Genetic Inhibition of CETP, Ischemic Vascular Disease and Mortality, and Possible Adverse Effects

Study Questions:

Is genetic reduction in cholesteryl ester transfer protein (CETP) associated with protection from cardiovascular disease (CVD)?

Methods:

The Copenhagen City Heart Study is a prospective cohort study of 10,261 individuals followed for up to 34 years. A total of 2,087 developed ischemic heart disease, 1,064 developed ischemic cerebrovascular disease, and 3,807 died during follow-up. Two common genetic variants in CETP previously associated with reduced CETP activity were analyzed, thus mimicking the effect of pharmacological CETP inhibition.

Results:

In individuals carrying 4 versus 0 high-density lipoprotein cholesterol (HDL)–increasing alleles, there was an increase in levels of HDL up to 14%, along with decreases in triglycerides, low-density lipoprotein, and non–HDL cholesterol of 6%, 3%, and 4% (p for trend, 0.004 to <0.001). Corresponding hazard ratios were 0.76 for any ischemic vascular event, 0.74 for ischemic heart disease, 0.65 for myocardial infarction (MI), 0.77 for ischemic cerebrovascular disease, 0.71 for ischemic stroke, and 0.88 for total mortality. CETP genotypes did not associate with markers of side effects previously reported for torcetrapib.

Conclusions:

The authors concluded that genetic CETP inhibition associates with reductions in risk of ischemic heart disease, MI, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects.

Perspective:

HDL levels are inversely associated with CVD and many preclinical studies have demonstrated vasculoprotective effects of HDL, suggesting that raising HDL should lead to protection from CVD. However, recent trials with CETP inhibitors that markedly raise HDL, and niacin that modestly raises HDL, have paradoxically shown adverse effects or no benefit toward vascular endpoints. These results, in addition to some mendelian randomization studies, have raised doubts regarding the direct role of HDL in atheroprotection. This genetic association study, however, indicates that there still may be benefits to raising HDL via CETP inhibition. Results from ongoing clinical trials with other CETP inhibitors devoid of off-target blood pressure effects should be illuminating.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol, Myocardial Infarction, Stroke, Cholesterol Ester Transfer Proteins, Biological Markers, Longevity, Quinolines, Genotype


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