist that is far more potent than the fibrates, which have a much weaker effect on this receptor. The study found that both drugs decreased triglycerides and increased HDL and serum creatinine at similar rates. The research compound also increased low-density lipoprotein cholesterol. Eli Lilly and Co. is considering whether research into this drug should continue, and it's unclear if it will go any further.

Despite these disappointments, many experts feel that research does make it increasingly clear that overall, raising HDL is a strong candidate for improving cardiovascular health. Not all HDL is equal, and most believe that eventually it will be possible to raise levels of it safely.

"When I test a hypothesis, usually I find out that I was wrong, but we learn from being wrong," 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 also was a researcher on the torcetrapib studies.

"Eventually, we do get there. Sometimes, it takes a little longer than we would like."

Another study, published March 26 on JAMA's Web site and presented at ACC, found that an infusion of reconstituted HDL could improve several markers of vascular health, although not all. It also caused liver problems at higher dosages.

Experts said this finding was proof that attempting to raise HDL was an appropriate target, but this method for doing so probably would not be practical on a wide scale because it is not available in pill form.

"The data are promising in terms of a proof of concept," said Ben Ansell, MD, co-director of the preventive cardiology program at the University of California, Los Angeles. "It will be difficult to translate these benefits into practice. IV drugs are expensive and not as well accepted by patients, although it may have a place in an acute setting if you want to get very aggressive with HDL very quickly."

Work also is continuing in earnest at the bench side to attack this problem from other angles. Several presentations at the American Chemical Society meeting in Chicago, also last month, explored them. These include compounds that modulate endothelial and hepatic lipases or work on the liver X and farnesoid X receptors. These approaches, though, are a long way from producing something that will affect patients.

"The major challenge is still ahead of us," said Marian Mosior, PhD, one of the presenters and a principal research scientist at Eli Lilly.

Improving niacin so that it no longer triggers flushing, a common and undesirable side effect, also was the focus of one lecture. The modified form of this vitamin is viewed as the closest to widespread use. The available form has long held great promise for improving HDL, but this side effect has limited its popularity.

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Why torcetrapib didn't work

Background: Researchers are examining various strategies to raise high-density lipoprotein cholesterol, and torcetrapib, a cholesteryl ester transfer protein inhibitor, was the drug furthest along the development and research path. In December 2006, Pfizer suspended a large phase III trial because of an unacceptable rate of adverse events.

Objective: Determine why this drug didn't work.

Method: A total of 1,188 patients with coronary disease had intravascular ultrasonography at the start of the study. After treatment with a statin that reduced low-density lipoprotein cholesterol to less than 100 mg per deciliter, they were randomized to receive atorvastatin with or without torcetrapib. After 2 years, 910 had a second ultrasonography.

Results: Patients on the combination therapy had a 61% increase in HDL and a 20% reduction in LDL. Torcetrapib increased blood pressure by 4.6 mm Hg. The percent of fatty deposits in the arteries increased by 0.19% in patients treated with the statin alone but increased by 0.12% in those receiving dual therapy. Those who took the experimental drug had a slight improvement in their normalized atheroma volume, but there was no significant change in the most diseased vessel.

Conclusions: Torcetrapib was associated with a substantial increase in HDL and a decrease in LDL. This drug also increased blood pressure and had no impact on the progression of atherosclerosis. These effects may be the result of the mechanism of the drug class or torcetrapib itself.

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External links

"Effect of Torcetrapib on Carotid Atherosclerosis in Familial Hypercholesterolemia," abstract, New England Journal of Medicine, online March 26 (link)

"Effect of Torcetrapib on the Progression of Coronary Atherosclerosis," abstract, New England Journal of Medicine, March 29 (link)

"CETP Inhibitors to Increase HDL Cholesterol Levels," abstract, New England Journal of Medicine, March 29 (link)

"Effects of a Potent and Selective PPAR-alpha Agonist in Patients With Atherogenic Dyslipidemia or Hypercholesterolemia," abstract, Journal of the American Medical Association, March 28 (link)

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