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Abstract
Considerable attention is being turned to the development of therapeutic agents that either raise serum levels of high-density lipoproteins (HDLs) or boost their functionality. These initiatives are driven by the need to more effectively attenuate the risk for cardiovascular events in both the primary- and secondary-prevention settings. High HDL levels appear to exert protective effects against the development of atherosclerotic disease. HDLs have been shown to promote reverse cholesterol transport and to protect against endothelial cell dysfunction; they also modulate a variety of anti-inflammatory, antithrombotic and antioxidative effects. Cholesterol ester transfer protein (CETP) mediates the stoichiometric exchange of triglycerides for cholesteryl ester between apolipoprotein B100-containing lipoproteins and HDL. A number of polymorphisms in the gene for CETP have been identified and may be associated with a reduced risk for cardiovascular events. Drugs that therapeutically modulate the activity of CETP are currently under development. Torcetrapib is a CETP inhibitor, which was in a late stage of development. This compound simultaneously increases serum HDL and its subspecies, and lowers serum low-density lipoprotein while increasing its size and buoyancy. Torcetrapib also significantly increases blood pressure. Torcetrapib therapy is associated with an increased risk for acute cardiovascular events and does not beneficially impact rates of atherosclerosis progression in coronary or carotid arteries. Despite these findings, work with other HDL therapeutic agents should continue. The torcetrapib trials did not negate the HDL hypothesis because its effects on serum lipids were confounded by elevations in blood pressure and perhaps direct vasculotoxicity.