Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community

Background—Plasma high-density lipoprotein cholesterol concentration is related inversely to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises high-density lipoprotein cholesterol and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was stopped prematurely because of increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting. Methods and Results—Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination in 1987–1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusted for standard risk factors including high-density lipoprotein cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio for activity, at or above the median of 0.72; 95% confidence interval, 0.57 to 0.90; P 0.004 [compared with below median]; hazard ratio per SD increment, 0.86; 95% confidence interval, 0.76 to 0.97; P 0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years and was maintained in analyses of incident “hard” CVD events (myocardial infarction, stroke, or heart failure). Conclusions—In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk. (Circulation. 2009;120:2414-2420.)