Elsevier

Journal of Clinical Lipidology

Volume 7, Issue 5, September–October 2013, Pages 484-525
Journal of Clinical Lipidology

Original Article
High-density lipoproteins: A consensus statement from the National Lipid Association

https://doi.org/10.1016/j.jacl.2013.08.001Get rights and content

Highlights

  • ► The National Lipid Association High Density Lipoprotein Consensus Panel concludes that low levels of high-density lipoprotein cholesterol (HDL-C) identifies individuals at elevated risk for cardiovascular disease.

  • ► A number of recent randomized studies, which attempted to test the HDL hypothesis, failed to show benefit, causing clinicians to question whether HDL-C is a legitimate therapeutic target. At this time, the expert panel agrees that there is insufficient evidence to support the use of therapeutic interventions to raise low serum levels of HDL-C. Rather, risk-stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non-HDL-C) should remain the primary and secondary therapeutic targets for patients at risk for cardiovascular disease.

  • ► However, consensus panel emphasizes the need for continued rigorous research into the biology and clinical significance of low levels of HDL-C, and into the development of novel drugs designed to modulate HDL structure and function.

Abstract

For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the “HDL hypothesis” have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panel's conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non–HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.

Section snippets

HDL-C as an independent risk factor for CVD

The epidemiologic evidence in support of HDL-C as an inverse predictor of CVD has been appreciated for >50 years. Gofman et al13 first reported an inverse association between HDL-C levels and risk of ischemic heart disease. Subsequently, an inverse association between HDL-C and CVD risk was found in the Norwegian Tromsø Heart Study,14 and this was soon followed by US longitudinal data available from the Honolulu Heart Study and the Framingham Heart Study (FHS).15, 16 Both of those studies found

Analytical methods

A need is increasing to characterize and quantify the diverse roles of HDL particles in atherogenesis to improve the diagnosis, prevention, and treatment of CVD.60, 61 This information provides a foundation for fostering improved understanding of the pathophysiology of atherosclerosis, direct the future course of research, and design interventions that effectively reduce CVD risk in various patient populations. This section describes features of the major analytic procedures used to assess HDL

HDL-targeted intervention studies in animals

Many studies have investigated the effects of increasing HDL concentration on atherosclerosis animal models. It should be emphasized, however, that all of these models have their limitations and that none is a true model for human disease. However, with this reservation, the animal studies have, with very few exceptions, provided powerful evidence that increasing HDL-C concentration does protect against atherosclerosis.

Badimon et al4 were the first to report direct antiatherogenic effects of

Dal-OUTCOMES

This was a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces CVD morbidity and mortality in patients with recent ACS. More than 15,000 patients, all of whom were being treated with statins to achieve recommended levels of LDL-C, were randomly assigned to receive dalcetrapib or matching placebo. The primary outcome was time to first occurrence of a composite CV end point. The trial was planned to continue

AIM-HIGH

This trial tested the hypothesis that treatment with niacin would reduce CVD events in statin-treated humans who had low levels of HDL-C. The rationale for AIM-HIGH was that niacin increases the level of HDL-C by up to 30% and also reduces the level of LDL-C by approximately 15%. When given as monotherapy, niacin has been shown to reduce clinical CVD events. Furthermore, when given in combination with a statin, niacin promotes regression of atherosclerosis as assessed by measuring cIMT.

AIM-HIGH

Intravenous infusion of reconstituted HDLs

rHDL-like particles consist of complexes of phospholipids with the main HDL apolipoprotein, apoA-I. Intravenous infusions of rHDLs have been shown consistently in a variety of animal models to inhibit experimental atherosclerosis.5, 88 Two proof-of-concept studies suggest a similar antiatherogenic effect of infusing rHDLs into humans.9, 10

ApoA-IMilano is a mutant form of apoA-I that was discovered in Italian families with low HDL-C but apparently decreased CV risk. In a small study in humans

Role of HDL in RCT

Plasma levels of HDL-C are inversely associated with incident CAD and CVD events such as MI and mortality. This highly consistent observation led to the HDL hypothesis that interventions to raise HDL-C will result in reduced risk of CAD. However, recent findings have raised serious questions about the validity of this hypothesis or the emphasis on whole body cholesterol excretion vs a focus on macrophage cholesterol efflux.73 A number of genetic polymorphisms associated with HDL-C have no

HDL consensus summary of conclusions and recommendations

  • A.

    Epidemiology

    • 1.

      Low serum levels of HDL-C have been found repeatedly to be the best predictor of CHD in observational studies, especially in men older than 50 years. After adjustment for established covariates, high levels of HDL-C in general correlate with low risk, whereas low levels correlate with higher risk of CHD. This is established from cohorts around the world and independent of race, ethnicity, and sex. However, most studies did not adjust for LDL particle concentration or apoB levels

Acknowledgments

Each author contributed in writing this consensus statement and each is responsible for the content. The chair (Dr Toth) and co-chairs (Drs Barter and Rosenson) were also responsible for reviewing and editing throughout the development of this article. We thank Mary R. Dicklin, PhD, Chad C. Cook, PhD, and Kevin C. Maki, PhD, with Biofortis Clinical Research for providing editorial assistance. The paper “High-Density Lipoproteins: A Consensus Statement from the National Lipid Association” has

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  • Cited by (0)

    The paper, ‘‘High-density lipoproteins: A consensus statement from the National Lipid Association” has been endorsed by the American Society for Preventive Cardiology, the International Atherosclerosis Society, the Association of Black Cardiologists and the Preventive Cardiovascular Nurses Association.

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