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Is raising HDL a futile strategy for atheroprotection?

Key Points

  • Low levels of high-density lipoprotein (HDL) cholesterol correlate with an increased risk of atherosclerosis. Thus, pharmacological agents that increase HDL should be associated with reductions in cardiovascular disease and has been the focus of recent pharmaceutical research.

  • The primary anti-atherogenic effects of HDL occur through the reverse cholesterol transport (RCT) pathway. However, HDL also has anti-oxidative, anti-thrombotic, anti-inflammatory and endovascular properties.

  • HDL-raising through the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was associated with increased cardiovascular morbidity and mortality, despite substantial increases of HDL levels (by 60%), leading to a suspension of all further research with this drug.

  • The strongest evidence for HDL-raising and beneficial cardiovascular outcomes is derived from trials with niacin. However, the use of niacin has been limited by its main side effect, skin flushing. The combination of extended-release niacin with a selective prostaglandin D2 receptor antagonist has been shown to decrease flushing, and clinical trials evaluating cardiovascular endpoints are underway.

  • Promising HDL-raising effects on cardiovascular outcomes have been shown using fibrates, statins, APOA1Milano, APOA1 mimetics and reconstituted HDL, although the actual beneficial mechanisms could be found to differ from theoretical mechanisms. Other potential therapies include liver X-receptor agonists, selective cannibinoid-1 receptor antagonists, pro-protein convertase activators and inhibitors of endothelial lipase, hepatic lipase or scavenger receptor-B1.

  • Despite the failure of torcetrapib, HDL-raising remains a potentially useful strategy for atheroprotection.

Abstract

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.

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Figure 1: Reverse cholesterol transport (RCT).

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Acknowledgements

Dr. Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, a Career Investigator award from the Heart and Stroke Foundation of Ontario and operating grants from the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Ontario, the Ontario Research Fund and Genome Canada through the Ontario Genomics Institute. Dr. Joy is supported by the Resident Research Fellowship Program through the Department of Medicine at the University of Western Ontario.

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Glossary

High-density lipoprotein

(HDL). A class of cholesterol-rich lipoprotein particles that drive the return of cholesterol from the periphery back to the liver; cholesterol carried by these particles is colloquially referred to as 'good cholesterol'.

Atherosclerosis

A complex, multifactorial disease process that results in the development of arterial wall plaques, which can eventually occlude the arterial lumen and compromise blood flow, resulting in a heart attack or stroke depending on the affected arterial bed. Plasma lipids — especially cholesterol — in circulating lipoprotein particles have a key role at several stages of atherosclerosis.

Apolipoprotein A-1

(APOA1). The major structural apolipoprotein on the vast majority of high-density lipoprotein particles, accounting for approximately 70% of the protein content of these particles.

Niacin

A member of the vitamin B family and effective cholesterol-lowering agent at high doses. It reduces low-density lipoprotein, triglyceride and total plasma cholesterol levels while raising high-density lipoprotein levels. It is the only known compound to effectively reduce the levels of lipoprotein A.

Low-density lipoprotein

(LDL). A class of cholesterol-rich lipoprotein particles that deliver cholesterol from the liver to peripheral cells, including cells within the evolving atherosclerotic plaque; cholesterol carried by these particles is colloquially referred to as 'bad cholesterol'.

Reverse cholesterol transport

(RCT). The general pathway through which cholesterol is transported from peripheral cells, such as cholesterol-laden macrophages, to the liver for excretion in bile. High-density lipoprotein (HDL) has a major role in RCT and this is thought to be the main mechanism by which HDL exerts its anti-atherogenic effects.

Cholesteryl ester transfer protein

(CETP). A hydrophobic glycoprotein that is primarily found bound to high-density lipoproteins (HDL). The major function of CETP is to facilitate the transfer of cholesteryl ester from HDL to low-density lipoproteins, intermediate density lipoproteins and very low-density lipoproteins in exchange for triglyceride from those particles during the latter stages of reverse cholesterol transport.

Fibrinolysis

The body's main mechanism of dissolving fibrin-formed clots and thus preventing adverse clot-initiated events such as heart attacks, deep vein thromboses or pulmonary emboli.

Familial hypercholesterolaemia

(FH). A genetically inherited lipoprotein disorder characterized by cutaneous manifestations of hyper-cholesterolaemia, very high levels of low-density lipoprotein and total cholesterol, as well as early, often fatal, cardiovascular disease. FH is most often caused by defects in the low-density lipoprotein receptor (LDLR) gene.

Heparin-affinity column

A chromatographic method that is used to separate and purify proteins based on their differential affinity to heparin.

Tangier disease

A rare autosomal recessive lipoprotein disorder characterized by low to absent high-density cholesterol levels with deposition of cholesterol esters in reticuloendothelial cells, leading to tonsillar enlargement, hepatomegaly, splenomegaly and lymphadenopathy. The disease is caused by mutations in the ATP-binding cassette subfamily A, member 1 (ABCA1) gene.

APOA1Milano mutation

A cysteine to arginine substitution at position 173 in the apolipoprotein A-1 (APOA1) gene. Individuals possessing this mutation have low levels of high-density lipoprotein cholesterol and increased levels of triglycerides without an associated increased risk for cardiovascular disease.

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Joy, T., Hegele, R. Is raising HDL a futile strategy for atheroprotection?. Nat Rev Drug Discov 7, 143–155 (2008). https://doi.org/10.1038/nrd2489

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