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HDL cholesterol: Clinical aspects of abnormal values

Authors
Robert S Rosenson, MD
Paul Durrington, MD
Section Editor
Mason W Freeman, MD
Deputy Editors
Howard Libman, MD, FACP
Gordon M Saperia, MD, FACC

INTRODUCTION

High-density lipoprotein (HDL) cholesterol is a biomarker inversely associated with an increased risk of coronary heart disease (CHD) events. It is of considerable use in assessing patients’ coronary artery disease risk. However, low levels of HDL cholesterol have not been established as causative of this increase in risk. (See 'Low HDL cholesterol as a CVD risk factor' below and 'Effect of increasing HDL cholesterol on clinical outcome' below.)

This topic will address clinical aspects of abnormal HDL (the particle) and HDL cholesterol. A more detailed discussion of the role of HDL in cholesterol metabolism is found elsewhere. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'High density lipoprotein' and "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'High density lipoprotein'.)

HDL VERSUS HDL CHOLESTEROL

High-density lipoprotein (HDL) is a complex circulating particle with many subspecies that vary in lipid and protein composition [1]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'High density lipoprotein'.)

Cholesterol is a major component of the particle and the amount of cholesterol contained in HDL particles can be directly measured; it is referred to as HDL cholesterol. In clinical practice, HDL cholesterol, rather than HDL, is used to risk stratify patients. (See "Measurement of blood lipids and lipoproteins", section on 'Total and HDL cholesterol'.)

LOW HDL CHOLESTEROL AS A CVD RISK FACTOR

The incidence of coronary heart disease (CHD) events in a multiple diverse population studies has been found to be inversely related to the serum high-density lipoprotein (HDL) cholesterol concentration, with low levels being associated with increased coronary risk (figure 1) [2-5]. Based on data from the Framingham Heart Study, the risk for myocardial infarction increases by about 25 percent for every 5 mg/dL (0.13 mmol/L) decrement in serum HDL cholesterol below median values for men and women [2]. Most of these studies have found that, after adjustment for other knows risk factors, a low level of HDL cholesterol is an independent predictor of risk. This does not mean, however, that it is causative of CHD. (See 'Low HDL cholesterol as a cause of CVD events' below.)

                     
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Literature review current through: Sep 2017. | This topic last updated: Oct 11, 2017.
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References
Top
  1. Rosenson RS, Brewer HB Jr, Chapman MJ, et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin Chem 2011; 57:392.
  2. Castelli WP. Cardiovascular disease and multifactorial risk: challenge of the 1980s. Am Heart J 1983; 106:1191.
  3. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993.
  4. Gordon DJ, Rifkind BM. High-density lipoprotein--the clinical implications of recent studies. N Engl J Med 1989; 321:1311.
  5. Rosenson RS. Low HDL-C: a secondary target of dyslipidemia therapy. Am J Med 2005; 118:1067.
  6. Sacks FM, Tonkin AM, Craven T, et al. Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors. Circulation 2002; 105:1424.
  7. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301.
  8. Acharjee S, Boden WE, Hartigan PM, et al. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). J Am Coll Cardiol 2013; 62:1826.
  9. van de Woestijne AP, van der Graaf Y, Liem AH, et al. Low high-density lipoprotein cholesterol is not a risk factor for recurrent vascular events in patients with vascular disease on intensive lipid-lowering medication. J Am Coll Cardiol 2013; 62:1834.
  10. Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992; 85:2025.
  11. Buring JE, O'Connor GT, Goldhaber SZ, et al. Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction. Circulation 1992; 85:22.
  12. Genest J Jr, McNamara JR, Ordovas JM, et al. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol 1992; 19:792.
  13. Kwiterovich PO Jr, Coresh J, Bachorik PS. Prevalence of hyperapobetalipoproteinemia and other lipoprotein phenotypes in men (aged < or = 50 years) and women (< or = 60 years) with coronary artery disease. Am J Cardiol 1993; 71:631.
  14. Genest J Jr, Bard JM, Fruchart JC, et al. Familial hypoalphalipoproteinemia in premature coronary artery disease. Arterioscler Thromb 1993; 13:1728.
  15. Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel. Circulation 1992; 86:839.
  16. Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation 2013; 128:1189.
  17. Mackey RH, Greenland P, Goff DC Jr, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol 2012; 60:508.
  18. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006; 113:1556.
  19. Rader DJ, Ikewaki K, Duverger N, et al. Very low high-density lipoproteins without coronary atherosclerosis. Lancet 1993; 342:1455.
  20. Funke H, von Eckardstein A, Pritchard PH, et al. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc Natl Acad Sci U S A 1991; 88:4855.
  21. Klein HG, Lohse P, Pritchard PH, et al. Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met). J Clin Invest 1992; 89:499.
  22. Bekaert ED, Alaupovic P, Knight-Gibson CS, et al. Apolipoprotein A-I Milano: sex-related differences in the concentration and composition of apoA-I- and apoB-containing lipoprotein particles. J Lipid Res 1993; 34:111.
  23. Sirtori CR, Calabresi L, Franceschini G, et al. Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation 2001; 103:1949.
  24. Ko DT, Alter DA, Guo H, et al. High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions: The CANHEART Study. J Am Coll Cardiol 2016; 68:2073.
  25. Liu X, Tao L, Cao K, et al. Association of high-density lipoprotein with development of metabolic syndrome components: a five-year follow-up in adults. BMC Public Health 2015; 15:412.
  26. Rana JS, Liu JY, Moffet HH, et al. Metabolic Dyslipidemia and Risk of Coronary Heart Disease in 28,318 Adults With Diabetes Mellitus and Low-Density Lipoprotein Cholesterol <100 mg/dl. Am J Cardiol 2015; 116:1700.
  27. Huxley RR, Barzi F, Lam TH, et al. Isolated low levels of high-density lipoprotein cholesterol are associated with an increased risk of coronary heart disease: an individual participant data meta-analysis of 23 studies in the Asia-Pacific region. Circulation 2011; 124:2056.
  28. Bartlett J, Predazzi IM, Williams SM, et al. Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights From the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes 2016; 9:206.
  29. Ahmed HM, Miller M, Nasir K, et al. Primary Low Level of High-Density Lipoprotein Cholesterol and Risks of Coronary Heart Disease, Cardiovascular Disease, and Death: Results From the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol 2016; 183:875.
  30. Rosenson RS. The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict? Arterioscler Thromb Vasc Biol 2016; 36:777.
  31. Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012; 125:1905.
  32. Haase CL, Tybjærg-Hansen A, Grande P, Frikke-Schmidt R. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab 2010; 95:E500.
  33. Haase CL, Tybjærg-Hansen A, Qayyum AA, et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab 2012; 97:E248.
  34. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380:572.
  35. Colantonio LD, Bittner V, Reynolds K, et al. Association of Serum Lipids and Coronary Heart Disease in Contemporary Observational Studies. Circulation 2016; 133:256.
  36. Rosenson RS, Brewer HB Jr, Ansell BJ, et al. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2016; 13:48.
  37. Vergeer M, Boekholdt SM, Sandhu MS, et al. Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. Circulation 2010; 122:470.
  38. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 2011; 17:594.
  39. Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351:1166.
  40. Glueck CJ, Gartside P, Fallat RW, et al. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med 1976; 88:941.
  41. Rubin EM, Krauss RM, Spangler EA, et al. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 1991; 353:265.
  42. Duverger N, Kruth H, Emmanuel F, et al. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation 1996; 94:713.
  43. Benoit P, Emmanuel F, Caillaud JM, et al. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. Circulation 1999; 99:105.
  44. Navab M, Anantharamaiah GM, Hama S, et al. 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.
  45. Ameli S, Hultgardh-Nilsson A, Cercek B, et al. Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation 1994; 90:1935.
  46. Tangirala RK, Tsukamoto K, Chun SH, et al. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999; 100:1816.
  47. Rosenson RS, Brewer HB Jr, Ansell B, et al. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation 2013; 128:1256.
  48. Oram JF, Johnson CJ, Brown TA. Interaction of high density lipoprotein with its receptor on cultured fibroblasts and macrophages. Evidence for reversible binding at the cell surface without internalization. J Biol Chem 1987; 262:2405.
  49. Kuhn FE, Mohler ER, Satler LF, et al. Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity. Am J Cardiol 1991; 68:1425.
  50. Kontush A, Chantepie S, Chapman MJ. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler Thromb Vasc Biol 2003; 23:1881.
  51. Soran H, Schofield JD, Liu Y, Durrington PN. How HDL protects LDL against atherogenic modification: paraoxonase 1 and other dramatis personae. Curr Opin Lipidol 2015; 26:247.
  52. Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL. Circ Res 2004; 95:764.
  53. Murphy AJ, Akhtari M, Tolani S, et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 2011; 121:4138.
  54. Saku K, Ahmad M, Glas-Greenwalt P, Kashyap ML. Activation of fibrinolysis by apolipoproteins of high density lipoproteins in man. Thromb Res 1985; 39:1.
  55. Griffin JH, Kojima K, Banka CL, et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest 1999; 103:219.
  56. Epand RM, Stafford A, Leon B, et al. HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. Arterioscler Thromb 1994; 14:1775.
  57. Aoyama T, Yui Y, Morishita H, Kawai C. Prostaglandin I2 half-life regulated by high density lipoprotein is decreased in acute myocardial infarction and unstable angina pectoris. Circulation 1990; 81:1784.
  58. Martin SS, Khokhar AA, May HT, et al. HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the Lipoprotein Investigators Collaborative. Eur Heart J 2015; 36:22.
  59. Khera AV, Demler OV, Adelman SJ, et al. Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 2017; 135:2494.
  60. Gotto AM Jr, Brinton EA. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol 2004; 43:717.
  61. Michael Gibson C, Korjian S, Tricoci P, et al. Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). Circulation 2016; 134:1918.
  62. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371:2383.
  63. Mody P, Joshi PH, Khera A, et al. Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction. J Am Coll Cardiol 2016; 67:2480.
  64. Nomura A, Won HH, Khera AV, et al. Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. Circ Res 2017; 121:81.
  65. Cohen JC, Kiss RS, Pertsemlidis A, et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305:869.
  66. Kasiske BL, Ma JZ, Kalil RS, Louis TA. Effects of antihypertensive therapy on serum lipids. Ann Intern Med 1995; 122:133.
  67. Wallace RB, Hunninghake DB, Reiland S, et al. Alterations of plasma high-density lipoprotein cholesterol levels associated with consumption of selected medications. The Lipid Research Clinics Program Prevalence Study. Circulation 1980; 62:IV77.
  68. Bagatell CJ, Heiman JR, Matsumoto AM, et al. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab 1994; 79:561.
  69. van Leeuwen HJ, Heezius EC, Dallinga GM, et al. Lipoprotein metabolism in patients with severe sepsis. Crit Care Med 2003; 31:1359.
  70. Khovidhunkit W, Kim MS, Memon RA, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res 2004; 45:1169.
  71. McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006; 54:2541.
  72. van Leuven SI, Hezemans R, Levels JH, et al. Enhanced atherogenesis and altered high density lipoprotein in patients with Crohn's disease. J Lipid Res 2007; 48:2640.
  73. Murali MR, Kratz A, Finberg KE. Case records of the Massachusetts General Hospital. Case 40-2006. A 64-year-old man with anemia and a low level of HDL cholesterol. N Engl J Med 2006; 355:2772.
  74. Vergani C, Bettale G. Familial hypo-alpha-lipoproteinemia. Clin Chim Acta 1981; 114:45.
  75. Glueck CJ, Daniels SR, Bates S, et al. Pediatric victims of unexplained stroke and their families: familial lipid and lipoprotein abnormalities. Pediatrics 1982; 69:308.
  76. Yamakawa-Kobayashi K, Yanagi H, Fukayama H, et al. Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey. Hum Mol Genet 1999; 8:331.
  77. Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 1999; 22:336.
  78. Emmerich J, Vergès B, Tauveron I, et al. Familial HDL deficiency due to marked hypercatabolism of normal apoA-I. Arterioscler Thromb 1993; 13:1299.
  79. Serfaty-Lacrosniere C, Civeira F, Lanzberg A, et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 1994; 107:85.
  80. Frikke-Schmidt R. Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population. Atherosclerosis 2010; 208:305.
  81. Rust S, Rosier M, Funke H, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999; 22:352.
  82. Marcil M, Brooks-Wilson A, Clee SM, et al. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet 1999; 354:1341.
  83. Lawn RM, Wade DP, Garvin MR, et al. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 1999; 104:R25.
  84. Bodzioch M, Orsó E, Klucken J, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22:347.
  85. Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451:904.
  86. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363:2220.
  87. Tato F, Vega GL, Grundy SM. Bimodal distribution of cholesteryl ester transfer protein activities in normotriglyceridemic men with low HDL cholesterol concentrations. Arterioscler Thromb Vasc Biol 1995; 15:446.
  88. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998; 338:86.
  89. Agerholm-Larsen B, Tybjaerg-Hansen A, Schnohr P, et al. Common cholesteryl ester transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease: The Copenhagen City Heart Study. Circulation 2000; 102:2197.
  90. Nordestgaard BG, Abildgaard S, Wittrup HH, et al. Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. Circulation 1997; 96:1737.
  91. Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation 1999; 99:2901.
  92. Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler Thromb 1993; 13:1227.
  93. Kuivenhoven JA, van Voorst tot Voorst EJ, Wiebusch H, et al. A unique genetic and biochemical presentation of fish-eye disease. J Clin Invest 1995; 96:2783.
  94. Abate N, Vega GL, Garg A, Grundy SM. Abnormal cholesterol distribution among lipoprotein fractions in normolipidemic patients with mild NIDDM. Atherosclerosis 1995; 118:111.
  95. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009; 338:b92.
  96. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410.
  97. Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001; 285:1585.
  98. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002; 90:22i.
  99. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583.
  100. Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000; 160:1177.
  101. Lavie CJ, Mailander L, Milani RV. Marked benefit with sustained-release niacin therapy in patients with "isolated" very low levels of high-density lipoprotein cholesterol and coronary artery disease. Am J Cardiol 1992; 69:1083.
  102. Vega GL, Grundy SM. Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia. Arch Intern Med 1994; 154:73.
  103. Zema MJ. Gemfibrozil, nicotinic acid and combination therapy in patients with isolated hypoalphalipoproteinemia: a randomized, open-label, crossover study. J Am Coll Cardiol 2000; 35:640.
  104. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255.
  105. Boekholdt SM, Arsenault BJ, Hovingh GK, et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation 2013; 128:1504.
  106. 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.
  107. Tardif JC, Grégoire J, L'Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007; 297:1675.
  108. Buitrago-Lopez A, Sanderson J, Johnson L, et al. Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis. BMJ 2011; 343:d4488.
  109. Baba S, Osakabe N, Kato Y, et al. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr 2007; 85:709.
  110. Neufingerl N, Zebregs YE, Schuring EA, Trautwein EA. Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial. Am J Clin Nutr 2013; 97:1201.
  111. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004; 350:1505.
  112. Forrester JS, Makkar R, Shah PK. Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians. Circulation 2005; 111:1847.
  113. Brewer HB Jr. Increasing HDL Cholesterol Levels. N Engl J Med 2004; 350:1491.
  114. Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res 2010; 51:3443.
  115. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011; 306:2099.
  116. Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2015; 386:452.
  117. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109.
  118. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009; 157:352.
  119. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010; 363:2406.
  120. HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med 2017; 377:1217.
  121. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002; 105:2159.
  122. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 2005; 95:1085.
  123. Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009; 104:82.
  124. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011; 378:1547.
  125. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009; 158:896.
  126. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367:2089.
  127. Tardif JC, Rhainds D, Brodeur M, et al. Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes. Circ Cardiovasc Genet 2016; 9:340.
  128. Cao G, Beyer TP, Zhang Y, et al. Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. J Lipid Res 2011; 52:2169.
  129. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med 2017; 376:1933.
  130. 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.
  131. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001; 104:3046.
  132. Gotto AM Jr, Whitney E, Stein EA, et al. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000; 101:477.
  133. 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.
  134. Colquhoun D, Keech A, Hunt D, et al. Effects of pravastatin on coronary events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results from the LIPID study. Eur Heart J 2004; 25:771.
  135. Moffatt RJ. Effects of cessation of smoking on serum lipids and high density lipoprotein-cholesterol. Atherosclerosis 1988; 74:85.
  136. Wood PD, Stefanick ML, Dreon DM, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med 1988; 319:1173.
  137. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med 1991; 325:461.
  138. Rahilly-Tierney CR, Spiro A 3rd, Vokonas P, Gaziano JM. Relation between high-density lipoprotein cholesterol and survival to age 85 years in men (from the VA normative aging study). Am J Cardiol 2011; 107:1173.
  139. Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003; 108:2751.
  140. Rosenson RS. Functional assessment of HDL: Moving beyond static measures for risk assessment. Cardiovasc Drugs Ther 2010; 24:71.
  141. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S1.
  142. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016; 37:2999.
  143. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 2014; 8:473.