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Prolonged-Release Nicotinic Acid

A Review of its Use in the Treatment of Dyslipidaemia

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Summary

Abstract

Prolonged-release (PR) nicotinic acid (niacin) [Niaspan®] is an oral, once-daily formulation of the lipid-modifying drug designed to produce less vasodilatory flushing than crystalline immediate-release (IR) nicotinic acid and less hepatotoxicity than previous sustained-release formulations of nicotinic acid.

PR nicotinic acid appears to retain the same level of efficacy as crystalline IR nicotinic acid and be better tolerated than older nicotinic acid formulations. Nicotinic acid has beneficial effects on all traditional blood lipid and lipoprotein fractions and is the most effective agent for increasing high-density lipoprotein (HDL)-cholesterol (HDL-C) and reducing lipoprotein(a). The effects of PR nicotinic acid are often additive when used in combination with HMG-CoA reductase inhibitors (statins), making it a useful addition when lipid goals are not achieved with the usual statin monotherapy or when additional correction of a specific lipid abnormality is required. PR nicotinic acid also slows atherosclerotic progression and even appears to produce regression of atherosclerosis in patients on stable statin therapy. PR nicotinic acid is a logical drug choice for treating atherogenic dyslipidaemia commonly associated with type 2 diabetes mellitus and the metabolic syndrome, and has been shown to be effective in patients with diabetes without adversely affecting glycaemic control in the majority of patients. The incidence of vasodilatory flushing with PR nicotinic acid is lower than with IR nicotinic acid and it decreases substantially over time as tolerance develops. To date, there has been no clinically significant hepatotoxicity observed with PR nicotinic acid. Therefore, once-daily PR nicotinic acid appears to maximise the potential benefits of nicotinic acid, while minimising any historical tolerability or safety concerns.

Pharmacological Properties

PR nicotinic acid appears to increase HDL-C levels by selectively blocking hepatic catabolic uptake of HDL particles containing apolipoprotein A-I and thereby augmenting reverse cholesterol transport. It selectively increases the proportion of larger HDL particles resulting in an overall increase in HDL particle size. The increase in HDL-C in patients with coronary artery disease was shown to correlate with improved endothelium-dependent vasodilation. PR nicotinic acid also reduces triglycerides and very low-density lipoprotein (VLDL) particles by decreasing the mobilisation of free fatty acids from peripheral adipose tissue to the liver. PR nicotinic acid decreases the number of low-density lipoprotein (LDL) particles and increases the mean LDL particle size.

Oral PR nicotinic acid is rapidly absorbed and undergoes extensive first-pass metabolism. The time to peak plasma concentration was 4–5 hours. Approximately 60–76% of the dose was recovered in the urine as unchanged nicotinic acid or metabolites. The ratio of non-conjugative to conjugative metabolites decreased with increasing dosage of PR nicotinic acid between 1000 (7.2) and 3000 (1.4) mg/day.

Therapeutic Efficacy

PR nicotinic acid beneficially altered all serum lipid components relative to placebo in patients with primary dyslipidaemia. The response was dose-proportional in the range 500–2000 mg/day. In two studies, PR nicotinic acid 2000 mg/ day increased HDL-C by 23% and 26% from baseline and decreased triglycerides by 29% and 35%, lipoprotein(a) by 24% and 27%, LDL-cholesterol (LDL-C) by 14% and 17%, apolipoprotein B by 16% and total cholesterol by 10% and 12%, respectively.

PR nicotinic acid maintained full efficacy for at least 2 years in open-label extension studies.

In a head-to-head comparison in patients with hyperlipidaemia, the efficacy of PR nicotinic acid was similar to that of IR nicotinic acid when administered at the same daily dosage (1500 mg/day). PR nicotinic acid 1500–2000 mg/day increased HDL-C and reduced lipoprotein(a) to a greater extent than did gemfibrozil 1200 mg/day in patients with low HDL-C, while gemfibrozil reduced triglycerides to a greater extent than did PR nicotinic acid. PR nicotinic acid tended to increase HDL-C more than lovastatin and to reduce lipoprotein(a) more than lovastatin or rosuvastatin in patients with hyperlipidaemia or mixed dyslipidaemia. Lovastatin and rosuvastatin each tended to reduce total cholesterol and LDL-C to a greater extent than PR nicotinic acid.

The combinations of PR nicotinic acid/lovastatin 1500mg/20mg and 2000mg/ 40mg produced generally additive responses. Combinations of PR nicotinic acid and rosuvastatin were generally superior to rosuvastatin alone only with respect to improvements in HDL-C, lipoprotein(a) or apolipoprotein A-I.

PR nicotinic acid in combination with a statin reduced the progression of carotid intima-media thickness compared with placebo, but the difference did not reach statistical significance. Atherosclerotic progression at 12 months in placebo recipients was statistically significant, while progression in recipients of PR nicotinic acid was not significant. Preliminary results from an open-label, 12-month extension study suggest that PR nicotinic acid added to a statin produces significant regression of atherosclerosis over 12–24 months.

PR nicotinic acid 1500 mg/day effectively increased HDL-C and decreased triglycerides and LDL-C in patients with dyslipidaemia and type 2 diabetes.

Tolerability

PR nicotinic acid is generally well tolerated with most adverse events being mild-to-moderate in intensity and transient in nature. Flushing was the most frequent adverse event, followed by gastrointestinal symptoms and other cutaneous reactions. PR nicotinic acid-induced flushing decreased over time and was associated with a low incidence of treatment discontinuation. The incidence of flushing with PR nicotinic acid was initially significantly lower than that with IR nicotinic acid.

PR nicotinic acid produced small, reversible elevations in liver transaminases, but there was no clinically significant hepatotoxicity. Similarly, elevated uric acid levels associated with recommended dosages of PR nicotinic acid did not result in any instances of clinical gout. PR nicotinic acid therapy in patients with type 2 diabetes and dyslipidaemia was associated with a small, but statistically significant, increase in glycosylated haemoglobin levels. However, fasting blood glucose levels were well controlled over the course of the 16-week study in most patients.

The incidence of adverse events and treatment discontinuation was higher with PR nicotinic acid than with lovastatin or rosuvastatin, predominantly as a result of flushing with PR nicotinic acid, while the overall tolerability of PR nicotinic acid was similar to that of gemfibrozil. No instances of myopathy or new adverse events occurred when PR nicotinic acid was given in combination with statins.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Carlson LA. Niaspan, the prolonged release preparation of nicotinic acid (niacin), the broad-spectrum lipid drug. Int J Clin Pract 2004 Jul; 58(7): 706–13

    Article  PubMed  CAS  Google Scholar 

  2. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med 2004 Apr 12; 164(7): 697–705

    Article  PubMed  CAS  Google Scholar 

  3. Crouse III JR. New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug. Coron Artery Dis 1996 Apr; 7(4): 321–6

    Article  PubMed  Google Scholar 

  4. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975 Jan 27; 231(4): 360–81

    Article  Google Scholar 

  5. 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 Dec; 8(6): 1245–55

    Article  PubMed  CAS  Google Scholar 

  6. 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 Nov 29; 345(22): 1583–92

    Article  PubMed  CAS  Google Scholar 

  7. 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(5): 405–18

    Article  PubMed  CAS  Google Scholar 

  8. 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 Nov 8; 323(19): 1289–98

    Article  PubMed  CAS  Google Scholar 

  9. Canner PL, Furberg CD, Terrin ML, et al. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2005 Jan 15; 95(2): 254–7

    Article  PubMed  CAS  Google Scholar 

  10. Yim BT, Chong PH. Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia. Ann Pharmacother 2003 Jan; 37(1): 106–15

    Article  PubMed  CAS  Google Scholar 

  11. 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 Jun 1; 91(11): 1304–10

    Article  PubMed  CAS  Google Scholar 

  12. National Cholesterol Education Program Expert Panel. 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 Dec 17; 106(25): 3143–421

    Google Scholar 

  13. Thompson GR. Management of dyslipidaemia. Heart 2004 Aug; 90(8): 949–55

    Article  PubMed  CAS  Google Scholar 

  14. Pieper JA. Understanding niacin formulations. Am J Manag Care 2002 Sep; 8 (12 Suppl.): S308–14

    PubMed  Google Scholar 

  15. Guyton JR, Capuzzi DM. Treatment of hyperlipidemia with combined niacin-statin regimens. Am J Cardiol 1998 Dec 17; 82 Suppl. 12A: 82U–4U

    Article  PubMed  CAS  Google Scholar 

  16. Knopp RH. Evaluating niacin in its various forms. Am J Cardiol 2000 Dec 21; 86 Suppl. 12A: 51L–6L

    Article  PubMed  CAS  Google Scholar 

  17. Pieper JA. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm 2003 Jul 1; 60 Suppl. 2: S9–14

    PubMed  CAS  Google Scholar 

  18. McKenney J. Niacin for dyslipidemia: considerations in product selection. Am J Health Syst Pharm 2003 May 15; 60(10): 995–1005

    PubMed  CAS  Google Scholar 

  19. Superko HR, McGovern ME, Raul E, et al. Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I. Am J Cardiol 2004 Sep 1; 94(5): 588–94

    Article  PubMed  CAS  Google Scholar 

  20. Morgan JM, Capuzzi DM, Baksh RI, et al. Effects of extended-release niacin on lipoprotein subclass distribution. Am J Cardiol 2003 Jun 15; 91(12): 1432–6

    Article  PubMed  CAS  Google Scholar 

  21. Morgan JM, Capuzzi DM, Guyton JR, et al. Treatment effect of Niaspan, a controlled-release niacin, in patients with hyperc-holesterolemia: a placebo-controlled trial. J Cardiovasc Pharmacol Ther 1996 Jul; 1(3): 195–202

    PubMed  CAS  Google Scholar 

  22. Sakai T, Kamanna VS, Kashyap ML. Niacin, but not gemfi-brozil, selectively increases LP-AI, a cardioprotective subtraction of HDL, in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol 2001 Nov; 21(11): 1783–9

    Article  PubMed  CAS  Google Scholar 

  23. Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med 2000 Apr 24; 160: 1177–84

    Article  PubMed  CAS  Google Scholar 

  24. Morgan JM, Capuzzi DM, de la Llera-Moya M, et al. The effects of crystalline and extended-release niacin, Niaspan, on HDL lipoprotein-mediated cellular cholesterol efflux as compared to placebo [abstract no. 1075-78]. J Am Coll Cardiol 1999 Feb; 33 Suppl. A: 245A

    Google Scholar 

  25. Kuvin JT, Patel AR, Kimmelstiel CD, et al. Extended-release niacin improves endothelial function in patients with coronary artery disease and controlled low density lipoprotein levels [abstract no. 899]. Circulation 1999 Nov 2; 100 Suppl.: 1–173

    Article  Google Scholar 

  26. Cefali EA, Adams MH. Extended-release niacin pharmacokinetics following multiple-dose administration [abstract no. 125]. Pharmacotherapy 2003 Mar; 23(3): 410

    Google Scholar 

  27. Kos Pharmaceuticals Inc. Niaspan® (niacin extended-release tablets): US prescribing information [online]. Available from URL: http://www.niaspan.com [Accessed 2005 Feb 11]

  28. Merck KGaA. Niaspan (prolonged release tablets): summary of product characteristics [online]. Available from URL: http://emc.medicines.org.uk [Accessed 2005 Feb 2]

  29. Goldberg A, Alagona Jr P, 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 May 1; 85: 1100–5

    Article  PubMed  CAS  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 Sep; 47(9): 1097–104

    Article  PubMed  CAS  Google Scholar 

  31. Insull Jr W, McGovern ME, Schrott H, et al. Efficacy of extended-release niacin with lovastatin for hypercholester-olemia: assessing all reasonable doses with innovative surface graph analysis. Arch Intern Med 2004 May 24; 164(10): 1121–7

    Article  PubMed  CAS  Google Scholar 

  32. Hunninghake DB, McGovern ME, Koren M, et al. A doseranging study of a new, once-daily, dual-component drug product containing niacin extended-release and lovastatin. Clin Cardiol 2003 Mar; 26: 112–8

    Article  PubMed  Google Scholar 

  33. 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 Dec 7; 110(23): 3512–7

    Article  PubMed  CAS  Google Scholar 

  34. 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. Diabetes Multicenter Research Group. Arch Intern Med 2002 Jul 22; 162: 1568–76

    CAS  Google Scholar 

  35. Capuzzi DM, Guyton JR, Morgan JM, et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol 1998 Dec 17; 82 Suppl. 12A: 74U–81U

    Article  PubMed  CAS  Google Scholar 

  36. Guyton JR, Goldberg AC, Kreisberg RA, et al. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolaemia. Am J Cardiol 1998 Sep 15; 82: 737–43

    Article  PubMed  CAS  Google Scholar 

  37. 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 Feb 15; 87(4): 476–9

    Article  PubMed  CAS  Google Scholar 

  38. Taylor AJ, Sullenberger LE, Lee HY. ARBITER 3: atherosclerosis regression during open-label continuation of extended-release niacin following ARBITER 2 [abstract no. 943]. Circulation 2005 Oct 25; 112 (17 Suppl.): 11–179

    Article  Google Scholar 

  39. Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998 Dec 17; 82 Suppl. 12A: 67U–73U; discussion 85U-86U

    Article  PubMed  CAS  Google Scholar 

  40. Berger W, Roze S, Valentine WJ, et al. Cost effectiveness of adding Niaspan to atorvastatin treatment in the secondary prevention of cardiovascular disease in patients with dyslipidemia in the UK [abstract no. PCV11]. Value Health 2004 Nov; 7(6): 688

    Article  Google Scholar 

  41. Goldberg AC. A meta-analysis of randomized controlled studies on the effects of extended-release niacin in women. Am J Cardiol 2004 Jul 1; 94(1): 121–4

    Article  PubMed  CAS  Google Scholar 

  42. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidaemia in non-insulin-dependent diabetes mellitus. JAMA 1990 Aug 8; 264(6): 723–6

    Article  PubMed  CAS  Google Scholar 

  43. Kane MP, Hamilton RA, Addesse E, et al. Cholesterol and glycemic effects of niaspan in patients with type 2 diabetes. Pharmacotherapy 2001 Dec; 21(12): 1473–8

    Article  PubMed  CAS  Google Scholar 

  44. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association. BMJ 2000 Mar 11; 320(7236): 705–8

    Article  Google Scholar 

  45. 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 May; 62(5): 707–14

    Article  PubMed  CAS  Google Scholar 

  46. Worz CR, Bottorff M. Treating dyslipidemic patients with lipid-modifying and combination therapies. Pharmacotherapy 2003 May; 23(5): 625–37

    Article  PubMed  CAS  Google Scholar 

  47. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995 Nov 16; 333(20): 1301–7

    Article  PubMed  CAS  Google Scholar 

  48. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Coordinating Committee of the National Cholesterol Education Program. Circulation 2004 Jul 13; 110(2): 227–39

    Google Scholar 

  49. Kashyap ML, Tavintharan S, Kamanna VS. Optimal therapy of low levels of high density lipoprotein-cholesterol. Am J Cardiovasc Drugs 2003; 3(1): 53–65

    Article  PubMed  CAS  Google Scholar 

  50. Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003; 171: 87–96

    Article  PubMed  CAS  Google Scholar 

  51. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987 Jun 19; 257(23): 3233–40

    Article  PubMed  CAS  Google Scholar 

  52. Cashin-Hemphill L, Mack WJ, Pogoda JM, et al. Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up. JAMA 1990 Dec 19; 264(23): 3013–7

    Article  PubMed  CAS  Google Scholar 

  53. Sacks FM, Pasternak RC, Gibson CM, et al. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Harvard Atherosclerosis Reversibility Project (HARP) Group. Lancet 1994 Oct 29; 344(8931): 1182–6

    CAS  Google Scholar 

  54. Kos Pharmaceuticals Inc. Kos Pharmaceuticals announces commencement of landmark long-term coronary heart disease outcomes study: AIM-HIGH study will evaluate whether combination therapy with Niaspan® and simvastatin is superior to simvastatin alone in preventing cardiovascular events [media release]. 2005 Jul 6

  55. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. American Heart Association. Circulation 2004 Feb 10; 109(5): 672–93

    Google Scholar 

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Acknowledgements

At the request of the journal, Merck KGaA provided a non-binding review of this article.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Paul L. McCormack & Gillian M. Keating

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  1. Paul L. McCormack
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Correspondence to Paul L. McCormack.

Additional information

Various sections of the manuscript reviewed by: D.M. Capuzzi, Cardiovascular Disease Prevention Center, Jefferson Heart Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; P.H. Chong, John H Stroger Jr Hospital of Cook County, Chicago, Illinois, USA; W. Insull Jr, Lipid Research Clinic, Baylor College of Medicine, Houston, Texas, USA; M.P. Kane, Department of Pharmacy Practice, Albany College of Pharmacy, Albany, New York, USA; R.A. Kreisberg, University of South Alabama, Mobile, Alabama, USA; J.M. McKenney, National Clinical Research Inc., Richmond, Virginia, USA; P.P. Toth, Sterling Rock Falls Clinic, Sterling, Illinois, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘niacin XR’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were (‘niacin’ or ‘nicotinic acid’) and (‘extended release’ or ‘controlled-release’ or ‘sustained-release’). Searches were last updated 30 November 2005.

Selection: Studies in patients with dyslipidaemia who received prolonged-release niacin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Nicotinic acid, lipid metabolism disorders, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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McCormack, P.L., Keating, G.M. Prolonged-Release Nicotinic Acid. Drugs 65, 2719–2740 (2005). https://doi.org/10.2165/00003495-200565180-00014

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