HDL-targeted therapies: progress, failures and future

Kingwell, Bronwyn A.; Chapman, M. John; Kontush, Anatol; Miller, Norman E.

doi:10.1038/nrd4279

Cited by 355Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthParaoxonase enzyme and polymorphisms

HDL-targeted therapies: progress, failures and future

Kingwell, Bronwyn A., Chapman, M. John, Kontush, Anatol, Miller, Norman E.·2014·Nature Reviews Drug Discovery

DOI 10.1038/nrd4279

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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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Results from studies on treatment that increase HDL-cholesterol levels have so far been disappointing.
“whereas results from studies on treatment that increase HDL-cholesterol levels have so far been disappointing (41)”
From Effects of low-carbohydrate dietsv. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials (2016) · cites this paper as [41]
Both in vitro and in vivo, these approaches can achieve a transient acceleration of RCT, sometimes without causing any significant change in HDL-C.
“Both in vitro and in vivo, these approaches can achieve a transient acceleration of RCT, sometimes without causing any significant change in HDL-C.”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [111]
Recent approaches primarily aim to optimise the function of HDL in RCT.
“Recent approaches primarily aim to optimise the function of HDL in RCT [110, 111].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [111]

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Relation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease
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ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden
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Authors: Kingwell, B. A., Chapman, M. J., Kontush, A., & Miller, N. E.
Affiliations: Baker Heart and Diabetes Institute (AU)
Inserm (FR)
University of Oxford (GB)
Corresponding author: Kingwell, Bronwyn A.
ORCID: Kingwell, Bronwyn A.
Chapman, M. John
Kontush, Anatol
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2014-05-23
Volume: 13
Issue: 6
Pages: 445-464
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd4279
OpenAlex: W1993577107
Cited by: 354
References: 228
Citations by year: 2026: 11 · 2025: 15 · 2024: 9 · 2023: 28 · 2022: 22 · 2021: 21 · 2020: 22 · 2019: 33 · 2018: 33 · 2017: 43 · 2016: 53 · 2015: 51 · 2014: 12
FWCI: 10.00
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords: HDL cholesterol, HDL-targeted therapy, HDL particle number, reverse cholesterol transport, atheroprotection, cardiovascular disease, clinical trial failure
MeSH terms: Animals, Hypolipidemic Agents, Cardiovascular Diseases, Clinical Trials as Topic, Humans, Phosphatidylcholine-Sterol O-Acyltransferase, Lipoproteins, HDL, Models, Biological, Niacin, Recombinant Proteins, Drugs, Investigational, Up-Regulation, Apolipoprotein A-I, Cholesterol Ester Transfer Proteins, Molecular Targeted Therapy

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HDL-targeted therapies: progress, failures and future

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