R3i Editorial

Undoubtedly, a low plasma level of high-density lipoprotein (HDL) cholesterol, a surrogate measure of HDL subpopulations, is an independent cardiovascular risk factor, as recognised by the recent ESC/EAS guidelines for dyslipidemia management.(1 )
Population studies have conclusively shown that HDL cholesterol is an inverse predictor of cardiovascular risk, at all levels of low-density lipoprotein cholesterol.(2)
However, the concept that raising HDL cholesterol levels will translate to clinical benefit is too simplistic. This was highlighted in a recent post on the R3i website focusing on the demise of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib. Consequently, improving the functionality of HDL is increasingly viewed as an important target in residual vascular risk.

Potentially atheroprotective biological activities of HDL, including a role in cellular cholesterol efflux, and anti-oxidative and anti-inflammatory effects, have been described in animal models.(3) However, the presence of prolonged inflammation and oxidative stress associated with atherosclerosis can modify HDL functionality, shifting the balance in favour of atherogenesis. For example, HDL from patients with stable coronary heart disease or acute coronary syndrome exhibit attenuated endothelial repair capacity, as well as reduced anti-inflammatory activity, compared with HDL from healthy individuals.(4) These decreases in HDL functionality may predispose to the development and progression of cardiovascular disease.

HDL anti-atherogenic function is also defective in diabetes. Prolonged hyperglycaemia is thought to promote the formation of HDL that are ‘pro-inflammatory’, and less able to inhibit monocyte migration induced by LDL.(5) Studies have shown that glycation of paraoxonase-1 (PON-1), an anti-oxidant enzyme associated with HDL, inhibits its ability to decrease endothelial cell production of monocyte chemotactic protein-1 (MCP-1) and thus prevent monocyte adhesion, one of the earliest stages of atherosclerosis. PON-1 levels are also substantially lower in individuals with diabetes and CHD.(6)

The mechanisms underlying these changes in HDL functionality are not yet clear, although some have suggested that HDL remodelling and/or changes in the protein and/or lipid composition of HDL may play a role. Additionally, which of the atheroprotective function(s) of HDL are more relevant to cardiovascular risk is not certain, although a recent study has implicated cellular cholesterol efflux capacity as an independent predictor of coronary heart disease risk.(7)

What is the relevance of HDL functionality to residual cardiovascular risk?

Statin therapy has been shown to improve HDL anti-atherogenic functionality in individuals with cardiovascular disease. Despite this, HDL function is still defective compared with controls.(8)

Thus, from the perspective of the R3i, strategies that are able to both normalise defective HDL function, as well as lower elevated levels of triglyceride-rich lipoproteins, might represent a complementary approach to reducing residual vascular risk.

Of the available pharmacological treatments, peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) offer specific advantages beyond enhancing HDL-mediated reverse cholesterol transport, given their pleiotropic effects, including anti-inflammatory activity, particularly in individuals with type 2 diabetes or metabolic syndrome. Niacin has also been shown to protect against experimentally induced endothelial dysfunction and inhibit vascular inflammation, independent of changes in plasma lipid levels.(9) However, the role of niacin in reducing residual cardiovascular risk has recently been questioned, given the lack of benefit reported with combination statin-niacin treatment in AIM-HIGH.(10)

For the future, there are a number of possibilities that might offer potential to improve defective HDL functionality, with or without lowering triglyceride-rich lipoproteins. In the acute coronary syndrome setting, apolipoprotein (apo) A-I mimetics and reconstituted HDL may offer promise for improving HDL number and /or functionality, although these do not target apoB-containing lipoproteins. CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression?), the first trial with one of these agents, CER-001, a first in class pre-beta HDL mimetic, is expected to report at AHA later this year.

No doubt the debate regarding the relevance of targeting HDL quality, together with lowering triglycerides, to reduce residual vascular risk will continue until we have data from ongoing clinical trials.


References

1. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
2. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
3. Rye KA, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res 2009;50 (Suppl):S195-S200.
4. Besler C, Heinrich K, Rohrer L, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693-708.
5. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidaemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58:342-74.
6. Elboudwarej O, Hojjat H, Safarpoor S et al. Dysfunctional HDL and cardiovascular disease risk in individuals with diabetic dyslipidemia. J Diabetes Metab 2011;doi:10.4172/2155-6156.
7. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.
8. Ansell BJ, Navab M, Hama S et al. Inflammatory/antiiflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favourably affected by simvastatin treatment. Circulation 2003;108:2751-6.
9. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: Pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 2010;126:314–45.
10. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.