Skip to main content
Log in

Beyond the Statins: New Therapeutic Perspectives in Cardiovascular Disease Prevention

  • Review Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Reduction of low-density lipoprotein cholesterol (LDL-C) with statin therapy is currently identified in treatment guidelines as the primary focus for patients with or at risk of coronary heart disease (CHD). Yet despite effective statin therapy there is still an unacceptably high residual coronary risk. A substantial proportion of patients with CHD have mixed dyslipidemia, including low levels of high-density lipoprotein cholesterol (HDL-C), an independent and predictive risk factor for CHD. Although effective in reducing LDL-C, statin therapy has only modest effects in raising HDL-C. Fibrate therapy is an alternative lipid-modifying strategy, and is effective in reducing CHD mortality and morbidity, with the magnitude of clinical benefit similar to statin therapy. Multi-drug therapy with complementary mechanisms of action has been proposed as a means of improving lipid-modifying efficacy. Nicotinic acid is the most potent agent for increasing HDL-C and also substantially reduces LDL-C and triglycerides. Addition of nicotinic acid to statin therapy would be a logical management approach, given the potential for complementary therapeutic benefit. The clinical benefits of this combination are supported by the results of the HDL Atherosclerosis Treatment Study, which showed reduction of 60–90% in the incidence of major coronary events when both agents were administered. In addition, combination treatment led to angiographic regression of stenosis, compared with placebo, rather than slowed progression as previously reported with statin monotherapy. Given that the prevalence of low HDL-C, particularly amongst individuals with CHD, is higher than previously anticipated, combining nicotinic acid and a statin represents an innovative approach to further reducing CHD risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sacks FM, Pfeffer MA, Moyle LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001–1009.

    Google Scholar 

  2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349–1357.

    Google Scholar 

  3. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1999;344:1383–1389.

  4. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–1307.

    Google Scholar 

  5. 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 Athersclerosis Prevention Study. J Am Med Assoc 1998;279:1615–1622.

    Google Scholar 

  6. 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). J Am Med Assoc 2001;285:2486–2497.

    Google Scholar 

  7. International Atherosclerosis Society. Harmonized clinical guidelines on prevention of atherosclerotic vascular disease. http://www.athero.org

  8. Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective Pravastatin Pooling Project. Circulation 2000;102:1893–1900.

    Google Scholar 

  9. 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;105:1424–1428.

    Google Scholar 

  10. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707–714.

    Google Scholar 

  11. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk: The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124:S11–S20.

    Google Scholar 

  12. Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. J Am Med Assoc 1988;260:641–651.

    Google Scholar 

  13. 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.

    Google Scholar 

  14. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341;498–511.

    Google Scholar 

  15. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046–3051.

    Google Scholar 

  16. 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.

    Google Scholar 

  17. Rubins HB, Robins SJ, Collins D, et al. Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol 1995;75:1196–1201.

    Google Scholar 

  18. Kannel WB. Range of serum cholesterol valves in the population developing coronary artery disease. Am J Cardiol 1995;76:69C–77C.

    Google Scholar 

  19. Schaefer EJ, Lamon-Fava S, Ordovas JM, et al. Factors associated with low and elevated plasma high density lipoprotein cholesterol and apolipoprotein A-I levels in the Framingham Offspring Study. J Lipid Res 1994;35:871–882.

    Google Scholar 

  20. Health Survey for England 1998: Cardiovascular disease. http://www.dh.gov.uk/Publications and Statistics/Published Survey/Health Survey for England/Health Survey Results/fs/en. Accessed 5 April 2004.

  21. Guérin M, Le Goff W, Lassel TS, et al. Proatherogenic role of elevated CE transfer from HDL to VLDL1 and dense LDL in type 2 diabetes. Impact of the degree of triglyceridemia. Arterioscler Thromb Vasc Biol 2001;21:282–288.

    Google Scholar 

  22. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Mnster Study. Am J Cardiol 1992;70:733–737.

    Google Scholar 

  23. International Task Force for Prevention of Coronary Heart Disease, http://www.chd-taskforce.de/guidelines/toc.htm

  24. Elisaf M. Effects of fibrates on serum metabolic parameters. Curr Med Res Opin 2002;18:269–276.

    Google Scholar 

  25. Chapman MJ. Fibrates in 2003: Therapeutic action in atherogenic dyslipidaemia and future perspectives. Atherosclerosis 2003;171:1–13.

    Google Scholar 

  26. Frick MH, Syvanne M, Nieminen MS, et al. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation 1997;96:2137–2143.

    Google Scholar 

  27. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357:905–910.

    Google Scholar 

  28. 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. J Am Med Assoc 2001;285:1585–1591.

    Google Scholar 

  29. Backman GT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002;72:685–691.

    Google Scholar 

  30. Miller M. Niacin as a component of combination therapy for dyslipidaemia. Mayo Clin Proc 2003;78:735–742.

    Google Scholar 

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

    Google Scholar 

  32. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. J Am Med Assoc 1975;231;360–381.

    Google Scholar 

  33. 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.

    Google Scholar 

  34. 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.

    Google Scholar 

  35. 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.

    Google Scholar 

  36. Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998;82:737–743

    Google Scholar 

  37. 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.

    Google Scholar 

  38. 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.

    Google Scholar 

  39. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997;80:278–286.

    Google Scholar 

  40. 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.

    Google Scholar 

  41. Weintraub WS, Boccuzzi SJ, Klein JL, et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med 1994;331:1331–1337.

    Google Scholar 

  42. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. 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.

    Google Scholar 

  43. Betteridge J. Dyslipidaemia and diabetes—the clinical realities. Br J Cardiol 2004;11(Suppl 2):S11–S15.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. John Chapman Ph.D., D.Sc..

Additional information

This review paper was funded by an unrestricted educational grant form Merck KgaA, Darmtadt, Germany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chapman, M.J. Beyond the Statins: New Therapeutic Perspectives in Cardiovascular Disease Prevention. Cardiovasc Drugs Ther 19, 135–139 (2005). https://doi.org/10.1007/s10557-005-1049-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-005-1049-z

Key Words

Navigation