Present therapeutic role of cholesteryl ester transfer protein inhibitors

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Lipid Metabolism

Background:

• Therapeutic strategies to increase high-density lipoprotein (HDL) levels for reducing residual cardiovascular (CV) risk have yielded limited success.
• HDL's atheroprotective function involves cholesterol transfer from peripheral tissues to the liver; elevating HDL may be a viable approach.
• Inhibiting cholesteryl ester transfer protein (CETP) raises HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I), potentially lowering LDL-cholesterol (LDL-C) and apoB.

Purpose of the Study:

• To evaluate the efficacy of CETP inhibition in managing cardiovascular risk.
• To investigate the impact of CETP inhibitors on lipid profiles and clinical CV events.
• To assess the complex mechanisms and outcomes associated with CETP inhibition.

Main Methods:

• Review of clinical trial data for CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, and anacetrapib.
• Analysis of results from the REVEAL trial, a secondary prevention study of anacetrapib.
• Consideration of ongoing clinical development of dalcetrapib and CKD-519.

Main Results:

• Previous CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) failed to demonstrate significant CV event reduction.
• The REVEAL trial showed anacetrapib significantly increased HDL-C (+104%) and reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91).
• Anacetrapib also reduced non-HDL cholesterol (-18%) and lipoprotein(a) (Lp(a)) (-25%).

Conclusions:

• Despite positive CV outcomes in the REVEAL trial, regulatory approval for anacetrapib was not pursued.
• The precise contribution of HDL-C elevation versus LDL-C reduction to the observed CV benefit requires further clarification.
• Dalcetrapib and CKD-519 are currently the main CETP inhibitors remaining in clinical development for cardiovascular risk reduction.