Skip to main content
SpringerLink
Log in

Niacin: Risk Benefits and Role in Treating Dyslipidemias

  • Chapter
  • First Online:
Dyslipidemias

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Niacin (nicotinic acid) was the first medication found to lower plasma cholesterol levels effectively and the first to demonstrate prevention of myocardial infarction. In 2011 and 2013, the clinical usefulness of niacin was challenged by two large clinical trials in which niacin failed to reduce major cardiovascular events in statin-treated patients with established atherosclerotic disease. Whether niacin use should be limited to patient subgroups such as those with statin intolerance or low high-density lipoprotein cholesterol (HDL-C)/high triglyceride is under debate as study details emerge. Recent discoveries on niacin’s mechanism of action raise the possibility that clinical efficacy could be improved by appropriate dosing strategy.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Elvehjem CA. The biological significance of nicotinic acid: Harvey lecture. Bull N Y Acad Med. 1940;16:173–89.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Broer S, Cavanaugh JA, Rasko JE. Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder. Biochem Soc Trans. 2005;33:233–6.

    Article  CAS  PubMed  Google Scholar 

  3. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem. 1955;54:558–9.

    Article  CAS  PubMed  Google Scholar 

  4. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. J Am Med Assoc. 1975;231:360–81.

    Google Scholar 

  5. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. 2005;258:94–114.

    Article  CAS  PubMed  Google Scholar 

  6. Guyton JR, Lakey WC, Campbell KB, Greyshock NG. Pharmacologic use of niacin for lipoprotein disorders. In: Preedy DR, editor. B vitamins: chemistry, analysis, function and effects food and nutritional components in focus. London: Royal Society of Chemistry; 2012. p. 660–74.

    Google Scholar 

  7. Butcher RW, Baird CE, Sutherland EW. Effects of lipolytic and antilipolytic substances on adenosine 3’,5’-monophosphate levels in isolated fat cells. J Biol Chem. 1968;243:1705–12.

    CAS  PubMed  Google Scholar 

  8. Lorenzen A, Stannek C, Lang H, Andrianov V, Kalvinsh I, Schwabe U. Characterization of a G protein-coupled receptor for nicotinic acid. Mol Pharmacol. 2001;59:349–57.

    CAS  PubMed  Google Scholar 

  9. Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, et al. Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun. 2003;303:364–9.

    Article  CAS  PubMed  Google Scholar 

  10. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003;9:352–5.

    Article  CAS  PubMed  Google Scholar 

  11. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, et al. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003;278:9869–74.

    Article  CAS  PubMed  Google Scholar 

  12. Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 2005;280:26649–52.

    Article  CAS  PubMed  Google Scholar 

  13. Carlson LA, Oro L. The effect of nicotinic acid on the plasma free fatty acids. Acta Med Scand. 1962;172:641–5.

    Article  CAS  PubMed  Google Scholar 

  14. Lauring B, Taggart AK, Tata JR, Dunbar R, Caro L, Cheng K, et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 2012;4:148ra15.

    Article  Google Scholar 

  15. Vega GL, Cater NB, Meguro S, Grundy SM. Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. Am J Cardiol. 2005;95:1309–13.

    Article  CAS  PubMed  Google Scholar 

  16. Carlson LA, Levi L, Oro L. Plasma lipids and urinary excretion of catecholamines in man during experimentally induced emotional stress, and their modification by nicotinic acid. J Clin Invest. 1968;47:1795–805.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Benyo Z, Gille A, Bennett CL, Clausen BE, Offermanns S. Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells. Mol Pharmacol. 2006;70:1844–9.

    Article  CAS  PubMed  Google Scholar 

  18. Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, et al. beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. J Clin Invest. 2009;119:1312–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Lai E, De Lepeleire I, Crumley TM, Liu F, Wenning LA, Michiels N, et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther. 2007;81:849–57.

    Article  CAS  PubMed  Google Scholar 

  20. Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, et al. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest. 2010;120:2910–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Digby JE, McNeill E, Dyar OJ, Lam V, Greaves DR, Choudhury RP. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. Atherosclerosis. 2010;209:89–95.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Digby JE, Martinez F, Jefferson A, Ruparelia N, Chai J, Wamil M, et al. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol. 2012;32:669–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981;22:24–36.

    CAS  PubMed  Google Scholar 

  24. Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML. Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res. 2004;45:1835–45.

    Article  CAS  PubMed  Google Scholar 

  25. Jin FY, Kamanna VS, Kashyap ML. Niacin accelerates intracellular ApoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells. Arterioscler Thromb Vasc Biol. 1999;19:1051–9.

    Article  CAS  PubMed  Google Scholar 

  26. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol. 2008;101:20B–6B.

    Article  CAS  PubMed  Google Scholar 

  27. Jin FY, Kamanna VS, Kashyap ML. Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 1997;17:2020–8.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang LH, Kamanna VS, Zhang MC, Kashyap ML. Niacin inhibits surface expression of ATP synthase beta chain in HepG2 cells: implications for raising HDL. J Lipid Res. 2008;49:1195–201.

    Article  CAS  PubMed  Google Scholar 

  29. Lamon-Fava S, Diffenderfer MR, Barrett PH, Buchsbaum A, Nyaku M, Horvath KV, et al. Extended-release niacin alters the metabolism of plasma apolipoprotein (Apo) A-I and ApoB-containing lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28:1672–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Rubic T, Trottmann M, Lorenz RL. Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin. BiochemPharmacol. 2004;67:411–9.

    CAS  Google Scholar 

  31. Lukasova M, Malaval C, Gille A, Kero J, Offermanns S. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest. 2011;121:1163–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Guyton JR, Gotto AM Jr. Drug therapy of dyslipoproteinemias. In: Fruchart JC, Shepherd J, editors. Human plasma lipoproteins. Berlin: Walter deGruyter; 1989. p. 335–61.

    Google Scholar 

  33. Keenan JM. Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia. J Clin Lipidol. 2013;7:14–23.

    Article  PubMed  Google Scholar 

  34. Abbott Laboratories. Niaspan product information. PDR Desk Reference. Montvale, NJ: PDR Network; 2011. p. 504–10.

    Google Scholar 

  35. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, et al. Extended-release niacin versus gemfibrozil for treatment of low levels of high density lipoprotein cholesterol. Arch Intern Med. 2000;160:1177–84.

    Article  CAS  PubMed  Google Scholar 

  36. McKenney JM, McCormick LS, Weiss S, Koren M, Kafonek S, Black DM. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin study group. Am J Med. 1998;104:137–43.

    Article  CAS  PubMed  Google Scholar 

  37. Knopp RH, Ginsberg J, Albers JJ, Hoff C, Ogilvie JT, Warnick GR, 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;34:642–50.

    Article  CAS  PubMed  Google Scholar 

  38. Yovos JG, Patel ST, Falko JM, Newman HA, Hill DS. Effects of nicotinic acid therapy on plasma lipoproteins and very low density lipoprotein apoprotein C subspecies in hyperlipoproteinemia. J Clin Endocrinol Metab. 1982;54:1210–5.

    Article  CAS  PubMed  Google Scholar 

  39. Gray DR, Morgan T, Chretien SD, Kashyap ML. Efficacy and safety of controlled-release niacin in dyslipoproteinemic veterans. Ann Intern Med. 1994;121:252–8.

    Article  CAS  PubMed  Google Scholar 

  40. Knopp RH, Retzlaff BM, Fish B, Dowdy A, Twaddell B, Nguyen T, et al. The SLIM study: Slo-Niacin(R) and atorvastatin treatment of lipoproteins and inflammatory markers in combined hyperlipidemia. J Clin Lipidol. 2009;3:167–78.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Brown BG, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher VM, et al. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol < 100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol. 1997;80:111–5.

    Article  CAS  PubMed  Google Scholar 

  42. Goldberg A, Alagona P, Jr., Capuzzi DM, Guyton J, Morgan JM, Rodgers J, et al. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol. 2000;85:1100–5.

    Article  CAS  PubMed  Google Scholar 

  43. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. J Am Med Assoc. 1990;264:723–6.

    Article  CAS  Google Scholar 

  44. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007;99:S22–S31.

    Article  Google Scholar 

  45. Guyton JR, Simmons PD. Flushing and other dermatologic adverse events associated with extended-release niacin therapy. J Clin Lipidol. 2009;3:101–8.

    Article  PubMed  Google Scholar 

  46. Brown BG, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. New Engl J Med. 1990;323:1289–98.

    Article  CAS  PubMed  Google Scholar 

  47. Dearing BD, Lavie CJ, Lohmann TP, Genton E. Niacin-induced clotting factor synthesis deficiency with coagulopathy. Arch Intern Med. 1992;152:861–3.

    Article  CAS  PubMed  Google Scholar 

  48. Gentile S, Tiribelli C, Persico M, Bronzino P, Marmo R, Orzes N, et al. Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert’s syndrome. J Lab Clin Med. 1986;107:166–71.

    CAS  PubMed  Google Scholar 

  49. Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson WC, Egan D, 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. J Am Med Assoc. 2000;284:1263–70.

    Article  CAS  Google Scholar 

  50. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes. Arch Intern Med. 2002;162:1568–76.

    Article  CAS  PubMed  Google Scholar 

  51. Guyton JR, Fazio S, Adewale AJ, Jensen E, Tomassini JE, Shah A, et al. Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial. Diabetes Care. 2012;35:857–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Millay RH, Klein ML, Illingworth DR. Niacin maculopathy. Ophthalmology. 1988;95:930–6.

    Article  CAS  PubMed  Google Scholar 

  53. 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;82:737–43.

    Article  CAS  PubMed  Google Scholar 

  54. Gershon SL, Fox IH. Pharmacologic effects of nicotinic acid on human purine metabolism. J Lab Clin Med. 1974;84:179–86.

    CAS  PubMed  Google Scholar 

  55. Sampathkumar K. Niacin and analogs for phosphate control in dialysis–perspective from a developing country. Int Urol Nephrol. 2009;41:913–8.

    Article  PubMed  Google Scholar 

  56. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–55.

    Article  CAS  PubMed  Google Scholar 

  57. 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;223:405–18.

    Article  CAS  PubMed  Google Scholar 

  58. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  PubMed  Google Scholar 

  59. Haynes R, Jang L, Hopewell JC, Li J, Chen F, Parish S, et al. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279–91.

    Google Scholar 

  60. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–12.

    Google Scholar 

  61. Guyton JR, Slee A, Anderson T, Fleg JL, Goldberg RB, Kashyap ML, et al. Relationship of lipoprotein levels to cardiovascular events in the AIM-HIGH trial. J Am Coll Cardiol 2013;62:1580–4.

    Google Scholar 

  62. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. New Engl J Med. 2001;345:1583–92.

    Article  CAS  PubMed  Google Scholar 

  63. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, 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.

    Article  PubMed  Google Scholar 

  64. Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up. J Am Med Assoc. 1990;264:3013–7.

    Article  CAS  Google Scholar 

  65. Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med. 2009;361:2113–22.

    Article  CAS  PubMed  Google Scholar 

  66. Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:1787–94.

    Article  CAS  PubMed  Google Scholar 

  67. 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;110:3512–7.

    Article  CAS  PubMed  Google Scholar 

  68. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin. 2006;22:2243–50.

    Article  CAS  PubMed  Google Scholar 

  69. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RC. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. J Am Med Assoc. 1990;264:3007–12.

    Article  CAS  Google Scholar 

  70. Thoenes M, Oguchi A, Nagamia S, Vaccari CS, Hammoud R, Umpierrez GE, et al. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract. 2007;61:1942–8.

    Article  CAS  PubMed  Google Scholar 

  71. Sacks FM, Pasternak RC, Gibson CM, Rosner B, Stone PH, Group H. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolemic patients. Lancet. 1994;344:1182–6.

    Article  CAS  PubMed  Google Scholar 

  72. Wakade C, Chong R, Bradley E, Thomas B, Morgan J. Upregulation of GPR109A in Parkinson’s disease. PLoS One. 2014;9:e109818. doi: 10.1371/journal.pone.0109818.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, 200 Trent Drive, 27710, Durham, NC, USA

    John R. Guyton MD

  2. Department of Pharmacy, Duke University Hospital, Duke Clinic, Red Zone, 14221Trent Drive, 27710, Durham, NC, USA

    Kristen Bova Campbell Pharm.D

  3. Department of Internal Medicine, Duke University Medical Center, 200 Trent Drive DUMC 3633, 27710, Durham, NC, USA

    Wanda C. Lakey MD, MHS

Authors
  1. John R. Guyton MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristen Bova Campbell Pharm.D
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanda C. Lakey MD, MHS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John R. Guyton MD .

Editor information

Editors and Affiliations

  1. Professor of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA

    Abhimanyu Garg

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Humana Press

About this chapter

Cite this chapter

Guyton, J., Campbell, K., Lakey, W. (2015). Niacin: Risk Benefits and Role in Treating Dyslipidemias. In: Garg, A. (eds) Dyslipidemias. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-424-1_26

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-424-1_26

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-423-4

  • Online ISBN: 978-1-60761-424-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation