CETP antagonism versus agonism in cardiovascular prevention and plaque regression

The recent failure of coronary prevention with torcetrapib, a major inhibitor of the cholesteryl ester transfer protein (CETP) system, indicated that this therapeutic approach is disputable. Evaluation of prior knowledge confirms that the rationale of CETP inhibition appears to be weak, thus leading to the general conclusion that a rise in HDL-C levels does not necessarily reflect a better reverse cholesterol transfer system and vice versa. While raising HDL by a variety of pharmaceutical approaches may provide a desirable target, CETP inhibitory treatment is potentially harmful. While torcetrapib raises blood pressure, as underlined by a number of authors, this does not appear to provide a satisfactory explanation for the failure of this treatment, whereas the dramatic increase of cancer and life-threatening infections in torcetrapib-treated patients gives a serious warning. By contrast, CETP stimulation has recently provided interesting openings for a successful approach to cardiovascular prevention. In particular, re-evaluation of data on probucol clearly suggest that this drug, while lowering HDL-C because of its mechanism of action, can also reduce carotid intima-media thickness and cause negative arterial remodeling in atherosclerotic conditions. By this last mechanism, probucol would not increase arterial lumen, but could clearly reduce the risk of acute coronary syndromes.