Certain Cholesterol Drugs Show Their Limits
MONDAY Nov. 5, 2007 -- New research is starting to show that certain cholesterol drugs have their limits and flaws.
One case in point is a study presented Monday at the American Heart Association annual meeting in Orlando, Fla. European researchers found that the statin Crestor did not reduce deaths in older patients with systolic heart failure. The drug did, however, reduce hospitalizations from cardiovascular causes. The report, which was released early to coincide with the presentation, will be published in the Nov. 29 issue of the New England Journal of Medicine.
Systolic heart failure occurs when the heart doesn't contract with enough force to push enough blood through the body. Generally, patients with systolic heart failure have not been included in statin trials because they are considered too high risk.
In this trial, more than 5,000 older patients (mean age 73) with New York Heart Association class II, III or IV ischemic systolic heart failure were randomly assigned to receive 10 milligrams of Crestor or a placebo each day.
After a median follow-up of almost three years, "there was no effect whatsoever on [cardiovascular] mortality, while there was a reduction in nonfatal [myocardial infarction] and nonfatal stroke," said Dr. Ake Hjalmarson, of the Wallenberg Laboratory for Cardiovascular Research at Sahlgrenska University Hospital in Goteberg, Sweden.
Patients taking Crestor also had 45 percent lower levels of LDL, or "bad" cholesterol, and 37.1 percent lower levels of C-reactive protein, a marker of inflammation.
"The statins did what statins are supposed to do. It's surprising that that did not translate into mortality," said Dr. Robert Bonow, immediate past president of the American Heart Association and chief of the division of cardiology at Northwestern Memorial Hospital in Chicago. "But in younger people, you may get different results."
"There are a lot of other things going on that just secondary prevention wasn't enough," Bonow said. "It doesn't mean we shouldn't be giving statins."
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.
The American Heart Association has more information on cholesterol.
Posted: November 2007