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  • Review Article
  • Published:

Novel HDL-directed pharmacotherapeutic strategies

Nature Reviews Cardiology volume 8, pages 266–277 (2011)Cite this article

Subjects

Abstract

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin–cholesterol acyltransferase.

Key Points

  • Four HDL-targeted drug approaches exist: directly augmenting apolipoprotein A-I (apo A-I) levels, indirectly augmenting apo A-I and HDL-cholesterol levels, mimicking the effects of apo A-I, and enhancing reverse cholesterol transport

  • From a pharmacodynamic standpoint, direct augmentation of lipid-poor apo A-I levels arguably represents the most validated HDL therapeutic approach in terms of antiatherogenic potential

  • The clinical efficacy of interventions that raise HDL-cholesterol levels through slowing its metabolism, such as inhibition of cholesteryl ester transfer protein or endothelial lipase, remains to be established

  • The discovery of the niacin receptor GPR109A helped to define the mechanisms underlying the effect of niacin on free fatty acids and flushing, although it is unclear how niacin raises HDL-cholesterol levels

  • With the exception of D-4F, apo A-I mimetic peptides require parenteral administration and, therefore, are likely to be initially targeted to patients at high risk with acute coronary syndromes

  • Intestinal-specific liver X receptor (LXR) agonism or LXRβ-specific agonism might enhance reverse cholesterol transport while avoiding toxicity associated with nonselective LXR activation, namely, hepatic lipogenesis and hypertriglyceridemia

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Figure 1: HDL metabolism and targets of therapeutic intervention.

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Acknowledgements

This work was supported by grants from the National Heart, Lung and Blood Institute (HL22633 and P50 HL70128) and the National Center for Research Resources (UL1-RR-024134). E. M. deGoma's salary is partially funded by a National Heart, Lung and Blood Institute grant (K12 HL083772-01).

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, University of Pennsylvania, Penn Tower, 6th Floor, 3400 Spruce Street, Philadelphia, 19104, PA, USA

    Emil M. deGoma

  2. Department of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 654 BRB II/III, 451 Curie Boulevard, Philadelphia, 19104, PA, USA

    Daniel J. Rader

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E. M. deGoma and D. J. Rader contributed equally to the discussion of content for the article, the research of data to include in the manuscript, writing the article and the reviewing and editing of the manuscript before submission.

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Correspondence to Emil M. deGoma.

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Competing interests

D. J. Rader is a consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Resverlogix. E. M. deGoma declares no competing interests.

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deGoma, E., Rader, D. Novel HDL-directed pharmacotherapeutic strategies. Nat Rev Cardiol 8, 266–277 (2011). https://doi.org/10.1038/nrcardio.2010.200

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