Atlanta, GA - With many cardiologists believing that HDL cholesterol is the next major target in the battle against heart disease, the excitement over new HDL-raising drug therapies is growing. One of those drugs, torcetrapib, a novel cholesteryl-ester-transfer-protein (CETP) inhibitor, is moving through the development pipeline, and researchers are excited by the prospect that the drug could boost HDL-cholesterol levels by as much as 50%.

However, according to one study presented recently at the American College of Cardiology 2006 Scientific Sessions, there is a concern about possible side effects with the drug. The study showed that patients taking the 60-mg dose of torcetrapib with atorvastatin (Lipitor, Pfizer) experienced an increase in systolic blood pressure [1].

"We've been aware of the increase in blood pressure with torcetrapib all along," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "It's not much, but it is something. I think the bottom line is that if it's going to affect the progression of disease we should see that in our upcoming IVUS [intravascular ultrasound] trial."

The increase in blood pressure was observed in a 12-week dose-ranging study in 493 individuals with elevated LDL-cholesterol levels but without overt cardiovascular disease. Subjects were randomized to torcetrapib (30, 60, and 90 mg) alone or in combination with atorvastatin (10, 20, 40, and 80 mg). Investigators, led by Dr Tom Thuren (Pfizer Global Research and Development, New London, CT), report that the torcetrapib/atorvastatin combination raised HDL-cholesterol subfractions and lowered the number of LDL particles.

Although the side effects of the two drugs were similar, patients taking 60 mg of torcetrapib with atorvastatin had an increase in systolic blood pressure of approximately 2 mm Hg, a finding that first surfaced in 2005. Investigators said the increase in blood pressure will continue to be studied in phase 3 testing. Torcetrapib is being studied in combination with atorvastatin, and Pfizer, the maker of both drugs, plans on selling torcetrapib and atorvastatin together in a combination tablet [2].

Dr Michael Davidson (Rush University Medical Center, Chicago, IL), who has conducted clinical trials with torcetrapib, said the increase in blood pressure appears to be dose related. He added that phase 2 testing revealed approximately 5% of subjects taking torcetrapib experienced an increase in systolic blood pressure >15 mm Hg, although a majority of these patients were still within the normal range. He said researchers are unsure why the drug increases blood pressure, pointing out that it is not related to CETP inhibition.

"I personally don't think the increase in pressure will pose a risk," Davidson told heartwire. "It is something that can be monitored. Obviously, cardiovascular outcomes are going to be the ultimate determinant of the drug's efficacy. But all things considered, I don't think it will be a major hurdle for the drug or for approval."

IVUS study first, outcomes study to follow

Nissen is currently leading the ILLUSTRATE study, a multicenter, randomized, 1200-person trial comparing atorvastatin/torcetrapib combination therapy with atorvastatin alone in preventing progression of coronary atherosclerosis as measured by IVUS in coronary heart disease patients. He said the effect of the blood-pressure increase on IVUS-derived end points should be evident when the results from this study are in, possibly by the end of the year. In the CAMELOT trial, for example, a 5-mm-Hg difference in blood pressure resulted in a significant difference in plaque progression between treatment arms, he said.

The major-end-point trial for torcetrapib is ILLUMINATE, a 13 000-patient trial that just completed enrollment. The study is a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin vs atorvastatin alone on the occurrence of major cardiovascular events in subjects with coronary heart disease or risk equivalents. Results of that study are not expected for another four or five years.

A report by Bloomberg News reporter Michelle Fay Cortez noted that Pfizer plans to seek early approval of torcetrapib based on the IVUS study [3]. There is concern about rushing the drug to market without sufficient long-term safety data, especially in light of the increase in systolic blood pressure, Cortez reports.

Davidson told heartwire that going forward with approval based on surrogate end points is an important strategy for future drugs, especially considering that it is inherently difficult to conduct end-point trials for HDL-raising therapies. By the time the IVUS study is completed, he said, there will be long-term safety data available for approximately 5000 patients in the larger outcomes study, which should provide enough power to evaluate safety risks, such as the incidence of hypertension or stroke caused by hypertension.