It is well known that low blood levels of high density lipoprotein cholesterol (HDL-C) are associated with an increased risk of coronary heart disease (CHD). However, strategies to increase plasma HDL-C levels have produced conflicting results. One of these strategies to raise HDL-C is by inhibiting cholesteryl ester transfer protein (CETP), but a clinical trial with a CETP inhibitor was stopped prematurely because of increased mortality in treated patients. The aim of this study was to evaluate prospectively (mean follow-up of 15 years) the relations of plasma CETP activity to CVD incidence in participants of the Framingham Heart Study. This study revealed an inverse relation of plasma CETP activity to CVD incidence after adjusting for standard risk factors. The hazard ratio for CVD events was 0.72 (p=0.004) for subjects with above median CETP activity compared with those with below median values. In addition, they observed a very modest inverse relation of plasma CETP activity with HDL-C. These results question the strategy of pharmocological inhibition of CETP to lower CVD risk. This article was accompanied by an editorial by Shah PK who reviews very clearly the story of CETP from the initial genetic studies in relation with HDL-C levels and all the conflicting studies on the relation between CETP activity and CVD risk. The author highlights the strengths of this study such as the large number of subjects, and of CVD events, the relatively long follow-up period and the prospective nature of the study. Shah also raises the issue that the relationship between CETP activity and CVD risk may not be entirely mediated through changes in circulating HDL-C levels. Finally, he points out that the failure of torcetrapib to decrease CVD risk has been in part attributed to non-CETP-dependent off-target effects such as an increase in arterial pressure. Thus, other studies with CETP inhibitors but without adverse off-target effects are warranted and underway.
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