Our purpose is to review recent research in the area of
high-density lipoprotein (
HDL) cholesterol raising and
coronary artery disease (CAD) risk reduction. It is known that a decreased
HDL cholesterol level is an important CAD risk factor and that raising
HDL cholesterol has been associated with CAD risk reduction. A relative new strategy for raising
HDL cholesterol, inhibition of
cholesteryl ester transfer protein (CETP), is markedly effective. CETP inhibitors prevent the transfer of
cholesteryl ester from HDL to
triglyceride-rich
lipoproteins in exchange for
triglyceride. One inhibitor,
torcetrapib, binds to CETP on HDL, markedly increases
HDL cholesteryl ester, has no effect on fecal
cholesterol excretion, but can raise blood pressure. A large clinical trial in patients with CAD who were taking
atorvastatin was recently stopped prematurely because of excess mortality in those receiving
torcetrapib versus placebo, and 2 other trials reported no benefit of
torcetrapib on
coronary atherosclerosis or carotid intima-media thickness as compared with subjects on
atorvastatin alone. The adverse effects of
torcetrapib may be compound specific, and because the crystal structure of CETP is now known, it should be possible to develop more optimal CETP inhibitors that do not form a nonproductive complex with CETP on the HDL particle, as has been reported for
torcetrapib. Another alternative for increasing HDL levels is to develop more effective and better tolerated
niacin preparations.