Coronary heart disease remains the leading cause of death globally despite the use of statin therapy. Although major statin studies suggest an average 31% reduction in relative risk of coronary events, a residual risk of 69% remains to be addressed. (1) The search for a medical therapy to ameliorate residual risk has become the holy grail of cardiologists and pharmaceutical companies alike. While high-density lipoprotein cholesterol levels (HDL) independently predict cardiovascular disease risk, interventions to raise circulating HDL levels have thus far been unsuccessful in reducing the risk of coronary heart disease. (2)
When controlling for LDL cholesterol, the odds of coronary heart disease fall by about 40% per 7.5 milligram per deciliter rise in HDL cholesterol (3). While this translates to a fall in major adverse cardiovascular events by about 1.1% for each 1 milligram per deciliter rise in HDL cholesterol when LDL cholesterol is 70 mg/dL, attempts at raising HDL cholesterol with pharmacotherapy in the post-statin era have not produced a similar risk reduction. (4)
HDL is a complex molecule with anti-oxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, which help protect LDL from oxidation. Each HDL particle carries between two and five molecules of apolipoprotein A1 (ApoA-I), over 80 proteins, and hundreds of lipid moieties, with many molecules containing antioxidant and antithrombotic properties (5-7).
There are multiple mechanisms by which HDL mitigates the process of atherogenesis, but the efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be central in reducing major adverse cardiovascular events. In macrophages in atherosclerotic lesions, enlargement of intracellular lipid droplets occurs when cholesterol delivery and storage is greater than cholesterol removal, promoting transformation into foam cells. HDL participates in cholesterol efflux via reverse cholesterol transport, relocating cholesterol from peripheral cell membranes via scavenger receptor class B type 1 to hepatocytes centrally. (8) ATP-binding cassette transporter A-1, present in macrophages, the liver, and the intestine, actively transports cholesterol to lipid-poor apolipoprotein A-I particles carried on HDL. In addition, HDL has a major effect on endothelial function, promotes endothelial repair and progenitor cell health, and also supports production of nitric oxide. (7)
There are several well-known examples in which HDL cholesterol levels have been raised without conferring cardio-protection. In preclinical studies, overexpression of hepatic ATP-binding cassette transporter A-1 in an animal model result in higher HDL cholesterol levels, but impaired HDL function and accelerated atherosclerosis. (9) Cholesteryl ester transfer protein (CETP) deficiency from mutations in the CETP gene also increases HDL cholesterol, but evidence varies about their protection against atherosclerosis. Conversely, patients with a specific genetic ezyme deficiency (lecithin cholesterol acyltransferase) or mutations within the ApoA-I gene resulting in hypo-function of apolipoprotein A-I secretion have marked HDL cholesterol deficiency but do not necessarily develop atherosclerosis at a higher rate than normal patients. (10)
HDL augmentation with pharmacotherapy has been wrought with both equivocal and negative studies. Specifically, raising HDL with estrogen (11, 12), fibrates (13, 14), niacin, or CETP inhibitors (15) has not improved outcomes, and in some cases increased adverse events. After the equivocal AIM-HIGH trial of niacin, the HPS2-THRIVE trial showed that among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant did not significantly reduce the risk of MCVE and actually increased the risk of serious adverse events when compared to statin-based LDL cholesterol-lowering therapy alone (16). CETP inhibitors as a class have variable efficacy in raising HDL levels and conferring cardio-protection, and additionally have shown some evidence for increased harm. (15, 17-19)
The fact remains that when LDL cholesterol is aggressively lowered, low HDL cholesterol levels are inversely related to major coronary vascular events. Raising HDL cholesterol has been a major target in the quest to reduce residual cardiovascular risk in the post-statin era; however raising HDL with pharmacotherapy has not meaningfully effected clinical endpoints and in some cases produced harm. There is a growing impression that HDL functionality, rather than abundance, is clinically important. (7) HDL efflux capacity has been inversely associated with both prevalent and incident cardiovascular disease risk, independent of established cardiovascular risk factors, even after adjusting for HDL cholesterol or apoA-I concentrations, and is an area of active research in the field of lipidology. (20-23)
For now, we should continue using validated risk models to prescribe statin therapy to those who need it and encourage our patients to attempt to raise their HDL levels through diet and exercise.
Dr. Kerrilynn Carney is a 2nd year resident at NYU Langone Medical Center
Peer reviewed by Alana Choy-Shan, MD, Cardiology, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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- Feng Y, Lievens J, Jacobs F, Hoekstra M, Van Craeyveld E, Gordts SC, Snoeys J, et al. Hepatocyte-specific ABCA1 transfer increases HDL cholesterol but impairs HDL function and accelerates atherosclerosis. Cardiovasc Res 2010;88:376-385.
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- Saleheen D, Scott R, Javad S, Zhao W, Rodrigues A, Picataggi A, Lukmanova D, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol 2015;3:507-513.
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