The Evolving Role of HDL in the Treatment of High-Risk Patients with Cardiovascular Disease

Context: Statin treatment of cardiovascular patients reduces clinical events by 25 to 45%. High-density lipoprotein (HDL) has been proposed as a therapeutic target to further reduce this residual cardiovascular risk. Evidence Acquisition: PubMed from 1940 to the present was searched for all relevant citations related to the structure, function, and role of HDL in atherosclerosis. Evidence Synthesis: Epidemiological data, animal models with increased plasma HDL levels, as well as initial clinical and cardiovascular imaging trials suggest that increasing HDL in clinical patients will decrease the risk of cardiovascular disease. Proposed mechanisms by which HDL may reduce atherosclerosis include facilitating cholesterol efflux from cholesterol-loaded foam cells, role as an antiinflammatory lipoprotein, decreasing atherogenic oxidized low-density lipoprotein, increasing nitric oxide synthesis, serving as a plasma transport lipoprotein for biologically important proteins, and as an antithrombotic agent. The identification of the major receptors, enzymes, cellular transporters, and plasma lipid transfer proteins has provided major new insights into the pathways for HDL metabolism and cholesterol transport as well as targets for future drug development to increase HDL. Conclusions: Clinical trials with new HDL-raising drugs are currently under way to provide definitive evidence that increasing HDL will reduce cardiovascular events. The marked increase in our knowledge of the roles of HDL in cholesterol transport and the development of atherosclerosis now provides the framework for a more effective assessment of the plasma level and the function of HDL in an individual patient, as well as the lipoprotein profile after new drugs that increase HDL. (J Clin Endocrinol Metab 96: 1246-1257, 2011)