Implications of torcetrapib failure for the future of HDL therapy: is HDL-cholesterol the right target?

Abstract

Owing to many potentially anti-atherogenic functions and the inverse correlation of high-density lipoprotein (HDL)-cholesterol (C) plasma levels with cardiovascular risk, HDLs have evolved as an attractive target for the prevention and therapy of coronary heart disease. Previously, the failure of torcetrapib, the frequent confounding of low HDL-C with other pro-atherogenic conditions, as well as inconsistent data from patients and animal models with genetic HDL dyslipidemias, left in doubt the suitability of HDL-C as a target for anti-atherogenic therapy. However, HDL-C is an integrative but nonfunctional measure of particle size and number. Therefore, biomarkers reflecting the functionality of HDL particles are needed to assess and monitor the cardiovascular risk exerted by disturbances and treatments of HDL metabolism, respectively. Moreover, the discovery of novel therapeutics that improve HDL metabolism, mimic HDL function, or cure the regulatory network underlying dyslipidemias and dysfunctions of HDL should be a major aim of atherosclerosis research.

Keywords::

• Apolipoprotein A-I
• Apolipoprotein A-I mimetics
• atherosclerosis
• ATP-binding cassette transporter A1
• biomarkers
• cholesteryl ester transfer protein
• dysfunctional HDL
• metabolic syndrome
• nicotinic acid
• reverse cholesterol transport
• sphingosine-1-phosphate

Financial & competing interests disclosure

Arnold von Eckardstein has received consulting fees and lecture honoraria from Astra Zeneca, Hoffmann-La Roche, and Merck-Sharpe & Dohme. His research on high-density lipoprotein is supported by grants from the European Commission (LSHM-CT-2006-037631), the Swiss National Science Foundation and the Zurich Center of Integrated Human Physiology. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.