High density lipoprotein-cholesterol (HDL-C) concentration in the blood is independently and inversely associated with an increased risk of
coronary heart disease. Some of the
cholesterol-lowering drugs (
niacin,
fibrates, and
statins) incidentally raise HDL-C. These drugs are not effective in causing major changes in HDL-C. Since the discovery of human genetic
cholesteryl ester transfer protein (
CETP) deficiency in a Japanese population with high levels of HDL-C and
apolipoprotein A-I, CETP inhibition has become a novel strategy for raising HDL-C in humans. Mice, a species naturally lacking CETP, were transduced with the human CETP gene, which resulted in dose-related reductions in HDL-C. Rabbits, a species with naturally high levels of CETP, were fed a synthetic CETP inhibitor,
JTT-705, leading to both a 90% increase in HDL-C and a 70% reduction in aortic atherosclerotic lesion area. Human intervention trials with a new potent and selective CETP inhibitor,
torcetrapib, have taken place. In a phase I multidose trial, HDL-C increased by 91% with
torcetrapib 120 mg twice daily. A phase II trial conducted with multiple combinations of
torcetrapib and
atorvastatin showed that the combination was well tolerated and doses 30 mg and higher of
torcetrapib caused 8.3-40.2% changes from baseline HDL-C across the dose range of
atorvastatin at 12 weeks. Recently the phase III clinical trial ILLUMINATE (Investigation of
Lipid Level Management to Understand its Impact in Atherosclerotic Events) was prematurely terminated because of an increase in mortality in the
torcetrapib/
atorvastatin treatment arm compared with
atorvastatin used alone. In companion studies no improvement in carotid or
coronary atherosclerosis could be detected in patients treated with the
torcetrapib/
atorvastatin combination despite favorable changes in both
low density lipoprotein (
LDL)- and
HDL-cholesterol levels. The future for CETP inhibition with
drug therapy is now unclear, and must include a closer look at CETP inhibitor's effects on blood pressure and HDL itself. Accordingly, it was recently shown in 2 double-blind, placebo-controlled, randomized, phase I studies with the CETP inhibitor
anacetrapib in healthy individuals and in patients with
dyslipidemias that the
drug increased HDL and reduced
LDL, while having no effect on blood pressure.