The European Society of Cardiology
Is high-density lipoprotein the protector of the cardiovascular system?
The Heart Research Institute, Sydney, New South Wales, Australia
* Professor Philip Barter, MD, PhD, FRACP, Director, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, NSW 2050, Australia. Tel.: +61-295503560; fax: +61-295503302
p.barter{at}hri.org.au
Abstract
Low high-density lipoprotein (HDL-C) cholesterol is a powerful predictor of risk for coronary heart disease (CHD), and raising HDL-C reduces CHD risk, with available data indicating a 1% decrease in risk with each 1% increase in HDL-C. Both epidemiological and intervention studies have shown that HDL is predictive of risk independent of low-density lipoprotein cholesterol. In treatment trials, both fibrates and statins have been shown to reduce risk in patients with low HDL-C. Statins reduce risk across all HDL-C levels from low to high, whereas fibrates appear to have benefits limited to low HDL-C in the context of the metabolic syndrome. The primary management component of increasing HDL-C is lifestyle intervention focusing on diet, exercise and smoking cessation. Drug options for raising HDL-C include niacin (+10–30%), fibrates (+5–25%) and statins (+3–12%). Niacin is poorly tolerated. Fenofibrate may pose advantages over gemfibrozil among fibrates. Findings in the large-scale Statin Therapies for Elevated Lipid Levels compared Across dose ranges to Rosuvastatin (STELLAR) trial indicate that rosuvastatin has the best HDL-C raising effect among statins. Selection of therapy requires consideration of the individual patient’s overall risk profile.
Key Words: Coronary heart disease • High-density lipoprotein cholesterol • Low-density lipoprotein • Statins • Fibrate • Niacin
Introduction
High-density lipoprotein (HDL-C) level is a powerful negative predictor of future coronary heart disease (CHD) events. Low HDL-C levels predict CHD at all levels of low-density lipoprotein (LDL-C) in both men and women and in the presence or absence of diabetes.1–3 Findings in epidemiological studies indicate that each 1% increase in HDL-C equates with an approximately 1% decrease in CHD risk.4 The strength of HDL-C as an independent predictor of CHD risk is reflected in incorporation of this measure in lipid management guidelines. Although optimal levels remain to be clearly defined, Australian guidelines5 indicate a target of >1.0 mmol/l (40 mg/dl) and US guidelines incorporate elevated HDL-C as a factor offsetting overall risk and identify levels <1.0 mmol/l (40 mg/dl) as an important component in defining risk.6
Mechanisms of high-density lipoprotein protection
Putative mechanisms of HDL in protecting against atherosclerosis can be briefly summarized. LDL enters the arterial wall, with accumulating lipoprotein undergoing modification (e.g. oxidization). Modified LDL induces expression of monocyte chemotactic protein-1, which recruits monocytes into the artery wall and stimulates their differentiation into macrophages. Macrophage uptake of modified LDL results in formation of foam cells, the hallmark cell of atherosclerosis. Foam cells and macrophages release growth factors and metalloproteinases that lead to cell proliferation, extracellular matrix degeneration, atherosclerotic plaque instability and plaque rupture, the cause of myocardial infarction. Macrophages also release a variety of cytokines, including tumour necrosis factor-
and interleukin-1, that stimulate endothelial cells to express adhesion molecules that bind monocytes, making them available for recruitment. HDL promotes efflux of cholesterol from cells, including foam cells (Fig. 1). The HDL apolipoproteins (apos)A-I and A-II and paraoxanase, also carried by HDL, inhibit oxidative modification of LDL. HDL also inhibits endothelial cell expression of monocyte chemotactic protein-1 and has been shown to inhibit expression of adhesion molecules in endothelial cells. In addition to these effects on cholesterol efflux and the anti-oxidative and anti-inflammatory effects, HDL likely induces additional anti-thrombotic and anti-apoptotic effects that are protective of the vasculature.
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Direct evidence of the protective effects of HDL comes largely from animal studies. An initial report by Badimon et al.7 in 1990 showed that infusion of HDL into cholesterol-fed rabbits promoted regression of diet-induced atherosclerosis. Since that time, many studies have been performed documenting direct protective effects; these have included studies showing that overexpression of human apo A-I in transgenic mice and rabbits increases HDL concentration and markedly reduces susceptibility to atherosclerosis.
Administration of an HDL mimetic in humans was recently investigated in a pilot trial. The study used intravascular ultrasound to measure and compare the effect of intravenous recombinant apo A-I Milano/phospholipid complexes (ETC-216) or placebo on coronary atheroma burden. Infusions of 15 or 45 mg/kg were given in five weekly treatments. Compared with baseline, the mean (SD) percent atheroma volume decreased by –1.06% in the treatment group and increased by 0.14% in the placebo group. This regression was considered significant, promising enough for confirmation in larger clinical trials.8
High-density lipoprotein cholesterol in human intervention studies
Evidence from drug treatment trials is quite consistent with a protective effect of HDL. In the secondary-prevention Scandinavian Simvastatin Survival Study (4S) trial of simvastatin in hypercholesterolaemic patients, each 1% increase in HDL-C predicted a 1% decrease in coronary events independent of changes in LDL-C,9 a finding consistent with epidemiological data. Similarly, the Lipid Research Clinics Coronary Primary Prevention Trial of cholestyramine indicated that each 1% increase in HDL-C predicted a 1% decrease in coronary events independent of LDL-C changes.10
Data from the 4S show that simvastatin treatment reduced the risk of events in every quartile of HDL-C (Fig. 2).11 Similarly, data from the Heart Protection Study 12 of simvastatin in high-risk patients indicate that simvastatin treatment reduced risk in every tertile of HDL-C. There remains residual risk associated with low HDL-C under statin treatment, with low HDL-C remaining predictive of increased CHD risk in the statin treatment groups. Findings in the Helsinki Heart Study of gemfibrozil indicated that each 1% increase in HDL-C predicted a 3% decrease in coronary events independent of changes in LDL cholesterol.13 In contrast to effects under statin therapy, which substantially reduces risk in patients with higher as well as lower HDL-C, little benefit was observed with gemfibrozil treatment in patients with HDL-C
1.0 mmol/l (40 mg/dl). Analysis of findings in the Veterans Affairs High-density lipoprotein Intervention Trial (VA-HIT)14 of gemfibrozil indicate that the major effect of fibrate treatment is in patients with low HDL-C occurring as part of the metabolic syndrome, along with such other features of the syndrome as elevated triglycerides, obesity and insulin resistance. Overall, the lesson from treatment studies is that raising HDL-C reduces coronary risk, with statins reducing risk in all patients and fibrates reducing risk in those with low HDL-C and other features of the metabolic syndrome.
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Raising high-density lipoprotein cholesterol
The most important component in increasing HDL-C is lifestyle change, including weight reduction, increased physical activity and smoking cessation. Alcohol consumption also raises HDL-C, but is associated with a variety of other medical and non-medical problems except when consumption is moderate. Pharmacotherapy options include niacin, which may increase HDL-C by 10–30% but is poorly tolerated.15 Fibrates increase HDL-C by 5–25%. Statins increase HDL-C modestly but significantly by 3–12% and have the advantage of having marked beneficial effects on LDL-C and other lipid risk factors.
Among statins, those with better effects in raising HDL-C are simvastatin and rosuvastatin. The Statin Therapies for Elevated Lipid Levels compared Across dose ranges to Rosuvastatin (STELLAR) trial16 was a large-scale, open-label, randomized, multicentre trial comparing lipid effects of rosuvastatin, atorvastatin, simvastatin and pravastatin across their dose ranges over 6 weeks of treatment in 2431 patients. Rosuvastatin had the greatest effect in increasing HDL-C across the dose range, and atorvastatin had the least (Fig. 3). Mean changes in HDL-C were 7.7–9.6% with rosuvastatin 10–40 mg, 2.1–5.7% with atorvastatin 10–80 mg, 5.3–6.8% with simvastatin 10–80 mg and 3.2–5.6% with pravastatin 10–40 mg. Significant increases with rosuvastatin vs equal or higher doses of other statins were found in comparisons of: rosuvastatin 10 mg vs pravastatin 10 mg; rosuvastatin 20 mg vs atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20 and 40 mg; and rosuvastatin 40 mg vs atorvastatin 40 and 80 mg, simvastatin 40 mg and pravastatin 40 mg (all 
). Interestingly, while higher doses of atorvastatin confer a trade-off of reduced HDL-C benefit, this effect does not appear to be observed with rosuvastatin.17 In addition, rosuvastatin decreased LDL-C significantly more than the same and some higher doses of other statins.
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Conclusion
Low levels of HDL-C are associated with increased CHD risk, and increasing HDL-C reduces coronary risk. Lifestyle measures should be the first line of management for increasing HDL-C. Pharmacotherapy options include niacin, fibrates and statins. Fibrates appear to reduce risk preferentially in patients with low HDL-C in the setting of the metabolic syndrome, whereas statins reduce risk across all levels of HDL-C. Selection of appropriate therapy depends on the overall risk profile of individual patients.
References
- Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis. 1988;8:207–211
[Abstract/Free Full Text] - Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease. Prospective Cardiovascular Münster study. Am. J. Cardiol. 1992;70:733–737[CrossRef][Web of Science][Medline]
- Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. Am. J. Med. 1977;62:707–714[CrossRef][Web of Science][Medline]
- Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15
[Abstract/Free Full Text] - Lipid management guidelines – 2001. National Heart Foundation of Australia and The Cardiac Society of Australia and New Zealand. Med J Aust 2001;175 (suppl):S57–S88
- Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97
[Free Full Text] - Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J. Clin. Invest. 1990;85:1234–1241
- Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant apoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–2300
[Abstract/Free Full Text] - Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453–1460
[Abstract/Free Full Text] - Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351–64
- Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995;345:1274–5[Web of Science][Medline]
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22[CrossRef][Web of Science][Medline]
- Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA. 1988;260:641–651
[Abstract/Free Full Text] - Robins SJ, Collins D, Wittes JT, et al. VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001;285:1585–1591
[Abstract/Free Full Text] - Miller M. Niacin as a component of combination therapy for dyslipidemia. Mayo. Clin. Proc. 2003;78:735–742
[Abstract/Free Full Text] - Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am. J. Cardiol. 2003;92:152–160[Web of Science][Medline]
- Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active aterial disease. Am. J. Cardiol. 2003;91:33–41
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