HDL-targeted therapies: progress, failures and future.

Since the discovery in the 1970s that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with cardiovascular outcome, it has been postulated that HDL is anti-atherogenic and that increasing HDL-C levels is a promising therapeutic strategy. However, the recent failure of three orally active, HDL-C-raising agents has introduced considerable controversy, prompting the question of whether increasing the cholesterol cargo of HDL in a non-selective manner is an effective pharmacological approach for the translation of its atheroprotective and vasculoprotective activities. The interrelationships between HDL-C concentration, HDL particle number and levels of diverse HDL particle subpopulations of defined composition are complex, as are their relationships with reverse cholesterol transport and other anti-atherogenic functions. Such complexity highlights the incompleteness of our understanding of the biology of HDL particles. This article examines the HDL hypothesis in molecular and mechanistic terms, focusing on features that have been addressed, those that remain to be tested, and potential new targets for future pharmacological interventions.