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

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HDL-targeted therapies: progress, failures and future

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

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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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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: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › 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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