"Torcetrapib treatment in patients with low HDL cholesterol levels resulted in robust and rapid increases in HDL cholesterol, independent of atorvastatin background therapy," said Dr Michael Davidson (Rush University Medical Center, Chicago, IL). "Decreases in LDL cholesterol were also observed, but with only moderate levels of effect, suggesting the need for concurrent therapy to control LDL cholesterol. The drug appears safe and well tolerated in short-term treatment."

The results of the study were presented today at the American College of Cardiology 2005 Scientific Sessions and provide further evidence of a potential one-two punch for treating dyslipidemia when the drug is used in conjunction with lipid-lowering therapies. A bit of controversy, however, surrounded the optimistic findings, as the manufacturer of torcetrapib, the drug giant Pfizer, said it plans to sell the drug only in combination with atorvastatin.

According to a report March 7, 2005 in the New York Times, Pfizer said that selling torcetrapib and atorvastatin together in a combination tablet is an effective means of targeting both LDL cholesterol and HDL cholesterol.[1] Pfizer said that given the costs of developing the drug and the fact it has worked closely with the Food and Drug Administration to design the clinical trials, it can market and sell the drug as it wishes.

Not surprisingly, some experts claim the move is designed to protect Lipitor, a drug that loses patent protection in 2010 and currently has sales of almost $11 billion. Others argue that torcetrapib should be made available on its own, leaving physicians the option of prescribing whatever statin they wish with the novel HDL-raising drug.

Dr Steven Nissen

Pfizer spokesperson Stephen Lederer told heartwire that by selling the two drugs together in one tablet, the company will be able to get the drug to the market in the safest, quickest way, serving the interests of the company, regulators, and the public. He said that the combination torcetrapib-atorvastatin tablet is not expected to reach the market until 2009 and the company does not envision any clinical reason the drug would be given as monotherapy.

According to Dr Steven Nissen (Cleveland Clinic, OH), the combination tablet essentially forces clinicians to address both LDL and HDL cholesterol. If the drug were made available as a stand-alone product only, he would be concerned that some clinicians would prescribe the drug as monotherapy, without the necessary statin to lower LDL cholesterol.

"There are arguments on both sides of this question," Nissen told heartwire. "If you have an HDL drug, there is the possibility of giving only an HDL-raising drug without prescribing the statin. Because of the way physicians work, I guarantee you that if the drug were available as monotherapy, a fair number of patients with LDL cholesterol levels of 100 and low HDL levels would get only torcetrapib."

During his presentation, Davidson reported data from a study that looked at the use of torcetrapib in statin-eligible patients with no vascular disease and no major concurrent illness who were not currently taking lipid-lowering therapy. Patients all had low levels of HDL cholesterol, with an approximate HDL level of 37 mg/dL.

A total of 150 subjects participated in the study and were randomized to placebo, 10 mg, 30 mg, 60 mg, or 90 mg of torcetrapib. All underwent an eight-week run-in period and were treated with atorvastatin 20 mg. After eight weeks, half the patients continued taking atorvastatin as background therapy, while the other half discontinued statin treatment.

In patients not taking atorvastatin, treatment with torcetrapib increased HDL cholesterol at every dose, increasing HDL cholesterol 28%, 45%, and 55% in patients taking the 30-mg, 60-mg, and 90-mg doses, respectively. In those randomized to statin background therapy, torcetrapib also increased HDL cholesterol levels, raising HDL cholesterol 24%, 33%, and 40%, respectively.

Davidson said the effect on HDL cholesterol occurred quickly, increasing levels within two weeks of initiating therapy in both study arms. Treatment with the 60-mg and 90-mg dose of torcetrapib did result in modest LDL reductions in those not taking atorvastatin, but greater reductions were observed in those treated with the statin.

The investigators report that there was a trend for torcetrapib use to increase blood pressure from baseline more than placebo. At the highest 90-mg dose tested, systolic blood pressure increases ranged from 1.8 mm Hg to 2.8 mm Hg, but increases of systolic blood pressure >15 mm Hg were rare.

For torcetrapib to be made available on its own, Nissen pointed out that the FDA would require it be tested against every available statin at every available dose, hurdles ezetimibe was forced to clear before approval. He added that there is evidence suggesting the lipoproteins produced when a CETP inhibitor is administered alone are different from those produced when the drug is administered with a statin, making it possible that torcetrapib monotherapy might not necessarily be antiatherogenic.

"My perspective is that I would like to see it sold both ways, but I would not prescribe torcetrapib as monotherapy," said Nissen.

Dr Roger Blumenthal (Source: Johns Hopkins University)

According to Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD), the abundance of data supporting statin therapy as the standard of care in patients with established coronary disease would pose challenges in trying to conduct a study testing torcetrapib as monotherapy.

"The idea that we need to do trials with the CETP inhibitor alone vs with a statin to see whether there are differences is a reasonable request," Blumenthal told heartwire. "But I don't think it is mandated by any means, especially as it would be very difficult to recruit for those trials, and many review boards would want the patients to be on a moderate dose of a statin. From a practical point of view, I can understand the decision not to look at a CETP inhibitor by itself."

Blumenthal added that there are other ways for clinicians to increase HDL cholesterol levels in their patients already taking statins. Results from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) study showed that the addition of niacin to statin therapy slowed the progression of atherosclerosis as measured by carotid intima-media thickness (IMT) among coronary heart disease patients with low HDL cholesterol levels, he noted.

Pfizer is currently testing torcetrapib with atorvastatin and will submit only the combination treatment for approval by the FDA. The company is conducting a phase 3 intravascular ultrasound study to determine whether the torcetrapib-atorvastatin combination can slow the progression of arterial plaque compared with atorvastatin alone.

Another study, involving 13 000 patients and lasting five years, just finished enrollment. The purpose of this study, comparing the combination therapy with atorvastatin alone, is to determine whether the combination can lower the risk of MI and stroke.