Certain Cholesterol Drugs Show Their Limits

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A second paper was the final analysis of a trial of the failed cholesterol drug torcetrapib. Pfizer Inc. pulled the drug, a CETP inhibitor, from development last December because there was an increased risk of death and other adverse outcomes, including elevated blood pressure. This study, which was released early to coincide with the meeting presentation, will be published in the Nov. 22 issue of the New England Journal of Medicine.

The adverse effects were a mystery to investigators, as the drug had succeeded in raising HDL, or "good" cholesterol levels, while lowering LDL levels.

As it turns out, the drug had unexpected side effects that may explain the paradox, according to the Australian researchers who conducted this latest analysis.

"The researchers are pointing out other things that torcetrapib did in addition to raising HDL, which is what you're trying to do," Bonow explained. "The drug also lowered LDL, but it did other things they were not anticipating."

One of these unintended consequences was to raise aldosterone levels, a hormone that helps keep a balance between sodium and potassium levels. "Aldosterone is a byproduct of angiotensin [a chemical that causes vessels to constrict], which is presumably why blood pressure was elevated," Bonow said.

"This trial leads the way open for further exploration. It neither validates nor invalidates the hypothesis that inhibition of CETP is a beneficial effect, but it will remain a hypothesis unless and until it is tested with CETP inhibitors that do not share the off-target pharmacology of torcetrapib," said study author Dr. Philip Barter, a professor at The Heart Research Institute in Sydney. "I personally look forward to more research. This drug had the potential to save hundreds of thousands of lives. I hope that the clinical benefit of this class of drug will be realized, but that is for the future."

Two other studies being presented at the meeting took a closer look at torcetrapib.

One, from the Cleveland Clinic, found that the increase in HDL cholesterol from torcetrapib did have an effect on plaque progression, as shown by intravascular ultrasound. "The target effect to raise HDL is probably beneficial because plaque didn't grow as much," Bonow said.

The second study found that the increase in blood pressure among patients taking torcetrapib was related to increased aldosterone.

The good news is that, because the negative effects of torcetrapib were "off target," the idea of targeting HDL is still sound.

"The concept is still a good concept, and other drugs will come down the pike," Bonow said.

More information

The American Heart Association has more information on cholesterol.