Cholesteryl ester transfer protein inhibition, high-density lipoprotein metabolism and heart disease risk reduction

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Abstract
Cholesteryl ester transfer protein (CETP) inhibitors (JTT-705 and torcetrapib) are currently in clinical testing, and significantly raise high-density lipoprotein (HDL) cholesterol levels. Low HDL cholesterol is a significant independent predictor of coronary heart disease (CHD) and HDL raising has been associated with coronary heart disease risk reduction, but there is debate about whether CETP inhibition will reduce coronary heart disease risk. It has been documented in transgenic mouse models that apolipoprotein (apo) C-I inhibits CETP, and that high mono-unsaturated fat diets prevent the normal stimulation of CETP activity by dietary cholesterol. In rabbits, torcetrapib markedly decreases clearance of HDL cholesteryl ester via an indirect pathway, but has no effect on total plasma cholesteryl ester clearance. In humans, torcetrapib raises HDL apoA-I by modestly decreasing its fractional catabolic rate, while having a very profound effect on raising HDL cholesterol and large alpha-1 migrating HDL particles by more than 50%, with no effect on fecal cholesterol excretion. When JTT-705 at 600 mg/day was given to hypercholesterolemic patients already on pravastatin 40 mg/day, the combination was well tolerated and increases in HDL cholesterol of 28% were noted. In our view, CETP inhibitors in combination with statins will be profoundly beneficial in reducing human atherosclerosis, primarily because they normalize HDL particles and prevent the transfer of cholesteryl ester from HDL to atherogenic lipoproteins.