Torecetrapib Trials: Key Points from Alan Tall's Editorial in NEJM
The primary end point in the ILLUSTRATE trial — the change in percent atheroma volume— did not show significant improvement in patients receiving torcetrapib. However,, [wrt] secondary endpoints. ..there was a significant improvement in the total atheroma volume in patients in the torcetrapib–atorvastatin group, as compared with those in the atorvastatin-only group, and a trend toward improvement in another secondary endpoint, the volume of plaque in the most diseased coronary artery segment.
The decrease in plaque volume in the torcetrapib–atorvastatin group was small but represented a reduction of 50% more than that in the atorvastatin-only group. The fact that the change in plaque volume was larger than the change in percent atheroma volume (the percentage of total vessel volume occupied by plaque) could suggest that a decrease in atheroma volume was offset by an overall shrinkage of the vessel
...the adverse clinical outcome of the ILLUMINATE trial cannot be readily attributed to a worsening of atherosclerotic plaque burden in the coronary arteries. Alternative explanations need to be sought. One possible reason is off-target toxic effects of torcetrapib.
The hypertensive effect of torcetrapib is probably not related to the drug’s mechanism,………..Although the increase in blood pressure seems modest, it may be indicative of an underlying adverse effect of torcetrapib, such as activation of the renin–angiotensin system or vasospasm.
...one would have expected more substantial improvements in coronary atheroma burden. Why was this not seen? One possibility is that off-target toxic effects of torcetrapib had an adverse effect on plaque volume. Another is that the HDL particles produced by CETP inhibition may be dysfunctional.
...although findings of the clinical and coronary-imaging studies involving torcetrapib are disappointing, it is likely that at least part of the adverse effects were caused by nonmechanism-related toxicity of this particular drug. There was no evidence that CETP inhibition actually worsens atherosclerotic plaque burden, and there was even some improvement in a secondary measure of plaque volume. This finding suggests modest regression of plaque and provides a glimmer of hope for the future development of this class of drugs. Although the lowering of LDL cholesterol by CETP inhibition is likely to be antiatherogenic, it still needs to be shown that an increase in HDL levels by this mechanism is beneficial.
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