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Addressing cardiovascular risk beyond low-density lipoprotein cholesterol: the high-density lipoprotein cholesterol story

Abstract

A large body of evidence from numerous, well-controlled, randomized trials demonstrates that treatment with statins reduce morbidity and mortality from cardiovascular disease (CVD). Although these observations are important and have resulted in the adoption of standard of care approaches to the management of CVD risk, they do not tell the whole story. When reviewing these landmark trials it is clear that on average two thirds of events are not prevented. This leads to the evaluation of risk beyond low-density lipoprotein cholesterol. This review focuses on the association of low high-density lipoprotein (HDL) cholesterol and increased CVD risk, the published trials that study the effect of raising HDL cholesterol on CVD outcomes, and the novel approaches toward HDL cholesterol raising that are on the horizon.

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References and Recommended Reading

  1. LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999, 282:2340–2346.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  3. Castelli WP, Garrison RJ, Wilson PWF, et al.: Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986, 256:2835–2838.

    PubMed  Article  CAS  Google Scholar 

  4. Gordon DJ, Probstfield JL, Garrison RJ, et al.: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989, 79:8–15.

    PubMed  CAS  Google Scholar 

  5. 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, 341:410–418. First clinical trial in patients with low HDL cholesterol and normal LDL cholesterol level that showed a reduction in CVD events with HDL cholesterol raising.

    PubMed  Article  CAS  Google Scholar 

  6. 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.

    PubMed  Article  CAS  Google Scholar 

  7. Shah PK, Kaul S, Nilsson J, Cercek B: 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.

    PubMed  CAS  Google Scholar 

  8. Brewer HB Jr.: High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004, 24:387–391.

    PubMed  Article  CAS  Google Scholar 

  9. Burke A, Fitzgerald GA: Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis 2003, 46:79–90.

    PubMed  Article  CAS  Google Scholar 

  10. Barua RS, Ambrose JA, Srivastava S, et al.: Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 2003, 107:2342–2347.

    PubMed  Article  CAS  Google Scholar 

  11. Izerman RG, Serne EH, van Weissenbruch MM, et al.: Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci (Lond) 2003, 104:247–252.

    Article  Google Scholar 

  12. Maeda K, Noguchi Y, Fukui T: The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med 2003, 37:283–290.

    PubMed  Article  CAS  Google Scholar 

  13. Thun MJ: Alcohol consumption and mortality among middle aged and elderly U.S. adults. N Engl J Med 1997, 337:1705–1714.

    PubMed  Article  CAS  Google Scholar 

  14. Daviglus ML, Stamler J, Orencia AJ: Fish oil consumption and the 30 year risk of myocardial infarction. N Engl J Med 1997, 336:1046–1053.

    PubMed  Article  CAS  Google Scholar 

  15. 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.

    PubMed  Article  Google Scholar 

  16. Spate-Douglas T, Keyser RE: Exercise intensity: its effect on the high-density lipoprotein profile. Arch Phys Med Rehabil 1999, 80:691–695.

    PubMed  Article  CAS  Google Scholar 

  17. Expert Panel ATP-III. 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. Current recommendation for management of dyslipidemia with and increased focus on the importance of increased non HDL cholesterol and low HDL cholesterol levels.

    Article  Google Scholar 

  18. Goldberg A, Alagona P Jr, Capuzzi DM, et al.: Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000, 85:1100–1105.

    PubMed  Article  CAS  Google Scholar 

  19. Malik S, Kashyap ML: Niacin, lipids, and heart disease. Curr Cardiol Rep 2003, 5:470–476.

    PubMed  Article  Google Scholar 

  20. Bays H, Stein EA: Pharmacotherapy for dyslipidemia — current therapies and future agents. Expert Opin Pharmacother 2003, 4:1901–1938.

    PubMed  CAS  Google Scholar 

  21. Superko HR, Krauss RM: Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis 1992, 95:69–76.

    PubMed  Article  CAS  Google Scholar 

  22. The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease. JAMA 1975, 231:360–381.

    Article  Google Scholar 

  23. Canner PL, Berge KG, Wenger NK, et al. for the Coronary Drug Project Research Group: Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986, 8:1245–1255.

    PubMed  CAS  Article  Google Scholar 

  24. Goldberg AC: Clinical trial experience with extended-release niacin (Niaspan): dose-escalation study. Am J Cardiol 1998, 82:35U-38U.

    PubMed  Article  CAS  Google Scholar 

  25. Jacobson TA, Jokubaitis LA, Amorosa LF: Fluvastatin and niacin in hypercholesterolemia: a preliminary report on gender differences in efficacy. Am J Med 1994, 96:64S-68S.

    PubMed  Article  CAS  Google Scholar 

  26. Elam MB, Hunninghake DB, Davis KB, et al.: Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 2000, 284:1263–1270.

    PubMed  Article  CAS  Google Scholar 

  27. Whelan AM, Price SO, Fowler SF, Hainer BL: The effect of aspirin on niacin-induced cutaneous reactions. J Fam Pract 1992, 34:165–168.

    PubMed  CAS  Google Scholar 

  28. McKenney JM, Proctor JD, Harris S, Chinchili VM: A comparison of the efficacy and toxic effects of sustained- vs. immediaterelease niacin in hypercholesterolemic patients. JAMA 1994, 271:672–677.

    PubMed  Article  CAS  Google Scholar 

  29. Pieper JA: Understanding niacin formulations. Am J Manag Care 2002, 8(12 Suppl):S308-S314.

    PubMed  Google Scholar 

  30. Knopp RH, Alagona P, Davidson M, et al.: Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia. Metabolism 1998, 47:1097–1104.

    PubMed  Article  CAS  Google Scholar 

  31. Fruchart JC, Duriez P, Staels B: Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 1999, 10:245–257.

    PubMed  Article  CAS  Google Scholar 

  32. 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.

    PubMed  CAS  Article  Google Scholar 

  33. Robins SJ, Collins D, Wittes JT, et al. for the VA-HIT study group: Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA 2001, 285:1585–1591.

    PubMed  Article  CAS  Google Scholar 

  34. BIP Study Group: Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000, 102:21–27.

    Google Scholar 

  35. Tanne D, Koren-Morag N, Graff E, Goldbourt U: Blood lipids and first-ever ischemic stroke/transient ischemic attack in the Bezafibrate Infarction Prevention (BIP) Registry: high triglycerides constitute an independent risk factor. Circulation 2001, 104:2892–2897.

    PubMed  CAS  Google Scholar 

  36. Ericsson CG, Hamsten A, Nilsson J, et al.: Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male post infarction patients. Lancet 1996, 347:849–853.

    PubMed  Article  CAS  Google Scholar 

  37. Diabetes Atherosclerosis Intervention Study Investigators: Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001, 357:905–910.

    Article  Google Scholar 

  38. Omar MA, Wilson JP: FDA adverse event reports on statinassociated rhabdomyolysis. Ann Pharmacother 2002, 36:288–295.

    PubMed  Article  CAS  Google Scholar 

  39. Davidson MH: Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol 2002, 90(Suppl):50K-60K.

    PubMed  Article  CAS  Google Scholar 

  40. Pasternak RC, Smith SC Jr., Bairey-Merz CN, et al.: ACC/AHA/ NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002, 40:567–572. An important publication that puts into focus safety issues with respect to statin monotherapy and statin therapy when used in combination with other lipid-lowering medication.

    PubMed  Article  Google Scholar 

  41. 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.

    PubMed  Article  CAS  Google Scholar 

  42. Schneck DW, Knopp RH, Ballantyne CM, et al.: Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003, 91:33–41.

    PubMed  Article  CAS  Google Scholar 

  43. Blasetto JW, Stein EA, Brown WV, et al.: Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol 2003, 91:3C-10C.

    PubMed  Article  CAS  Google Scholar 

  44. Brown WV, Bays HE, Hassman DR, et al.: Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, doubleblind, 52-week trial. Am Heart J 2002, 144:1036–1043.

    PubMed  Article  CAS  Google Scholar 

  45. Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998, 279:1615–1622.

    PubMed  Article  CAS  Google Scholar 

  46. 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.

    PubMed  CAS  Google Scholar 

  47. Carlson LA, Rosenhamer G: Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988, 223:405–418.

    PubMed  CAS  Article  Google Scholar 

  48. 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. This study demonstrates the beneficial effects on lipid lowering, angiographic progression, and clinical outcome when combination therapy is used safely in high-risk patients with dyslipidemia.

    PubMed  Article  CAS  Google Scholar 

  49. Cressman MD, Hoogwerf BJ, Moodie DS, et al.: HMG-CoA reductase inhibitors. A new approach to the management of hypercholesterolemia. Cleve Clin J Med 1988, 55:93–100.

    PubMed  CAS  Google Scholar 

  50. Hunninghake DB: Drug treatment of dyslipoproteinemia. Endocrinol Metab Clin North Am 1990, 19:345–360.

    PubMed  CAS  Google Scholar 

  51. Goldman JA, Fishman AB, Lee JE, Johnson RJ: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis. Arthritis Rheum 1989, 32:358–359.

    PubMed  Article  CAS  Google Scholar 

  52. Wanner C, Kramer-Guth A, Galle J: Use of HMG-CoA reductase inhibitors after kidney and heart transplantation: lipidlowering and immunosuppressive effects. BioDrugs 1997, 8:387–393.

    CAS  Article  PubMed  Google Scholar 

  53. Hanston PD, Horn JR: Drug interactions with HMG CoA reductase inhibitors. Drug Interactions Newsletter 1998:103–106.

  54. Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy. JAMA 2003, 289:1681–1690.

    PubMed  Article  CAS  Google Scholar 

  55. Wierzbicki AS, Mikhailidis DP, Wray R, et al.: Statin-fibrate combination: therapy for hyperlipidemia: a review. Curr Med Res Opin 2003, 19:155–168.

    PubMed  Article  CAS  Google Scholar 

  56. Murdock DK, Murdock AK, Murdock RW, et al.: Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999, 138:151–155.

    PubMed  Article  CAS  Google Scholar 

  57. Iliadis EA, Rosenson RS: Long-term safety of pravastatingemfibrozil therapy in mixed hyperlipidemia. Clin Cardiol 1999, 22:25–28.

    PubMed  CAS  Google Scholar 

  58. Ellen RL, McPherson R: Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 1998, 81:60B-65B.

    PubMed  Article  CAS  Google Scholar 

  59. Vega GL, Ma PT, Cater NB, et al.: Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003, 91:956–960.

    PubMed  Article  CAS  Google Scholar 

  60. Martin PD, Dane AL, Schneck DW, Warwick MJ: An open-label, randomized, three-way crossover trial of the effects of co administration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther 2003, 25:459–471.

    PubMed  Article  CAS  Google Scholar 

  61. Kashyap ML, McGovern ME, Berra K, et al.: Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002, 89:672–678.

    PubMed  Article  CAS  Google Scholar 

  62. Wolfe ML, Vartanian SF, Ross JL, et al.: Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol 2001, 87:476–479.

    PubMed  Article  CAS  Google Scholar 

  63. Capuzzi DM, Morgan JM, Weiss RJ, et al.: Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels. Am J Cardiol 2003, 91:1304–1310.

    PubMed  Article  CAS  Google Scholar 

  64. Shah PK, Yano J, Reyes O: High dose recombinant apolipoprotein A-I Milano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Circulation 2001, 103:604–616.

    Google Scholar 

  65. 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. A novel approach to raising HDL cholesterol with promising results.

    PubMed  Article  CAS  Google Scholar 

  66. Okamoto H, Yonemori F, Wakitani K, et al.: A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000, 406:203–207.

    PubMed  Article  CAS  Google Scholar 

  67. 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, 105:2159–2165.

    PubMed  Article  CAS  Google Scholar 

  68. Clark RW, Sutfin TA, Ruggeri RB, et al.: Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 2004, 24:490–497.

    PubMed  Article  CAS  Google Scholar 

  69. 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, 350:1505–1515. A novel approach to raising HDL cholesterol with promising results.

    PubMed  Article  CAS  Google Scholar 

  70. Mosca L, Appel LJ, Benjamin EJ, et al.: Evidence-based guidelines for cardiovascular disease prevention in women. Arterioscler Thromb Vasc Biol 2004, 24:e29-e50. Most recent guidelines with a focus on the importance of HDL cholesterol as a marker of risk and target for intervention in women at risk for future vascular events.

    PubMed  Article  CAS  Google Scholar 

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Meagher, E.A. Addressing cardiovascular risk beyond low-density lipoprotein cholesterol: the high-density lipoprotein cholesterol story. Curr Cardiol Rep 6, 457–463 (2004). https://doi.org/10.1007/s11886-004-0055-2

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Keywords

  • Rosuvastatin
  • Gemfibrozil
  • Cholesteryl Ester Transfer Protein
  • Reverse Cholesterol Transport
  • Cholesterol Ester Transfer Protein