Perspective:

This article is the second in a series on lipids and cardiovascular disease (CVD). The following are 10 points to remember about high-density lipoprotein (HDL) and CVD:

1. HDL remains a consistent predictor of risk, and has been included in risk scores including those from American College of Cardiology/American Heart Association and the European guidelines. Currently, there are not enough data to support the routine use of additional measures related to HDL such as apoA1 or HDL in the clinical setting.

2. However, it remains unclear whether therapies to increase HDL are clearly associated with reductions in CVD events. Much has been learned from the study of Mendelian disorders of low HDL as well as high HDL. The three Mendelian disorders causing primary extreme low HDL include mutations in apoA-I, ABCA1, and LCAT. Among patients with Tangier disease (due to ABCA1 mutations) who have extremely low plasma HDL and apoA-I concentrations, the occurrence of premature coronary heart disease (CHD) is not common. A variant of endothelial lipase (LIPG), which is associated with elevated HDL levels, has been found not to be associated with lower risk for CHD.

3. In addition to human genetics, reports from randomized clinical trials have not supported various therapies that raise HDL. Niacin, which has been used for decades, has not been found to reduce CVD events in the era of statin use. Both AIM-HIGH and HPS2-THRIVE trials did not demonstrate reductions in CVD events among patients already on statins.

4. Cholesteryl ester transfer protein (CETP) inhibitors also have not demonstrated a reduction in events, despite raising HDL levels. The ILLUMINATE trial was stopped prematurely due to increased CHD events and total mortality in patients who were being randomized to torcetrapib plus standard statin treatment. Similarly, the dal-OUTCOMES trial, which examined use of dalcetrapib in patients who had acute coronary syndrome, was ended prematurely for futility.

5. HDL metabolism is complex. Both the liver and intestine synthesize and secrete apoA-1, which then acquires lipids via the ABCA1 transporter, thereby forming a nascent HDL particle. Additional lipids and apolipoproteins are added to the nascent HDL from hydrolysis of triglyceride risk lipoproteins. The enzyme lecithin cholesteryl acyl transferase (LCAT) acts on cholesterol in nascent HDL particles to generate cholesteryl ester, which forms the core of the mature HDL particle. Clearance of the cholesteryl ester (from HDL) can occur through uptake in the liver of steroidogenic tissues or through transfer to apoB-containing lipoproteins (by CETP). Hence, HDL metabolism is a complex interaction of various enzymes, receptors, and proteins, resulting in HDL particles of various sizes, density, and composition.

6. Emerging data suggest that HDL level is not as important as the function of HDL. Most studies have reported only a slight correlation between HDL cholesterol efflux capacity and HDL cholesterol concentration, suggesting that HDL cholesterol concentration does not predict the ability of an individual’s HDL to promote macrophage cholesterol efflux. Thus, new methods to measure HDL cholesterol efflux may help further understanding of the relationship of HDL to CVD risk.

7. Further research on therapies to influence HDL includes two CETP inhibitors (anacetrapib and evacetrapib), which are effective in raising HDL-C, but also appear to promote cholesterol efflux capacity. These drugs also appear to lower LDL-C and Lp(a) levels.

8. Additional therapies that are being explored include infusion of apoA-I containing recombinant HDL particles or of lipid-poor HDL particles and use of recombinant apoA-I–phospholipid particles.

9. Efforts to influence or up-regulate efflux pathways through up-regulation of ABCA1 and ABCG1 in macrophages are also ongoing. Alternatively, the reduction of ABCA1 and ABCG1 expression in macrophages may also promote cholesterol efflux.

10. The authors concluded that HDL cholesterol is a highly effective biomarker for predicting CV risk. However, the classic HDL hypothesis defined as the concept that intervention to raise HDL cholesterol concentrations will reduce CV risk is questionable and is increasingly difficult to defend in its simplest form. The HDL cholesterol hypothesis is gradually being replaced by the HDL function hypothesis, but much research is needed before clinically effective therapies are in use.