Current Cardiology Reports

, Volume 10, Issue 6, pp 488–496 | Cite as

When high is low: Raising low levels of high-density lipoprotein cholesterol



Low serum levels of high-density lipoprotein cholesterol (HDL-C) are highly prevalent and are recognized as an independent risk factor for cardiovascular morbidity (myocardial infarction, stroke, peripheral arterial disease, and restenosis after coronary stenting) and mortality. HDL plays an important role in modulating atherogenesis, although its functions are varied and complex and the mechanisms for its antiatherogenic effects have not been completely elucidated. The inverse relationship between HDL-C and cardiovascular risk is well established, and epidemiologic studies and clinical trials have provided ample evidence that higher levels of HDL-C are vasculoprotective. Although considerable interest exists in the development of novel approaches to raise serum HDL-C and to augment HDL functionality, this article discusses currently available therapies to raise suboptimal levels of this important lipoprotein.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): 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). Final report. Circulation 2002, 106:3143–3421.Google Scholar
  2. 2.
    Gordon T, Castelli WP, Hjortland MC, et al.: High-density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977, 62:707–714.PubMedCrossRefGoogle Scholar
  3. 3.
    Gordon T, Kannel WB: Multiple risk functions for predicting coronary heart disease: the concept, accuracy, and application. Am Heart J 1982, 103:1031–1039.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldbourt U: Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year followup of 8000 men. Arterioscler Thromb Vasc Biol 1997, 17:107–113.PubMedGoogle Scholar
  5. 5.
    Shai I, Rimm EB, Hankinson SE, et al.: Multivariate assessment of lipid parameters as predictors of coronary heart disease among postmenopausal women: potential implications for clinical guidelines. Circulation 2004, 110:2824–2830.PubMedCrossRefGoogle Scholar
  6. 6.
    Packard CJ, Ford I, Robertson M, et al.: Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation 2005, 112:3058–3065.PubMedCrossRefGoogle Scholar
  7. 7.
    Olsson AG, Schwartz GG, Szarek M, et al.: Effects of high-dose atorvastatin in patients >= 65 years of age with acute coronary syndrome (from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering [MIRACL] study. Am J Cardiol 2007, 99:632–635.PubMedCrossRefGoogle Scholar
  8. 8.
    Barter P, Gotto AM, LaRosa JC, et al.: HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007, 357:1301–1310.PubMedCrossRefGoogle Scholar
  9. 9.
    Toth PP: Novel therapies for increasing serum levels of HDL. Endocrinol Metab Clin North Am 2008 (in press).Google Scholar
  10. 10.
    Nicholls SJ, Tuzcu EM, Sipahi I, et al.: Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007, 297:499–508.PubMedCrossRefGoogle Scholar
  11. 11.
    Brown BG, Stukovsky KH, Zhao XQ: Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials. Curr Opin Lipidol 2006, 17:631–636.PubMedCrossRefGoogle Scholar
  12. 12.
    Ford ES: Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the US. Diabetes Care 2005, 28:2745–2749.PubMedCrossRefGoogle Scholar
  13. 13.
    Nigam A, Bourassa MG, Fortier A, et al.: The metabolic syndrome and its components and the long-term risk of death in patients with coronary heart disease. Am Heart J 2006, 151:514–521.PubMedCrossRefGoogle Scholar
  14. 14.
    Mooradian AD, Haas MJ, Wong NC: Transcriptional control of apolipoprotein A-I gene expression in diabetes. Diabetes 2004, 53:513–520.PubMedCrossRefGoogle Scholar
  15. 15.
    Toth PP: High-density lipoprotein: epidemiology, metabolism, and antiatherogenic effects. Dis Mon 2001, 47:369–416.PubMedCrossRefGoogle Scholar
  16. 16.
    Sacks FM: The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations. Am J Cardiol 2002, 90:139–143.PubMedCrossRefGoogle Scholar
  17. 17.
    American College of Physicians: Guidelines for using serum cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as screening tests for preventing coronary heart disease in adults. Ann Intern Med 1996, 124:515–517.Google Scholar
  18. 18.
    American Diabetes Association: Dyslipidemia management in adults with diabetes. Diabetes Care 2004, 27(Suppl 1):S68–S71.Google Scholar
  19. 19.
    American Heart Association: Cholesterol levels. AHA Recommendation. Available at Accessed June 4, 2008.
  20. 20.
    Ascaso JF, Fernández-Cruz A, González Santos P, et al.: Significance of high density lipoprotein-cholesterol in cardiovascular risk prevention: recommendations of the HDL Forum. Am J Cardiovasc Drugs 2004, 4:299–314.PubMedCrossRefGoogle Scholar
  21. 21.
    Chapman MJ, Assmann G, Fruchart JC, et al.: Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid-a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004, 20:1253–1268.PubMedCrossRefGoogle Scholar
  22. 22.
    Wood D, De Backer G, Faergeman O, et al.: Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998, 140:1434–1503.CrossRefGoogle Scholar
  23. 23.
    Toth PP: Reverse cholesterol transport: high-density lipoprotein’s magnificent mile. Curr Atheroscler Rep 2003, 5:386–393.PubMedCrossRefGoogle Scholar
  24. 24.
    Toth PP, Davidson MH: Therapeutic interventions targeted at the augmentation of reverse cholesterol transport. Curr Opin Cardiol 2004, 19:374–379.PubMedCrossRefGoogle Scholar
  25. 25.
    Ballantyne CM, Herd JA, Ferlic LL, et al.: Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999, 99:736–743.PubMedGoogle Scholar
  26. 26.
    Gordon DJ, Probstfield JL, Garrison RJ, et al.: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989, 79:8–15.PubMedGoogle Scholar
  27. 27.
    Sharrett AR, Ballantyne CM, Coady SA, et al.: Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001, 104:1108–1113.PubMedCrossRefGoogle Scholar
  28. 28.
    Shaten BJ, Kuller LH, Neaton JD, et al.: Association between baseline risk factors, cigarette smoking, and CHD mortality after 10.5 years. Prev Med 1991, 20:655–659.PubMedCrossRefGoogle Scholar
  29. 29.
    Thompson PD, Buchner D, Pina IL, et al.: Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003, 107:3109–3116.PubMedCrossRefGoogle Scholar
  30. 30.
    Dattilo AM, Kris-Etherton PM: Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992, 56:320–328.PubMedGoogle Scholar
  31. 31.
    Hodson L, Skeaff CM, Chisholm WA: The effect of replacing dietary saturated fat with polyunsaturated or monounsaturated fat on plasma lipids in free-living young adults. Eur J Clin Nutr 2001, 55:908–915.PubMedCrossRefGoogle Scholar
  32. 32.
    Knoops KT, de Groot LC, Kromhout D, et al.: Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 2004, 292:1433–1439.PubMedCrossRefGoogle Scholar
  33. 33.
    Moffatt RJ: Normalization of high density lipoprotein cholesterol following cessation from cigarette smoking. Adv Exp Med Biol 1990, 273:267–272.PubMedGoogle Scholar
  34. 34.
    Sillanaukee P, Koivula T, Jokela H, et al.: Alcohol consumption and its relation to lipid-based cardiovascular risk factors among middle-aged women: the role of HDL(3) cholesterol. Atherosclerosis 2000, 152:503–510.PubMedCrossRefGoogle Scholar
  35. 35.
    Ellison RC, Zhang Y, Qureshi MM, et al.: Lifestyle determinants of high-density lipoprotein cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2004, 147:529–535.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilsgaard T, Arnesen E: Change in serum lipids and body mass index by age, sex, and smoking status: the Tromso study 1986–1995. Ann Epidemiol 2004, 14:265–273.PubMedCrossRefGoogle Scholar
  37. 37.
    Lamon-Fava S, Diffenderfer MR, Barrett PH, et al.: Extendedrelease niacin alters the metabolism of plasma apolipoprotein (apo) A-I and apoB-containing lipoproteins. Arterioscler Thromb Vasc Biol 2008 Jun 19 (Epub ahead of print).Google Scholar
  38. 38.
    Tunaru S, Kero J, Schaub A, et al.: PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 2003, 9:352–355.PubMedCrossRefGoogle Scholar
  39. 39.
    Rubic T, Trottmann M, Lorenz RL: Stimulation of CD36 and the key effector of reverse cholesterol transport ATPbinding cassette A1 in monocytoid cells by niacin. Biochem Pharmacol 2004, 67:411–419.PubMedCrossRefGoogle Scholar
  40. 40.
    Knopp RH, Ginsberg J, Albers JJ, et al.: Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin. Metabolism 1985, 34:642–650.PubMedCrossRefGoogle Scholar
  41. 41.
    Canner PL, Berge KG, Wenger NK, et al.: Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986, 8:1245–1255.PubMedCrossRefGoogle Scholar
  42. 42.
    Goldberg A, Alagona P Jr, Capuzzi DM, et al.: Multipledose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000, 85:1100–1105.PubMedCrossRefGoogle Scholar
  43. 43.
    Martin G, Duez H, Blanquart C, et al.: Statin-induced inhibition of the Rho-signaling pathway activates PPA-Ralpha and induces HDL apoA-I. J Clin Invest 2001, 107:1423–1432.PubMedCrossRefGoogle Scholar
  44. 44.
    Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES: Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2005, 45:185–197.PubMedCrossRefGoogle Scholar
  45. 45.
    Nordestgaard B, 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, 96:1737–1744.PubMedGoogle Scholar
  46. 46.
    Reymer P, Gagné E, Groenemeyer B, et al.: A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nat Genet 1995, 10:28–34.PubMedCrossRefGoogle Scholar
  47. 47.
    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, 34:410–418.CrossRefGoogle Scholar
  48. 48.
    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, 285:1585–1591.PubMedCrossRefGoogle Scholar
  49. 49.
    Frick MH, Elo O, Haapa K, et al.: Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987, 317:1237–1245.PubMedGoogle Scholar
  50. 50.
    Manninen V, Tenkanen L, Koskinen P, et al.: Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992, 85:37–45.PubMedGoogle Scholar
  51. 51.
    Tenkanen L, Manttari M, Kovanen PT, et al.: Gemfibrozil in the treatment of dyslipidemia. An 18-year mortality follow-up of the Helsinki Heart Study. Arch Intern Med 2006, 166:743–748.PubMedCrossRefGoogle Scholar
  52. 52.
    Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study [no authors listed]. Circulation 2000, 102:21–27.Google Scholar
  53. 53.
    Goldenberg I, Goldbourt U, Boyko V, et al.: Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial). Am J Cardiol 2006, 97:466–471.PubMedCrossRefGoogle Scholar
  54. 54.
    Schaefer EJ, Asztalos BF: The effects of statins on high-density lipoproteins. Curr Atheroscler Rep 2006, 8:41–49.PubMedCrossRefGoogle Scholar
  55. 55.
    Nissen SE, Nicholls SJ, Sipahi I, et al.: Effects of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID Trial. JAMA 2006, 295:1556–1565.PubMedCrossRefGoogle Scholar
  56. 56.
    Liao JK, Laufs U: Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005, 45:89–118.PubMedCrossRefGoogle Scholar
  57. 57.
    Gotto AM, 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, 101:477–484.PubMedGoogle Scholar
  58. 58.
    Rader DJ: Effects of nonstatin lipid drug therapy on high-density lipoprotein metabolism. Am J Cardiol 2003, 91(Suppl):18E–23E.PubMedCrossRefGoogle Scholar
  59. 59.
    Goldberg RB, Kendall DM, Deeg MA, et al.: A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005, 28:1547–1554.PubMedCrossRefGoogle Scholar
  60. 60.
    Mazzone T, Meyer PM, Feinstein SB: Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2007, 296:2572–2581.CrossRefGoogle Scholar
  61. 61.
    Dormandy JA, Charbonnel B, Eckland DJ, et al.: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in MacroVascular Events): a randomised controlled trial. Lancet 2005, 366:1279–1289.PubMedCrossRefGoogle Scholar
  62. 62.
    Nissen SE, Nicholls SJ, Wolski K, et al.: Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008, 299:1561–1573.PubMedCrossRefGoogle Scholar
  63. 63.
    Grundy SM, Vega GL, Yuan Z, et al.: Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005, 95:462–468.PubMedCrossRefGoogle Scholar
  64. 64.
    Davidson MH, Armani A, McKenney JM, Jacobson TA: Safety considerations with fibrate therapy. Am J Cardiol 2007, 99:3C–18C.PubMedCrossRefGoogle Scholar
  65. 65.
    Davidson MH, Toth PP: Combination therapy in the management of complex dyslipidemias. Curr Opin Lipidol 2004, 15:423–431.PubMedCrossRefGoogle Scholar
  66. 66.
    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, 345:1583–1592.PubMedCrossRefGoogle Scholar
  67. 67.
    Taylor AJ, Sullenberger LE, Lee HJ, et al.: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004, 110:3512–3517.PubMedCrossRefGoogle Scholar
  68. 68.
    Karas RH, Kashvap ML, Knopp RH, et al.: Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: the OCEANS Study. Am J Cardiovasc Drugs 2008, 8:69–81.PubMedCrossRefGoogle Scholar
  69. 69.
    Brown G, Albers JJ, Fisher LD, et al.: Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990, 323:1289–1298.PubMedGoogle Scholar
  70. 70.
    Brown BG, Zambon A, Poulin D, et al.: Use of niacin, statins, and resins in patients with combined hyperlipidemia. Am J Cardiol 1998, 81:52B–59B.PubMedCrossRefGoogle Scholar
  71. 71.
    Whitney EJ, Krasuski RA, Personius BE, et al.: A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005, 142:95–104.PubMedGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Preventive CardiologySterling Rock Falls Clinic, Ltd.SterlingUSA

Personalised recommendations