Key Points
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The association of low plasma high-density lipoprotein cholesterol (HDL-C) concentration with elevated cardiovascular disease risk is firmly established in men and women over a wide age range, across several cardiometabolic disease states, including type 2 diabetes, and in many populations and ethnic groups.
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These associations underpinned the HDL hypothesis coined 40 years ago, stating that “a reduction of plasma HDL concentration may accelerate the development of atherosclerosis, and hence ischaemic heart disease, by impairing the clearance of cholesterol from the arterial wall”.
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Although the hypothesis was about HDL particle concentration, the evidence for the idea was based on HDL-C concentration data, as there was no method of measuring the former at the time.
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Genetic studies, including Mendelian randomization analysis, have shown that plasma HDL-C itself is not anti-atherogenic. However, genetic epidemiology has not yet been used to test the causality of low HDL particle number and coronary heart disease.
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Two short-term clinical trials of the effects of intravenous reconstituted HDLs on coronary lesions in patients with acute coronary syndrome gave encouraging results, but failed to provide unequivocal evidence of benefit.
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The small molecules tested to date in Phase III outcome trials do not specifically target HDL, and more specifically HDL particle number, and therefore the HDL hypothesis is yet to be tested. Three classes of agents that raise HDL-C in addition to lowering low-density lipoprotein (LDL) and/or plasma triglycerides have been tested. Although trial results with fibrates and niacin produced variable outcomes, meta-analyses supported the beneficial effects of both, although it was not possible to attribute them to HDL. Two trials of cholesteryl ester transfer protein (CETP) inhibitors have failed to show benefit, in one case possibly owing to an increase in blood pressure.
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The interrelationships between HDL-C concentration, HDL particle number and HDL particle subpopulations of defined composition are complex, as are their relationships to reverse cholesterol transport and other anti-atherogenic properties. Nevertheless, an understanding of these relationships will be essential for the rational development of new HDL therapies.
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Several novel approaches are under clinical development, including second-generation CETP inhibitors, new HDL infusion therapies, recombinant lecithin–cholesterol acyltransferase (LCAT) infusion therapy, and apolipoprotein A1 (APOA1) transcriptional upregulators.
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Additional strategies to target HDL metabolism that are emerging include APOA1-mimetic peptides, liver X receptor agonists, farnesoid X receptor agonists, endothelial lipase inhibitors, antagonists of microRNAs and antisense oligonucleotides targeted at the genes that are implicated in HDL metabolism.
Abstract
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.
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Acknowledgements
B.A.K. holds a National Health and Medical Research Council of Australia Senior Principal Research Fellowship. M.J.C. is Emeritus Director at INSERM. A.K. is a Research Director at INSERM. The authors are indebted to W. James (william.james@bakeridi.edu.au) for assistance with the original artwork for the figures in the article.
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B.A.K. has received product funding (but no research funding) from CSL and patient plasma (but no research funding) from Hoffman La Roche, both for investigator-initiated clinical trials. She has also partnered with Resverlogix to jointly fund an investigator-initiated trial. M.J.C. and A.K. have received research grant funding from CSL. N.E.M. has no disclosures.
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FURTHER INFORMATION
Glossary
- APOA1
-
Apolipoprotein A1; the major apolipoprotein in human high-density lipoprotein (HDL).
- LCAT
-
Lecithin–cholesterol acyltransferase; an enzyme that esterifies free cholesterol to cholesteryl ester and hydrolyses phosphatidylcholine. LCAT is bound to both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in plasma, and is activated by apolipoprotein A1.
- ABCA1
-
ATP-binding cassette subfamily A member 1; a cell membrane transporter that exports cholesterol and phospholipid to lipid-poor high-density lipoprotein (HDL) particles in humans, including nascent pre-β HDL particles and, to a lesser degree, HDL3.
- CETP
-
Cholesteryl ester transfer protein; a protein that transfers triglycerides from very-low-density lipoproteins (VLDLs) or low-density lipoproteins (LDLs) and exchanges them for cholesteryl esters from high-density lipoproteins (HDLs).
- Hepatic lipase
-
An enzyme that primarily hydrolyses triglycerides, remodelling high-density lipoprotein (HDL) into smaller particles and dissociating apolipoprotein A1.
- SRB1
-
Scavenger receptor class B member 1; these receptors were identified as oxidized low-density lipoprotein (LDL) receptors but are equally involved in cholesterol transport to and from high-density lipoprotein (HDL) particles.
- Endothelial lipase
-
(LIPG). An enzyme that functions primarily as a phospholipase and remodels high-density lipoprotein (HDL) into smaller particles without mediating the dissociation of apolipoprotein A1.
- PLTP
-
Phospholipid transfer protein; a lipid transfer protein that transfers phospholipids from triglyceride-rich lipoproteins (low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL)) to high-density lipoprotein (HDL), and also between different HDL subpopulations.
- Pre-β HDL
-
A heterogeneous population of dense, lipid-poor or nascent high-density lipoprotein (HDL) particles, frequently discoidal, with diameters of 5.5–7.5 nm.
- HDL3
-
A major subfraction of native high-density lipoprotein (HDL) predominantly containing lipid-poor, spherical HDL particles that are smaller in diameter (between 7.2nm and 8.8nm) than HDL2.
- APOA1 Milano
-
A naturally occurring apolipoprotein A1 (APOA1) protein that is associated with a low frequency of cardiovascular disease.
- LPL
-
Lipoprotein lipase; an enzyme that primarily hydrolyses triglycerides in triglyceride-rich lipoproteins (for example, chylomicrons and very-low- density lipoprotein (VLDL)).
- APOA2
-
Apolipoprotein A2; the second most abundant apolipoprotein in human high-density lipoprotein (HDL).
- HDL2
-
A major subfraction of native high-density lipoprotein (HDL)-containing lipid-rich, spherical HDL particles of a large diameter (between 8.8 nm and 12.9 nm).
- ABCG1
-
ATP-binding cassette subfamily G member 1; a cell membrane transporter that may promote cholesterol efflux to mature cholesteryl ester-rich spherical high-density lipoprotein (HDL) particles in humans.
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Kingwell, B., Chapman, M., Kontush, A. et al. HDL-targeted therapies: progress, failures and future. Nat Rev Drug Discov 13, 445–464 (2014). https://doi.org/10.1038/nrd4279
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DOI: https://doi.org/10.1038/nrd4279
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