Current guidelines for high-density lipoprotein cholesterol in therapy and future directions

Abstract

Many studies have suggested that a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) is low high-density lipoprotein cholesterol (HDL-C). Therefore, increasing HDL-C with therapeutic agents has been considered an attractive strategy. In the prestatin era, fibrates and niacin monotherapy, which cause modest increases in HDL-C, reduced ASCVD events. Since their introduction, statins have become the cornerstone of lipoprotein therapy, the benefits of which are primarily attributed to decrease in low-density lipoprotein cholesterol. Findings from several randomized trials involving niacin or cholesteryl ester transfer protein inhibitors have challenged the concept that a quantitative elevation of plasma HDL-C will uniformly translate into ASCVD benefits. Consequently, the HDL, or more correctly, HDL-C hypothesis has become more controversial. There are no clear guidelines thus far for targeting HDL-C or HDL due to lack of solid outcomes data for HDL specific therapies. HDL-C levels are only one marker of HDL out of its several structural or functional properties. Novel approaches are ongoing in developing and assessing agents that closely mimic the structure of natural HDL or replicate its various functions, for example, reverse cholesterol transport, vasodilation, anti-inflammation, or inhibition of platelet aggregation. Potential new approaches like HDL infusions, delipidated HDL, liver X receptor agonists, Apo A-I upregulators, Apo A mimetics, and gene therapy are in early phase trials. This review will outline current therapies and describe future directions for HDL therapeutics.

Keywords: atherosclerosis; cardiovascular disease; cholesterol; high-density lipoprotein; lipids; therapy.

Figure 1

Life cycle of HDL. Adapted by permission from Macmillan Publishers Ltd: Nature Medicine, © 2012. Abbreviations: ABCA, ATP-binding cassette transporter family A; ABCG, ATP-binding cassette transporter family G; Apo, apolipoprotein; HDL, high-density lipoprotein; SR-B1, scavenger receptor class B1.

Figure 2

Therapeutic targets for HDL therapy (adapted by permission from Macmillan Publishers Ltd: Nature Reviews Cardiology, © 2011). Abbreviations: ABCA, ATP-binding cassette transporter family A; ABCG, ATP-binding cassette transporter family G; ACAT, acyl-CoA cholesterol acyltransferase; Apo, apolipoprotein; CE, cholesteryl esters; CETP, cholesterol ester transfer protein; EL, endothelial lipase; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate density lipoprotein; LCAT, lecithin cholesterol acyl transferase; LXR, liver X receptor; PL, phospholipid; PLTP, phospholipid transfer protein; PPAR, peroxisome proliferator-activated receptor; R, receptor; SR-B1, scavenger receptor class B1; TG, triglycerides; VLDL, very low-density lipoprotein.