NEW ORLEANS — Torcetrapib profoundly raised HDL cholesterol values and decreased LDL cholesterol levels, yet failed to halt the progress of atherosclerosis in two separate international trials, Dr. Steven Nissen said at the annual meeting of the American College of Cardiology.

The combined conclusions of the studies led Dr. Nissen, one of the trial investigators and president of the ACC, to conclude, “At this point, obviously, this molecule is dead.”

Investigators remain puzzled why the investigational cholesterol ester transfer protein inhibitor, which led to unparalleled increases in HDL cholesterol, failed to reduce atheroma volume on carotid ultrasounds.

In a late-breaking clinical trial session at the meeting, Dr. Nissen cited three possible explanations for the findings: An increase in blood pressure may have “counterbalanced” beneficial lipid effects, blood pressure may be a marker for an unknown toxicity associated with the drug, or cholesterol ester transfer protein (CETP) inhibition “may not generate HDL particles that function normally in facilitating reverse cholesterol transport,” Dr. Nissen said.

Whatever the mechanism, the resulting antiatherogenic outcomes with torcetrapib reminded Dr. John J.P. Kastelein of “Dutch pancake—you can't get it any flatter. There was no difference whatsoever.”

Dr. Nissen held out hope that other agents in the CETP class might prove beneficial. “My view is, you can't slam the door on the whole class when the only data we have are for a drug that had this unusual toxicity,” he said at a press briefing.

The trials presented by Dr. Nissen and Dr. Kastelein were part of a huge development program of the first CETP inhibitor by Pfizer, manufacturer of torcetrapib. In December 2006, a third clinical trial was terminated early because of an excess of deaths and cardiovascular events among subjects who received torcetrapib. Pfizer immediately suspended the entire program.

Serious cardiovascular events also were higher with torcetrapib in the trials presented at the meeting; however, these were relatively small trials and not statistically powered to show a significant increase in adverse clinical events.

In the ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) trial, investigators at 137 medical centers throughout North America and Europe used intravascular ultrasound to assess coronary atheroma volume in 910 patients with known coronary atherosclerosis. The subjects were randomly assigned to receive either atorvastatin plus torcetrapib (464 subjects) or atorvastatin plus placebo (446 subjects) for 2 years, said Dr. Nissen of the Cleveland Clinic.

Adding torcetrapib to the statin induced an unparalleled 60% rise in HDL cholesterol and a 20% decline in LDL cholesterol, relative to atorvastatin alone.

“Thus, at the end of 24 months, treatment with torcetrapib resulted in an average HDL level that was actually higher than the LDL level, with an LDL to HDL ratio of 0.93: a ratio never before achieved in any major clinical trial,” Dr. Nissen said in his presentation. However, it also induced a “substantial” increase in systolic blood pressure of 4.6 mm Hg, he said.

Further, percent atheroma volume, the primary efficacy measure, was not affected. Neither was progression of atherosclerosis in the most diseased segment of the target artery, a secondary measure. Another secondary measure—progression in total atheroma volume—improved with torcetrapib, but “the treatment difference was relatively small, particularly considering the long duration of the trial,” wrote Dr. Nissen and his associates in an article published simultaneously with the presentation (N. Engl. J. Med. 2007; 356:1304–16).

In the RADIANCE 1 trial (Rating Atherosclerotic Disease Change by Imaging with a New DETP Inhibitor), investigators used ultrasound to assess the progression of carotid intima-media thickness over 2 years in 850 patients with familial hypercholesterolemia who were treated at 37 medical centers in North America, Europe, and South Africa. A total of 423 subjects were randomly assigned to receive torcetrapib and atorvastatin, while 427 received atorvastatin plus placebo.

“The net effect of torcetrapib was a 51.9% relative increase in HDL cholesterol and a 20.6% relative decrease in LDL cholesterol,” wrote Dr. John J. P. Kastelein of the University of Amsterdam and his associates in an article published at the time of the meeting (N. Engl. J. Med. 2007 March 29 [Epub doi:10.1056/NEJMoa071359]).

Yet the drug failed to halt progression of carotid intima-media thickness and actually appeared to accelerate the atherosclerotic process in one segment of the artery. As in the study by Dr. Nissen and colleagues, torcetrapib significantly raised systolic blood pressure. It also induced more adverse cardiovascular events, particularly those related to increased blood pressure, than did placebo, Dr. Kastelein and his associates said.

The RADIANCE 2 study, which studied torcetrapib in 752 patients with mixed hyperlipidemia, showed “strikingly similar results,” Dr. Kastelein said at the meeting.

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Although torcetrapib led to unparalleled increases in HDL cholesterol, it failed to reduce atheroma volume. DR. NISSEN

Torcetrapib Fails to Halt Atherosclerosis