High-density lipoprotein cholesterol as a therapeutic target to reduce cardiovascular events
Article Outline
See related article on page 966.
The benefits of reducing low-density lipoprotein (LDL) cholesterol levels for the prevention and treatment of atherosclerosis are well established.1, 2, 3 A number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of LDL cholesterol level reducing therapy, with a significant reduction in fatal and nonfatal cardiovascular events.1, 2 These studies have primarily targeted LDL cholesterol through pharmacotherapy (most effectively with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [statins]), with or without lifestyle modification, or surgery.2 Overall, significant and clinically relevant risk reductions ranging from 20% to 42% in major cardiovascular events have been achieved with these strategies, without increased noncardiovascular mortality rates.1, 2, 3 The cardiovascular benefits of LDL cholesterol level reducing therapies extend to men and women, old and young, diabetic and nondiabetics, and even to patients with baseline LDL-cholesterol levels <100 mg/dL.3 Current national and international guidelines identify the reduction of LDL cholesterol levels as the primary target for cardiovascular risk reduction therapy.2, 4
Although LDL is currently recognized as the major atherogenic lipoprotein and the primary target of lipid-lowering therapy, other lipoprotein species appear to be involved in atherogenesis.5 These include very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and high-density lipoproteins (HDL). In the quest to further reduce the risk of major coronary events and stroke, other therapeutic strategies have been sought, and the field of preventative cardiology has been turning attention to the other lipoproteins that appear to be involved in atherosclerosis, especially HDL.5
Prospective epidemiological studies have shown that there is a strong inverse relationship between HDL cholesterol levels and coronary heart disease (CHD).6, 7 This cardiovascular risk associated with low HDL cholesterol levels has been shown to be independent of LDL levels, other lipid parameters, and other nonlipid cardiovascular risk factors.6, 7 These studies established that risk for CHD decreases by 2% to 3% for each 1 mg/dL increase in HDL cholesterol levels, after correction for other CHD risk factors. Similarly, an inverse relationship has also been demonstrated between the levels of apolipoprotein A-I, the major structural protein component of HDL, and CHD.8 The prevalence of HDL deficiency (<35 mg/dL) in men with premature coronary artery disease (CAD) reaches as high as 40%.9
Experimental studies have demonstrated antiatherogenic properties of HDL, including anti-inflammatory, antioxidative, anti-aggregatory, anticoagulant, and profibrinolytic activities.10 HDL has been shown to inhibit chemotaxis of monocytes, adhesion of leucocytes to the endothelium, endothelial dysfunction, LDL oxidation, complement activation, and platelet activation.10 There is evidence to suggest that oxidative modification of LDL trapped in the vessel wall is critical for the stimulation of proinflammatory genes that are critical for inflammatory cell recruitment and the initiation and progression of atherosclerosis.11 Therefore, the ability of HDL to inhibit LDL oxidation in the vessel wall may translate into a potent anti-inflammatory and antiatherogenic effect. HDL also stimulates production of prostacyclin, proliferation of endothelial cells and smooth muscle cells, and activation of proteins C and S.10 Transgenic manipulation of HDL metabolism has been shown to protect susceptible animals from atherosclerosis. The overexpression of the human apolipoprotein A-I gene increases HDL cholesterol levels and markedly attenuates atherosclerosis in transgenic atherosclerosis prone rabbits and mice, despite significant hypercholesterolemia.12 In addition, adenovirus-mediated apolipoprotein A-I gene transfer inhibits the progression of atherosclerosis in genetically hyperlipidemic apolipoprotein E-null mice.13 Treatment with an oral apolipoprotein A-1 mimetic peptide reduced atherosclerotic lesion area by 79% in LDL receptor-null mice receiving a Western diet and by 75% in apolipoprotein E-null mice.14 Thus, there is evidence from several lines of investigations that suggests that low HDL cholesterol levels directly play a role in the atherosclerosis disease process. Together, this research makes HDL a very promising target for pharmacological intervention in atherosclerosis.
However, beneficial effects of increasing HDL levels on cardiovascular outcomes in patients have not been established. Low HDL cholesterol levels are often associated with other risk factors, including diabetes, insulin resistance, obesity, physical inactivity, genetic factors, and high blood pressure, raising the possibility that these factors, instead of a low HDL cholesterol level itself, is primarily responsible for the observed relationship with cardiovascular events.5 Some genetic mutations in apolipoprotein A-I produce low HDL levels without a corresponding increased risk for atherosclerosis, and some mutations in cholesterol ester transfer protein (CETP) cause an increase in HDL level without conferring a protective effect against atherosclerosis.10 There have been no reports of clinical trials designed specifically to determine whether raising the level of the total HDL fraction, or specific HDL subpopulations, results in a reduced incidence of CHD.
Circulating HDL levels can be increased directly by increasing the synthesis of apolipoprotein A-I, by inhibiting the clearance of apolipoprotein A-I, or both.10 HDL levels have been shown to increase with regular aerobic exercise, modest alcohol consumption, weight loss, a high-fat diet, and smoking cessation.2 HDL levels decrease with smoking, obesity, menopause, and high-carbohydrate diets.2 Pharmacological agents that increase HDL include statins, niacin, fibric acid derivatives, phenytoin, and hormone replacement therapy.2 However, the magnitude of HDL level elevationwith clinically available drug therapy is generally small and highly variable.
In this issue of the Journal, Dean et al make an important contribution to this area of research.15 They have performed a comprehensive systematic review of the clinical trials reporting changes in HDL levels, LDL levels, and clinical events. Observed CHD risk reductions were compared with those predicted by changes in total and LDL cholesterol levels alone. Despite including 51 trials, which involved tens of thousands of patients, changes in HDL cholesterol levels were not a significant linear predictor of the difference between observed and expected CHD mortality rates (on the basis of changes in total and LDL cholesterol levels alone).15 Although the number of trials evaluating nonstatin lipid modifying therapy was limited, no significant relationship between HDL levels and difference between observed and expected CHD events could be demonstrated.15
Should this negative analysis be taken as evidence that HDL level raising therapy is of no benefit in reducing cardiovascular events? As the authors point out, there are significant limitations to this study. Most notably, the studies of currently available agents produced small changes in HDL level, generally <10%.15 Despite epidemiologic relationships, more robust changes in HDL levels will likely be required to demonstrate cardiovascular risk reduction. It is worth recalling that many physicians remained unconvinced about the benefits of LDL level reduction therapy with early clinical trials (with small reductions in LDL levels and CHD events) until trials with statins produced robust reductions in LDL levels and resulting robust CHD risk reductions.2, 16 Also because of the complexity of lipid metabolism, it is difficult to isolate the effects of HDL levels on CHD risk with current lipid modifying therapies that impact multiple parameters. The method of assessing differences between observed and expected CHD risk as used in this study may be too insensitive to detect a significant impact of changes in HDL levels. This study analyzed entire trial means for changes in HDL levels from baseline rather than individual patient level data. It is entirely possible that increases in HDL levels in individual patients in these trials would be linearly related to reduction in CHD risk.
Another potential explanation for the negative findings is that quantitative changes in HDL levels as measured in this analysis do not fully reflect the change in atherogenicity of therapeutic alterations in HDL levels.10 Steady-state HDL levels are a static measure and may not fully reflect the actual efficiency of cholesterol fluxes between tissues and reverse cholesterol transport. The antiatherogenic effects of reverse cholesterol transport may be better assessed by the flow of cholesterol through this pathway than by the mere concentration of HDL.10 The size and composition of HDL may significantly affect its function and vascular protective effects. Qualitative function of HDL may be a better measure than quantitative levels of atherogenic potential. Navab et al demonstrated that during the acute phase response HDL loses its paroxonase and apolipoprotein A-I content and becomes pro-oxidant and proinflammatory.11 Patients with angiographically proven CAD, reference range LDL levels, and quantitatively high HDL levels and no other risk factors had HDL that was dysfunctional in preventing the formation and inactivation of oxidized phospholipids in comparison with that of control HDL.11 Thus, the qualitative function of HDL and the molecular mechanisms by which HDL levels are altered likely significantly influence the biological function and vascular protective effects of HDL.
A number of exciting agents to impact HDL and apolipoprotein A-I are currently in various stages of clinical trials.17 Direct administration of plasma-derived apolipoprotein A-I, reconstituted HDL containing recombinant apolipoprotein A-IMilano (a mutant form of apolipoprotein A-I), or their synthetic mimetics are being tested.17 Medications that activate specific subtypes of nuclear hormone receptors, particularly the rexinoids, have entered clinical trials. Pharmacologic therapy to enhance the expression, activity, or both of hepatic HDL scavenger receptors represents a novel strategy for augmenting reverse cholesterol transport. HDL therapy may also have an acute therapeutic application to treat cardiovascular disease at the site of the vulnerable, unstable atherosclerotic plaque.17 Single high-dose infusions and repeated injections of lower doses of apoA-I variants or mimetics complexed to phospholipids have produced remarkable effects on the progression and regression of atherosclerosis in animal models.14, 17 The positive results of these studies have lead to clinical trials testing the hypothesis and the potential use of synthetic HDL as a new treatment modality for acute coronary syndromes. Nissen et al recently reported that ApoA-I milano/phospholipids complex (ETC-216, Esperion Therapeutics, Ann Arbor, Mich) administered intravenously for 5 doses at weekly intervals in patients with acute coronary syndrome produced statistically significant regression in coronary atheroma volume in the target segment compared with baseline measurements with intravascular ultrasound scanning (IVUS), whereas no change was seen with saline placebo control.18 This study provides the best example to date that directly targeting HDL can have an impact on atherosclerosis in humans.
Thus, a wealth of epidemiologic and experimental data has demonstrated that HDL produces significant cardiovascular protective effects. Qualitative HDL function measurements may be crucial in evaluating these effects. Elevations in HDL levels through statins, niacin, fibrates, lifestyle changes, or combination therapy may not be adequate to achieve significant cardiovascular risk reduction. Despite the lack of compelling clinical outcome trials to date, new therapies that substantially raise HDL levels and enhance function will likely prove to be to be important therapeutic agents for reducing cardiovascular risk. However, many unanswered questions that require testing in prospective randomized clinical trials remain.
References
- . Effect of statins on risk of coronary disease (a meta-analysis of randomized controlled trials). JAMA. 1999;282:2340–2346
- . 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;285:2486–2497
- . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals (a randomised placebo-controlled trial). Lancet. 2002;360:7–22
- Prevention of coronary heart disease in clinical practice (recommendations of the second joint task force of European and other societies on coronary prevention). Eur Heart J. 1998;19:1434–1503
- . Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy. Circulation. 2002;106:2526–2529
- Incidence of coronary heart disease and lipoprotein cholesterol levels (the Framingham Study). JAMA. 1986;256:2835–2838
- . Twelve-year incidence of coronary heart disease in middle-age adults during the era of hypertensive therapy (the Framingham offspring study). Am J Med. 1991;90:11–16
- Associations of lipoprotein cholesterols, apolipoproteins A-I and B, and triglycerides with carotid atherosclerosis and coronary heart disease (the Atherosclerosis Risk in Communities (ARIC) study). Arterioscler Thromb. 1994;14:1098–1104
- . The epidemiology of low levels of high-density lipoprotein cholesterol in patients with and without coronary artery disease. Am J Cardiol. 2000;86:11–14L
- Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins (an idea whose time for testing is coming, part I). Circulation. 2001;104:2376–2383
- HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol. 2001;21:481–488
- . Human apolipoprotein A-I gene expression increases high-density lipoprotein and suppresses atherosclerosis in the apolipoprotein E- deficient mouse. Proc Natl Acad Sci U S A. 1994;91:9607–9611
- Effects of adenovirus-mediated human apo A-I gene transfer on neointima formation after endothelial denudation in apo E-deficient mice. Circulation. 1997;96:4349–4356
- Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105:290–292
- Dean BB, Borenstein JE, Henning JM, et al. Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk? Am Heart J 2004;147:966–76
- . The ALLHAT lipid lowering trial—less is less. JAMA. 2002;288:3042–3044
- Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins (an idea whose time for testing is coming, part II). Circulation. 2001;104:2498–2502
- Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes (a randomized controlled trial). JAMA. 2003;290:2292–2300
PII: S0002-8703(04)00052-3
doi:10.1016/j.ahj.2004.01.014
© 2004 Elsevier Inc. All rights reserved.
