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Mulling over the odds of CETP inhibition.

Both elevated plasma concentrations of LDL cholesterol and low concentrations of HDL cholesterol are important risk factors of coronary heart disease. In randomized controlled trials of .100 000 individuals, lowering of LDL cholesterol with statins was found to be safe and effective in reducing cardiovascular morbidity and mortality by 20–40%. As the flip side of the coin, 60–80% of cardiovascular events are not prevented by statin treatment. Therefore, and because low HDL cholesterol explains some of the residual risk of patients with well controlled LDL cholesterol levels, both lower treatment goals for LDL cholesterol (,70 mg/dL/,1.7 mmol/L) and elevation of HDL cholesterol above at least 40 mg/dL (.1.05 mmol/L) are propagated. The clinical validity of this concept is currently evaluated in ongoing randomized clinical endpoint trials of statin combination therapies with ezitimibe, fenofibrate, nicotinic acid, or the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib. CETP exchanges cholesteryl esters of HDL with triglycerides of apolipoprotein B (apoB)-containing lipoproteins (Figure 1). This has two important consequences in lipoprotein metabolism. First, notably large HDL2 particles lose their cholesteryl esters which have accumulated there as the result of efflux of phospholipids and unesterified cholesterol from hepatocytes, enterocytes, macrophages, and other cells, as well as subsequent esterification by the enzyme lecithin:cholesterol acyltransferase (LCAT). The HDL2 particles shrink in size and liberate lipid-free apoA-I that undergoes either lipidation for regeneration of HDL or glomerular filtration for renal elimination. Secondly, CETP supports the transformation of the triglyceride-rich very low density lipoproteins (VLDLs) into cholesteryl-ester rich LDLs by enhancing the otherwise mainly lipolytic removal of triglycerides and by inducing the accumulation of cholesteryl esters (Figure 1). The physiological importance of CETP for the regulation of VLDL/LDL and HDL metabolism originally emerged from the observation of high HDL cholesterol and low LDL cholesterol in Japanese subjects with homozygous CETP deficiency. These observations as well as reports on reduced incidence of chronic heart disease (CHD) and increased life expectancy of CETP-deficient patients prompted several pharmaceutical companies to develop CETP inhibitors for the prevention and treatment of atherosclerosis. However, the first clinical evaluation of this concept using the CETP inhibitor torcetrapib recently failed to fulfil the hopes of patients, doctors, scientists, and the pharmaceutical industry. Despite further reducing LDL cholesterol by 15% and increasing HDL cholesterol by .50%, the combination of atorvastatin with torcetrapib did not prevent progression of carotid or coronary atherosclerosis more effectively than atorvastatin alone, but produced an excess of cardiovascular and overall mortality. However, it is as yet unkown whether the failure of torcetrapib was caused directly by CETP inhibition or indirectly by off-target effects because torcetrapib also increased blood pressure, by stimulating the synthesis of cortisol and aldosterone independently of CETP inhibition. The researchers involved in the two imaging torcetrapib trials tried to address these questions by post hoc data analyses but they obtained discrepant results: the ILLUSTRATE investigators found a significant regression of coronary atheroma volume in the 25% subgroup of patients who experienced the stongest increase in HDL cholesterol or reached the highest HDL cholesterol levels. In contrast the RADIANCE investigators found correlations of changes in carotid intima-media thickness with changes of LDL cholesterol and blood pressure but not HDL cholesterol. Thus it is still undecided whether CETP inhibition is a useful target for anti-atherogenic therapy. In fact at least two other CETP inhibitors, anacetrapib and dalcetrapib (formerly designated as JTT705), which do not affect blood pressure and mineralocorticoid synthesis are undergoing clinical evaluation. Like the chemically related torcetrapib, anacetrapib fixes CETP to HDL, irreversibly inhibits CETP by 90%, decreases LDL choleserol by 15%, and increases HDL cholesterol by 100% at the highest dosage. In contrast, the chemically unrelated dalcetrapib is a