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Update on strategies to increase HDL quantity and function

Abstract

Low levels of HDL cholesterol are a significant predictor of atherosclerotic cardiovascular events. HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport, and potentially through anti-inflammatory, antioxidative, antithrombotic and nitric oxide effects. The multiple mechanisms of action, as well as a limited ability to measure these properties, make HDL a complex therapeutic target, albeit one with immense potential for the treatment of patients with atherosclerosis. Here, we discuss new therapeutic strategies currently being developed, which have the potential to increase plasma levels of HDL cholesterol and/or improve HDL function.

Key Points

  • The simplified goals of new HDL therapeutics in development are to raise HDL-cholesterol plasma levels and/or improve HDL function

  • Niacin is currently the best available therapy for raising HDL-cholesterol levels; strategies have been developed to make it more tolerable, and studies are underway to assess its benefit when added to a statin

  • Inhibitors of cholesteryl ester transfer protein raise plasma HDL-cholesterol levels substantially, although the overall effect on atherosclerotic cardiovascular disease is still unknown

  • Apolipoprotein A-I small-molecule upregulators and mimetic peptides have promise as therapies that may enhance HDL function, even without necessarily increasing plasma HDL-cholesterol levels

  • Strategies that aim to enhance macrophage reverse cholesterol transport, for example with liver X receptor agonists, are of interest and continue to be explored

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Figure 1: HDL metabolism and reverse cholesterol transport.
Figure 2: Cholesterol efflux from macrophages.

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Correspondence to Daniel J. Rader.

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Daniel Rader is a consultant for Merck, Roche, Abbott, Resverlogix and Novartis, and has been on the speakers bureau/received honoraria from Merck and Abbott.

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Duffy, D., Rader, D. Update on strategies to increase HDL quantity and function. Nat Rev Cardiol 6, 455–463 (2009). https://doi.org/10.1038/nrcardio.2009.94

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