Trial Cholesterol Drug Strikes Out
Three new studies show that the novel cholesterol drug torcetrapib fails to slow plaque buildup in the arteries.
Torcetrapib was also recently linked to an increased risk of heart attacks and death. Additionally, the new drug may raise blood pressure, the research suggests.
Despite the setbacks, experts say there may still be a role for drugs similar to torcetrapib aimed at preventing heart disease by raising "good" HDL cholesterol.
In December, Pfizer Inc. announced it was stopping clinical trials of torcetrapib because of the increased heart risks associated with its use. But researchers are continuing to analyze previously accumulated data in hopes of finding out why the drug failed.
"A lot of people think it's the next big thing, so we need to understand what went wrong with torcetrapib to move forward," says Steven Nissen, M.D., head of cardiovascular medicine at The Cleveland Clinic and president of the American College of Cardiology (ACC). "We believe the failure doesn't necessarily rule out the possibility that another drug in the class, one that is completely clean, with no blood pressure effects and no other evidence of toxicity, could possibly work."
Nissen notes that if Baycol had been the first statin tested and research had stopped after safety problems emerged, statins would never have been developed. Baycol, sold by Bayer AG, was withdrawn from the market in 2001 after reports of a severe and sometimes fatal muscle disorder.
"We don't want to abandon a potentially lifesaving drug, but the bar has been raised. We have to move forward carefully," he says.
Doctors say there is an urgent need for drugs that fight heart disease in novel ways. While credited with making a substantial dent in heart disease, statin drugs that lower "bad" LDL cholesterol don't help everyone: Some statin users suffer heart attacks anyway.
"You could put statins in the blood supply, and cardiovascular disease would
still be the leading cause of death. We need something else," Nissen says.
That's why doctors have been trying to boost levels of HDL cholesterol, which ferries cholesterol from the bloodstream to the liver where it can be disposed of.
Torcetrapib works by inhibiting an enzyme responsible for transforming good cholesterol into bad cholesterol. "If you block this enzyme, HDL goes up and LDL goes down," Nissen says.
In the new studies, torcetrapib boosted HDL cholesterol just like it was supposed to. However, there were negative effects as well. In one study, known as "Illustrate,"1,188 patients with heart disease were randomly assigned to receive the statin Lipitor plus torcetrapib or Lipitor plus placebo.
Results showed that torcetrapib boosted levels of HDL by 61 percent and decreased LDL by 20 percent. However, people on the drug experienced a 4.6-point increase in blood pressure. As shown by imaging, there was no significant difference in plaque buildup between the two groups.
Similarly, in the "Radiance" 1 and 2 studies, people who suffered from inherited cholesterol disorders were randomly assigned to treatment with the Lipitor-torcetrapib combination or Lipitor alone.
Torcetrapib again led to robust increases in HDL cholesterol and dramatic decreases in LDL cholesterol. However, there was again no benefit in plaque buildup. Again, blood pressure increased, although less than in the "Illustrate" trial.
"You would think the LDL decrease is more important than the blood pressure increase, so even ignoring HDL, we should have seen benefit," says researcher John Kastelein, M.D., of the Academic Medical Center in Amsterdam. "Something very strange is going on here," he tells WebMD.
The researchers say they will continue to analyze the data.
There are still many unanswered questions, says James Stein, MD, of the University of Wisconsin Medical School in Madison and chairman of the session at which the results were presented.
"The big question that every scientist and everybody on Wall Street wants to know is whether or not it was the drug or the approach to raising HDL cholesterol. Most people seem to think it's unique to torcetrapib alone, but we still don't know," he says.
Nissen says there are three possible reasons why the drug failed. First, increases in blood pressure may have countered any beneficial effects. Second, the rise in blood pressure may reflect some other unique toxicity that doomed the drug to fail. Or third, the strategy itself may be flawed.
Also at the meeting, researchers reported that infusions of a reconstituted form of HDL slightly slowed plaque buildup in arteries.
"They took blood, extracted HDL, turned it into a product, and reinfused it. The results offer a glimmer of hope," Nissen says.
By Charlene Laino
Reviewed by Louise Chang
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