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  • Review Article
  • Published:

HDL as a target in the treatment of atherosclerotic cardiovascular disease

Nature Reviews Drug Discovery volume 4, pages 193–205 (2005)Cite this article

A Correction to this article was published on 01 August 2005

Key Points

  • Atherosclerosis is the leading cause of mortality in industrialized nations, despite substantial therapeutic progress resulting from the widespread use of statins.

  • Large-scale clinical trials using statins for both primary and secondary prevention have shown a marked reduction in coronary events, mainly owing to the lowering of plasma concentrations of low-density lipoprotein (LDL) cholesterol.

  • However, recent studies could herald the limits of statin monotherapy in inhibiting the development of established atherosclerotic disease, and there is therefore considerable interest in the therapeutic potential of targeting other lipid-related risk factors.

  • HDL-cholesterol levels are inversely correlated with the risk of coronary heart disease, and studies indicate a potential for HDL-raising therapies to reduce the risk of cardiovascular disease.

  • This article first overviews the mechanisms that are thought to be responsible for the protective effect of HDL cholesterol, and then discusses several new molecular targets and strategies that have emerged for increasing HDL levels, which is the next frontier in the prevention of atherosclerotic cardiovascular disease.

Abstract

Lipid abnormalities are among the key risk factors for cardiovascular disease. Indeed, lipid-modifying drugs — in particular, the statins, which primarily lower plasma levels of low-density lipoprotein (LDL) cholesterol — considerably reduce the risk of cardiovascular events, leading to their widespread use. Nevertheless, it seems that there might be limits to the degree of benefit that can be achieved by lowering LDL-cholesterol levels alone, which has led to increased interest in targeting other lipid-related risk factors for cardiovascular disease, such as low levels of high-density lipoprotein (HDL) cholesterol. In this article, we first consider the mechanisms that underlie the protective effect of HDL cholesterol, and then discuss several strategies that have recently emerged to increase levels of HDL cholesterol to treat cardiovascular disease, including nuclear receptor modulation, inhibition of cholesteryl ester transfer protein and infusion of apolipoprotein/phospholipid complexes.

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Figure 1: Mechanisms of cholesterol efflux from the arterial wall.
Figure 2: Overview of high-density lipoprotein metabolism and potential targets for therapeutic intervention.
Figure 3: Chemical structures of selected investigational agents that target high-density lipoprotein.

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Authors and Affiliations

  1. Division of Molecular Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, 10027, New York, USA

    Patrick Linsel-Nitschke & Alan R. Tall

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  1. Patrick Linsel-Nitschke
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Correspondence to Patrick Linsel-Nitschke or Alan R. Tall.

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DATABASES

Entrez Gene

ABCA1

ABCG1

ABCG4

ABCG5

ABCG8

apoA-I

apoB

apoE

CETP

eNOS

FXR

LCAT

LIPC

LIPG

LPL

PLTP

PPARα

PPARγ

PPARδ

RARγ

SR-BI

SRC1

TNF

OMIM

familial hypoalphalipoproteinaemia

Tangier's disease

type II diabetes

Glossary

ATHEROSCLEROSIS

Atherosclerosis is a systemic disease that is characterized by the accumulation of lipid-rich plaques within the walls of large arteries. Major clinical manifestations of atherosclerosis include myocardial infarction (heart attack), stroke and peripheral vascular disease.

METABOLIC SYNDROME

A common condition associated with increased risk for cardiovascular disease. The diagnosis requires three or more of the following symptoms: central obesity; high blood pressure; low plasma-HDL; high triglycerides; or elevated fasting blood glucose.

MACROPHAGE

A type of white blood cell that is specialized for the uptake of material by phagocytosis.

SINGLE NUCLEOTIDE POLYMORPHISM

(SNP). A specific location in a DNA sequence at which different people can have a different DNA base. Differences in a single base could change the protein sequence, leading to disease, or have no known consequences.

INTRACORONARY VASCULAR ULTRASOUND

(IVUS). Procedure in which a miniature ultrasound transducer on the tip of a coronary catheter is used to produce detailed images of the interior wall of coronary arteries.

CHOLELITHIASIS

Presence of gallstones in the gallbladder.

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Linsel-Nitschke, P., Tall, A. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov 4, 193–205 (2005). https://doi.org/10.1038/nrd1658

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