HDL-cholesterol levels and cardiovascular risk: acCETPing the context.

High levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with a decreased risk of cardiovascular disease. Cholesterol ester transfer protein (CETP) facilitates the transfer or cholesteryl esters from HDL to triglyceride-rich lipoproteins, and its inhibition raises HDL-C levels. Accordingly, interest has focused on CETP inhibition to augment current lipid-lowering strategies. In a substudy from the Regression Growth Evaluation Statin Study (REGRESS) angiographic trial cohort, Regieli and colleagues evaluated 812 statin-treated participants and found that the 60% who were carriers of the TaqIB-B2 CETP gene allele had 20% lower CETP and 15% higher HDL-C serum concentrations than those without the allele, and a markedly increased risk of atherosclerotic disease mortality. The hazard ratio per each B2 copy was 1.60 (P 1⁄4 0.01). The authors concluded that statin use in the setting of low CETP levels worsens clinical outcome in patients with proven cardiovascular disease. In light of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial—which showed a 61% increase in combined mortality and cardiovascular events in 15 000 individuals at high risk for coronary events who were treated with atorvastatin plus torcetrapib, a CETP inhibitor, compared with atorvastatin alone—the Regieli study highlights the fact that much remains unknown about the interaction between HDL-C metabolism and cardiovascular disease. CETP is a plasma glycoprotein that shuttles cholesteryl esters, phospholipids, and triglycerides between HDL-C, very low-density lipoprotein and low-density lipoprotein (LDL). CETP genotypes that result in moderate inhibition of CETP activity are associated with increased serum HDL-C levels and reduced coronary risk. In contrast, pharmacological CETP inhibition has not proven to be clinically beneficial. In statin-treated patients, concomitant CETP inhibition with torcetrapib did not slow the progression of atherosclerosis and was associated with a 25% increase in cardiovascular events and 58% increase in mortality, despite increased HDL-C levels. Although this increase in events has been attributed to the ‘off-target’ effects of torcetrapib (i.e. increased systemic arterial pressure and serum aldosterone), the possibility remains that combination statin and CETP inhibition therapy is harmful. There are several possible mechanisms that may account for the negative outcomes. While CETP synthesis is generally assigned to liver and adipose tissue, many organs express CETP mRNA, including spleen, bone marrow, adrenal gland, intestine, kidney, lung, prostate, brain, heart, and skeletal muscle. Apart from its role in regulating HDL-C, CETP may be an important anti-inflammatory mediator. For example, overexpressing human CETP in transgenic mice increases their survival rate following endotoxin exposure, attenuates the associated tumour necrosis factor-a and interleukin-6 responses, and enhances endotoxin binding to HDL-C to increase its clearance via the liver. Thus, CETP may play a role in the regulation of cytokines and inflammation. Interestingly, in the ILLUMINATE trial, CETP inhibition with torcetrapib was associated with increased serum C-reactive protein levels and a 2-fold increased incidence of death from non-cardiovascular causes, primarily from infection and cancer. Although CETP inhibition increases serum HDL-C levels, the resultant particle may be dysfunctional or even pro-atherogenic. Pharmacological inhibition of CETP increases the levels of a larger, less dense HDL-C (so called, HDL2), which may be less effective in mediating reverse cholesterol transport than the small, more dense HDL1 particle. Furthermore, oxidation of ‘quiescent’ HDL particles or an increase in the ‘pro-atherogenic’ apolipoprotein A-II component of HDL-C as a consequence of CETP inhibition may render them pro-inflammatory. While the current study demonstrates that the B2 CETP gene allele is associated with increased mortality in comparison with