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Torcetrapib Does Not Limit Atherosclerosis Progression

Negative results from ILLUSTRATE follow the halting of ILLUMINATE.

In December 2006, the manufacturer of torcetrapib, a cholesterol ester transfer protein (CETP) inhibitor aimed at raising HDL levels, halted the entire development program for this drug. The decision was made on the basis of data from ILLUMINATE, a randomized trial comparing torcetrapib/atorvastatin combination therapy with atorvastatin monotherapy. The data showed increased rates of cardiovascular events and mortality in the combination-therapy group.

We now have data from a separate, previously completed, manufacturer-funded trial of torcetrapib known as ILLUSTRATE, which focused on endpoints measured by intravascular ultrasound (IVUS). The trial, conducted in patients with coronary disease, started with a 4- to 10-week run-in phase of atorvastatin monotherapy. The 1188 subjects who came within 15 mg/dL of reaching the LDL target of 100 mg/dL were then randomized to receive daily atorvastatin monotherapy or atorvastatin plus 60-mg torcetrapib. After 2 years of treatment, there remained 910 patients (77%) who had both baseline and 2-year IVUS data.

By 2 years, the combination-therapy group had experienced a significant increase in mean HDL (from 46 to 72 mg/dL) and a decrease in mean LDL (from 83 to 70 mg/dL); the monotherapy group had experienced a slight HDL decrease and a slight LDL increase. However, mean blood pressure rose significantly more with torcetrapib/atorvastatin than with atorvastatin alone (by 6.5/2.8 vs. 2.0/0.8 mm Hg).

The primary endpoint — mean change in percent atheroma volume, an IVUS-measured surrogate marker of disease progression — was similar in the two groups (+0.12% with combination therapy, +0.19% with monotherapy). One secondary IVUS measure significantly favored combination therapy (reduction in normalized atheroma volume, –9.5 mm³ vs. –6.3 mm³); however, the atheroma-volume change in the most diseased 10-mm subsegment was similar in the two groups.

Comment: Despite significantly raising HDL levels in patients with coronary disease, torcetrapib/atorvastatin combination therapy failed to limit IVUS-assessed disease progression and, consistent with previous data, raised blood pressure substantially. Given these negative findings and those from ILLUMINATE, the value of adding torcetrapib to aggressive LDL-lowering therapy clearly has not been demonstrated. We don’t yet know whether the negative findings are due to BP effects, direct vascular effects, or effects on the functionality of HDL. Further studies will be required to truly "illuminate" these matters and, more broadly, the issue of whether raising HDL levels via CETP inhibition has an appropriate role in atherosclerosis treatment. Results of the RADIANCE trial, testing torcetrapib’s effects on carotid atherosclerosis, are to be published imminently.

— JoAnne M. Foody, MD

Published in Journal Watch Cardiology March 26, 2007

Citation(s):

Nissen SE et al. for the ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007 Mar 29; 356:1304-16.

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• Medline abstract (Free)

Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med 2007 Mar 29; 356:1364-6.

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• Medline abstract (Free)