ILLUSTRATE, RADIANCE, and ERASE: What Do the Imaging Trials With Torcetrapib Tell Us?

Linda Brookes, MSc

Disclosures

June 12, 2007

In This Article

Rating Atherosclerotic Disease Change by Imaging With A New CETP Inhibitor (RADIANCE)

The Rating Atherosclerotic Disease change by Imaging With A New CETP Inhibitor (RADIANCE) studies investigated the effects of torcetrapib-atorvastatin compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT). The results of the RADIANCE studies, which were also supported by Pfizer, were presented at the ACC meeting by John J.P. Kastelein, MD, PhD (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands).[7,8] The RADIANCE 1 study was published simultaneously in The New England Journal of Medicine.[9]

The 2 randomized, double-blind, controlled RADIANCE trials enrolled eligible subjects in North America, Europe, and South Africa. All subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL cholesterol levels as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines.[10,11] Subjects then proceeded to a double-blind randomized treatment period in which they received 1 of 2 regimens: atorvastatin monotherapy or atorvastatin at the dose established during the run-in period plus torcetrapib 60 mg.

In RADIANCE 1 the dose of atorvastatin was 20 mg titrated to 80 mg, and in RADIANCE 2 atorvastatin was begun at 10 mg, titrated to 80 mg. B-mode ultrasonography was performed in duplicate at baseline and at 24 months, and every 6 months in between. The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT for 12 predefined carotid artery segments (near and far walls of the right and left common carotid artery, the carotid bifurcation, and the internal carotid artery).

RADIANCE 1 randomized 904 subjects with heterozygous familial hypercholesterolemia (average age, 46 years; body mass index [BMI] 27). At baseline, average HDL cholesterol was 52 mg/dL and LDL cholesterol 128 mg/dL. At 24 months, the net effect of torcetrapib plus atorvastatin was a 51.9% relative increase in HDL and a 20.6% decrease in LDL cholesterol compared with atorvastatin alone (both P < .0001) ( Table 6 ).

Beneficial effects were seen on all levels of all apolipoprotein subclasses (apoA and apoB). Despite the effects on all lipids (described by Prof. Kastelein as "unparalleled," and "a lipidologist's dream"), however, torcetrapib-atorvastatin did not result in regression of atherosclerosis, with no difference between the 2 treatment groups in the primary efficacy measure ( Table 7 ). A secondary endpoint of the study, CIMT of the common carotid artery, showed progression in the torcetrapib-atorvastatin group, compared with regression in the atorvastatin monotherapy group.

AEs included 2 deaths in each group, and 56 serious AEs in the torcetrapib-atorvastatin group (including 24 serious cardiovascular AEs) compared with 39 serious AEs (11 cardiovascular) in the atorvastatin monotherapy group.

Blood pressure averaged 116/73 mm Hg at baseline, but mean blood pressure rose in both treatment groups, by an average of 1.3 mm Hg in the atorvastatin monotherapy group but by 4.1 mm Hg in the torcetrapib-atorvastatin group. Patients on torcetrapib-atorvastatin had more investigator-reported hypertensive AEs, more blood pressure values > 140/90 mm Hg, and a higher rate of patients with an increase of > 15 mm Hg in SBP ( Table 8 ).

RADIANCE 2 randomized 752 subjects with mixed dyslipidemia, average age 58 years, BMI 30. At baseline, average LDL/HDL cholesterol levels were 100/47 mg/dL, respectively. At 24 months, the net effect of torcetrapib on top of atorvastatin was a 63.5% relative increase in HDL and a 17.7% decrease in LDL cholesterol compared with atorvastatin alone (both P < .0001). The annualized rate of change in maximum CIMT was a decrease of 0.0180 mm/year in the torcetrapib-atorvastatin group compared with an increase of 0.0082 mm/year in the atorvastatin monotherapy group (P = .4621). AEs included 1 death in each group and 47 serious AEs in the torcetrapib-atorvastatin group (including 36 serious cardiovascular AEs), compared with 40 serious AEs (21 cardiovascular) in the atorvastatin monotherapy group.

Again, blood pressure averaged 120/74 mm Hg at baseline, with mean blood pressure rising in both treatment groups, by an average of 6.6 mm Hg in the torcetrapib-atorvastatin compared with only 1.5 mm Hg in the atorvastatin monotherapy group.

Prof. Kastelein said that despite the effects of torcetrapib on SBP and on LDL cholesterol seen in the 2 RADIANCE studies, there should have been a residual benefit associated with the effect on HDL cholesterol with torcetrapib. Instead, if anything there was a trend toward harm, "The fact that none was observed leaves no possibility of any beneficial effect of the large increase in HDL cholesterol," he said. The results could only partly be explained by the torcetrapib-driven increase in SBP, he believes. His suggestions as to the possible mechanism for the lack of efficacy for torcetrapib were similar to those of Dr. Nissen. He suggests that:

  1. CETP inhibition is not an antiatherogenic strategy;

  2. HDL particles carrying the CETP/torcetrapib complex are directly vasculotoxic; and

  3. The combination of torcetrapib-atorvastatin has broader adverse effects on the vasculature that are not currently understood.

An analysis of the merged data from the RADIANCE 1 and 2 trials is under way. This may provide some very significant answers about torcetrapib, such as the relation of the changes in blood pressure and HDL cholesterol to changes in carotid diameter or in atherosclerosis volume in the trial, Prof. Kastelein said.

Prof. Kastelein believes that, given the ability of CETP inhibitors to raise HDL cholesterol levels by 50%, there is a need for research with "clean" compounds that do not have the adverse effects of torcetrapib. Clinical studies have indicated that neither JTT-705 nor MK-0859 appear to be associated with a rise in blood pressure. Both of these drugs are in phase 2 trials. Pfizer has 2 backup compounds, PF-3,186,043, a torcetrapib analog, and CP-800,569, a structurally new compound -- both also in phase 2. AVANT Immunotherapeutics (Needham, Massachusetts) is developing an anti-CETP vaccine. Further studies with these other agents are assumed to be on hold until the ILLUMINATE results become available.

In an editorial accompanying publication of the ILLUSTRATE and RADIANCE 1 trials,[12] Alan Tall, MB, BS (Columbia University, New York, NY) said that the "somewhat surprising" outcome of ILLUSTRATE showed that "the adverse clinical outcome of the ILLUMINATE trial cannot be readily attributed to a worsening of atherosclerotic plaque burden in the coronary arteries." For the future he believes that, "it would seem reasonable to proceed with caution in studies of other classes of CETP inhibitors that do not cause hypertension, while monitoring for potential adverse effects on vascular function."

During his delivery of the 38th Annual Louis F. Bishop Lecture,[2] Dr. Rader said that he believes that CETP inhibition is still viable as a therapeutic strategy. "We have data that suggest that this might be an approach. With a clean compound that doesn't have some of the blood pressure and potentially other vascular toxic issues, there is still potentially the opportunity to demonstrate beneficial effects," he said. "I, for one, would like to see that if those compounds exist, they continue to move forward at least to test whether they have the chance to reduce cardiovascular risk," he added. He believes that the blood pressure effect of torcetrapib is molecule-specific and does not require the presence of CETP. However, he also believes that in the "post-torcetrapib era," increasing HDL cholesterol levels may be neither adequate nor necessary for predicting cardiovascular benefit of an HDL-targeted therapeutic approach. "HDL as a biomarker for assessing efficacy is certainly under question," he said.

Dr. Rader went on to predict that improving HDL function, including reverse cholesterol transport, will be the focus of new therapies. "This will require better and standardized methods to assess both reverse cholesterol transport and HDL function, especially in humans, but also in preclinical models to begin to better address these issues in new compounds to putatively improve HDL function," he stressed.

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