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

Area of Science:

• Cardiovascular Pharmacology
• Lipid Metabolism Research
• Atherosclerosis Therapeutics

Background:

• Low high-density lipoprotein (HDL) cholesterol is a key predictor of coronary heart disease (CHD).
• Cholesteryl ester transfer protein (CETP) inhibitors are under clinical investigation for their potential to raise HDL cholesterol.
• The clinical benefit of CETP inhibition in reducing CHD risk remains debated.

Purpose of the Study:

• To review the effects of CETP inhibitors (JTT-705 and torcetrapib) on HDL cholesterol levels and related cardiovascular risk factors.
• To evaluate the potential of CETP inhibition in combination with statins for treating atherosclerosis.

Main Methods:

• Review of studies involving CETP inhibitors in animal models (transgenic mice, rabbits) and human clinical trials.
• Analysis of the impact of torcetrapib and JTT-705 on HDL cholesterol, apolipoprotein A-I (apoA-I), HDL particle size, and cholesterol excretion.
• Assessment of the tolerability and efficacy of JTT-705 in combination with pravastatin in hypercholesterolemic patients.

Main Results:

• Transgenic mouse models show apolipoprotein C-I inhibits CETP; high monounsaturated fat diets can prevent CETP stimulation by dietary cholesterol.
• Torcetrapib decreases HDL cholesteryl ester clearance indirectly in rabbits but does not affect total plasma cholesteryl ester clearance.
• In humans, torcetrapib increases HDL apoA-I by reducing its catabolic rate, significantly raises HDL cholesterol and large HDL particles, without affecting fecal cholesterol excretion.
• Combination therapy with JTT-705 (600 mg/day) and pravastatin (40 mg/day) was well-tolerated, yielding a 28% increase in HDL cholesterol.

Conclusions:

• CETP inhibitors show promise in normalizing HDL particles and preventing cholesteryl ester transfer to atherogenic lipoproteins.
• Combination therapy with CETP inhibitors and statins is anticipated to be highly beneficial in reducing human atherosclerosis.
• Further research is warranted to confirm the long-term cardiovascular benefits of CETP inhibition.