HDL-C: does it matter? An update on novel HDL-directed pharmaco-therapeutic strategies.

It has long been recognized that elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of cardiovascular disease (CHD) and that pharmacologic therapy to decrease LDL-C significantly reduces cardiovascular events. Despite the effectiveness of statins for CHD risk reduction, even optimal LDL-lowering therapy alone fails to avert 60% to 70% of CHD cases. A low plasma concentration of high-density lipoprotein cholesterol (HDL-C) is also associated with increased risk of CHD. However, the convincing epidemiologic data linking HDL cholesterol (HDL-C) to CHD risk in an inverse correlation has not yet translated into clinical trial evidence supporting linearity between HDL-C increases and CHD risk reduction. It is becoming clear that a functional HDL is a more desirable target than simply increasing HDL-C levels. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights, in turn, have fueled the development of new HDL-targeted drugs, which can be classified according to four different therapeutic approaches: directly augmenting the concentration of apolipoprotein A-I (apo A-I), the major protein constituent of HDL; indirectly augmenting the concentration of apo A-I and HDL cholesterol; mimicking the functionality of apo A-I and enhancing reverse cholesterol transport. This review discusses the latest in novel HDL directed therapeutic strategies.