steady decline in cardiovascular mortality has occurred in recent decades, but a substantial burden of cardiovascular mortality remains. Intervention with statins, for example, has resulted in significant reductions in cardiovascular event rates in a broad range of patient populations, but these agents reduce cardiovascular event rates by only about 20—40%, despite profound reductions in low-density lipoprotein cholesterol (LDL-C) in some trials. Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for adverse cardiovascular outcomes independent of levels of LDL-C. Well designed intervention trials have demonstrated marked improvements in cardiovascular outcomes with agents that raise levels of HDL-C. Combinations of statins with nicotinic acid, the most potent agent for increasing levels of HDL-C currently available, appear to be the most effective strategy for managing cardiovascular risk. Indeed, reductions in the risk of cardiovascular events of up to 90% relative to placebo with a nicotinic acid-statin combination were observed in the double-blind, randomised HDL Atherosclerosis Treatment Study (HATS). A once-daily, prolonged-release formulation of nicotinic acid, Niaspan® is as effective as immediate-release nicotinic acid with superior tolerability and safety. A randomised, double-blind placebo-controlled evaluation of Niaspan® added to a statin, the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, demonstrated significant inhibition of atherosclerosis in men with low HDL-C over only one year of treatment. Patients with low HDL-C are at elevated cardiovascular risk and combination treatment with nicotinic acid and a statin represents a rational and evidence-based treatment for this population.
Gu K., Cowie CC, Harris MIDiabetes and decline in heart disease mortality in US adults. JAMA1999;281:1291-7.
2.
Fox CS, Coady S., Sorlie PD et al. Trends in cardiovascular complications of diabetes. JAMA2004;292:2495-9.
3.
Heart Protection StudyCollaborative Group.MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet2002;360:7-22.
4.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet1994;344:1383-9.
5.
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 . Circulation2000;102:1893-900.
6.
ALLHAT Collaborative Research Group.Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA2002; 288:2998-3007.
7.
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 Med1995;333: 1301-07.
8.
Sever PS, Dahlof B., Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet2003;361: 1149-58.
9.
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. JAMA1998;279:1615-22.
10.
Shepherd J. , Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet2002;360:1623-30.
11.
Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet2004;364:685-96.
12.
Plehn JF, Davis BR, Sacks FM et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation1999;99:216-23.
13.
Schwartz GG , Olsson AG, Ezekowitz MD et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA2001;285:171118.
14.
UK Prospective Diabetes Study Group.Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ1998;317:703-13.
15.
UK Prospective Diabetes Study (UKPDS) Group.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet1998;352:837-53.
16.
LaRosa JC, He J., Vupputuri S.Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA1999; 282:2340-6.
17.
Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice. Eur J Cardiovasc Prev Rehabil2003;10:S1-S10.
18.
National Cholesterol Education Program.Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). National Institutes of Health/National Heart Lung and Blood Institute. Available at www.nhlbi.nih.gov/guidelines/cholesterol
19.
Gordon T., Castelli WP, Hjortland MC, Kannel WB, Dawber TRHigh density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med1977;62:707-14.
20.
Castelli WP , Garrison RJ, Wilson PW, Abbott RD, Kalousdian S., Kannel WBIncidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA1986;256:2835-8.
21.
Assmann G., Schulte H.Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol1992;70:733-7.
22.
Alagona C., Soro A., Ylitalo K. et al. A low high density lipoprotein (HDL) level is associated with carotid artery intima-media thickness in asymptomatic members of low HDL families . Atherosclerosis2002;165:309-16.
23.
Laakso M., Voutilainen E., Pyorala, K., Sarlund H.Association of low HDL and HDL2 cholesterol with coronary heart disease in noninsulindependent diabetics. Arteriosclerosis1985;5:653-8.
24.
Turner RC, Millns H., Neil HA et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ1998;316:823-8.
25.
Robins SJTargeting low high-density lipoprotein cholesterol for therapy: lessons from the Veterans Affairs High-density Lipoprotein Intervention Trial. Am J Cardiol2001;88:19N-23N.
26.
Goldbourt U., Yaari S., Medalie JHIsolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol1997;17:107-13.
27.
International Diabetes Federation. Available at http://www.idf.org/webdata/docs/Meta_syndrome_definition.pdf, last accessed May 2005.
28.
Drexel H., Aczel S., Marte T. et al. Is atherosclerosis in diabetes and impaired fasting glucose driven by elevated LDL cholesterol or by decreased HDL cholesterol?Diabetes Care2005;28:101-07.
29.
Bressler P., Bailey SR, Matsuda M., DeFronzo RAInsulin resistance and coronary artery disease. Diabetologia1996;39:1345-50.
30.
Ginsberg HN, Tuck C.Diabetes and dyslipidemia. Heart Fail Monit2001;2:14-20.
31.
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 Med1999;341:410-18.
32.
Frick MH, Elo O., Haapa K., Heinonen OP 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 Med1987;317:1237-45.
33.
Coronary Drug ProjectResearch Group.Clofibrate and niacin in coronary heart disease. JAMA1975;231:360-81.
34.
Canner PL, Berge KG, Wenger NK et al. Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol1986 ;8:1245-55.
35.
Canner PL, Furberg CD, Terrin ML, McGovern MEBenefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol2005;95:254-7.
36.
Canner PL, Furberg CD, Terrin ML, McGovern MENiacin decreases total mortality and myocardial infarction in patients with metabolic syndrome: results from the Coronary Drug Project. J Am Coll Cardiol2003;41(6 suppl A):291A.
37.
Cashin-Hemphill L., Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DHBeneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA1990;264:3013-17.
38.
Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJRegression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA1990; 264:3007-12.
39.
Mack WJ, Selzer RH, Hodis HN et al. One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke1993;24:1779-83.
40.
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 Med1990;323:1289-98.
41.
Brown BG, Brockenbrough A., Zhao X-Q. et al. Very intensive lipid therapy with lovastatin, niacin and colestipol for prevention of death and myocardial infarction: A 10-year familial atherosclerosis treatment study (FATS) follow up. Circulation1998;98:I-635 (Abstract).
42.
Brown BG, Zhao X.-Q, Chait A. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med2001;345:1583-92.
43.
Guyton JRExtended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother2004;5:1385-98.
44.
Insull W. Jr, McGovern ME, Schrott H. et al. Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis. Arch Intern Med2004;164:1121-7.
45.
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KAArterial 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. Circulation2004;110:3512-17.
46.
Tato F., Vega GL, Grundy SMEffects of crystalline nicotinic acidinduced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase . Am J Cardiol1998;81:805-07.
47.
McKenney JM , Proctor JD, Harris S., Chinchili VMA comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients . JAMA1994;271:672-7.
48.
Schwartz MLSevere reversible hyperglycemia as a consequence of niacin therapy. Arch Intern Med1993;153:2050-2.
49.
Capuzzi DM, Guyton JR, Morgan JM et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol1998;82:74U-81U.
50.
Guyton JR, Capuzzi DMTreatment of hyperlipidemia with combined niacin-statin regimens. Am J Cardiol1998;82:82U-84U.
51.
Grundy SM, Vega GL, McGovern ME et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med2002; 162:1568-76.
52.
McGovern M.Niaspan®: creating a new concept for raising HDL-cholesterol. Eur Heart J2005;7(suppl):F41-F47.
