Pleiotropic effects of niacin: Current possibilities for its clinical use

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Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin’s role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.

1. [No authors listed] Clofibrate and niacin in coronary heart disease, JAMA 231 (1975) 360-381; DOI: 10.1001/jama.1975.03240160024021.

2. P. L. Canner, K. G. Berge, N. K. Wenger, J. Stamler, L. Friedman, R. J. Prineas and W. Friedewald, Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J. Am. Coll. Cardiol. 8 (1986) 1245-1255; DOI: 10.1016/S0735-1097(86)80293-5.

3. W. Hochholzer, D. D. Berg and R. P. Giugliano, The facts behind niacin, Ther. Adv. Cardiovasc. Dis. 5 (2011) 227-240; DOI: 10.1177/1753944711419197.

4. L. A. Carlson, A. Hamsten and A. Asplund, Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid, J. Intern. Med. 226 (1989) 271-276; DOI: 10.1111/j.1365-2796.1989.tb01393.x.

5. R. S. Birjmohun, B. A. Hutten, J. J. Kastelein and E. S. Stroes, Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials, J. Am. Coll. Cardiol. 45 (2005) 185-197; DOI: 10.1016/j.jacc.2004.10.031.

6. L. A. Carlson, Nicotinic acid and other therapies for raising high-density lipoprotein, Curr. Opin.Cardiol. 21 (2006) 336-344; DOI: 10.1097/01.hco.0000231404.76930.e9.

7. V. S. Kamanna and M. L. Kashyap, Mechanism of action of niacin, Am. J. Cardiol. 101 (2008) 20B-26B; DOI: 10.1016/j.amjcard.2008.02.029.

8. L. H. Zhang, V. S. Kamanna, S. H. Ganji, X. M. Xiong and M. L. Kashyap, Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells, J. Lipid Res. 53 (2012) 941-950; DOI: 10.1194/jlr.M020917.

9. T. Sakai, V. S. Kamanna and M. L. Kashyap, Niacin, but not gemfibrozil, selectively increases LPAI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol, Arterioscler. Thromb. Vasc. Biol. 21 (2001) 1783-1789; DOI: 10.1161/hq1001.096624.

10. A. Otocka-Kmiecik, D. P. Mikhailidis, S. J. Nicholls, M. Davidson, J. Rysz and M. Banach, Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease, Prog.Lipid Res. 51 (2012) 314-324; DOI: 10.1016/j.plipres.2012.03.003.

11. C. Mineo and P. W. Shaul, Novel biological functions of high-density lipoprotein cholesterol, Circ. Res. 111 (2012) 1079-1090; DOI: 10.1161/CIRCRESAHA.111.258673.

12. L. A. Carlson and G. Rosenhamer, Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid, Acta Med. Scand. 223 (1988) 405-418; DOI: 10.1111/j.0954-6820.1988.tb15891.x.

13. D. H. Blankenhorn, S. A. Nessim, R. L. Johnson, M. E. Sanmarco, S. P. Azen and L. Cashin-Hemphill, Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts, JAMA 257 (1987) 3233-3240; DOI: 10.1001/jama.1987.03390230069027.

14. G. Brown, J. J. Albers, L. D. Fisher, S. M. Schaefer, J. T. Lin, C. Kaplan, X. Q. Zhao, B. D. Bisson, V. F. Fitzpatrick and H. T. Dodge, Regression of coronary artery disease as a result of intensive lipidlowering therapy in men with high levels of apolipoprotein B, N. Engl. J. Med. 323 (1990) 1289-1298; DOI: 10.1056/NEJM199011083231901.

15. W. E. Boden, J. L. Probstfield, T. Anderson, B. R. Chaitman, P. Desvignes-Nickens, K. Koprowicz, R. McBride, K. Teo, W. Weintraub and collaborators (316), Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N. Engl. J. Med. 365 (2011) 2255-2267; DOI: 10.1056/ NEJMoa1107579.

16. HPS2-THRIVE collaborative group (1472), M. J. Landray, R. Haynes, J. C. Hopewell, S. Parish, T. Aung, J. Tomson, K. Wallendszus, M. Craig, L. Jiang, R. Collins and J. Armitage, Effects of extended- release niacin with laropiprant in high-risk patients, N. Engl. J. Med. 371 (2014) 203-212; DOI: 10.1056/NEJMoa1300955.

17. J. R. Guyton, M. E. McGovern and L. A. Carlson, Niacin (Nicotinic Acid), in Clinical Lipidology. A Companion to Braunwald´s Heart Disease (Ed. C. M. Ballantyne), 2nd ed., Elsevier, Sainders, Philadelphia 2015, pp. 274-284.

18. S. J. Nicholls, Is niacin ineffective? Or did AIM-HIGH miss its target?, Clev. Clin. J. Med. 79 (2012) 38-43; DOI: 10.3949/ccjm.79a.11166.

19. Z. Blomgarden and Y. Handelsman, Did AIM-HIGH aim too low?, J. Diabetes 4 (2012) 1-2; DOI: 10.1111/j.1753-0407.2011.00176.x.

20. J. R. Guyton, A. E. Slee, T. Anderson, J. L. Fleg, R. B. Goldberg, M. L. Kashyap, S. M. Marcovina, S. D. Nash, K. D. O‘Brien, W. S. Weintraub, P. Xu, X. Q. Zhao and W. E. Boden, Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis intervention in metabolic syndrome with low HDL/high triglycerides and impact on global health outcomes), J. Am. Coll. Cardiol. 62 (2013) 1580-1584; DOI: 10.1016/j.jacc.2013.07.023.

21. I. Gaidarov, X. Chen, T. Anthony, D. Maciejewski-Lenoir, C. Liaw and D. J. Unett, Differential tissue and ligand-dependent signaling of GPR109A receptor: Implications for anti-atherosclerotic therapeutic potential, Cell. Signal. 25 (2013) 2003-2016; DOI: 10.1016/j.cellsig.2013.06.008.

22. Y. L. Yang, M. Hu, M. Chang and B. Tomlinson, A high incidence of exanthematous eruption associated with niacin/laropiprant combination in Hong Kong Chinese patients, J. Clin. Pharm. Ther. 38 (2013) 528-532; DOI: 10.1111/jcpt.12096.

23. M. Zeman, M. Vecka, F. Perlík, R. Hromádka, B. Stanková, E. Tvrzická and A. Žák, Niacin in the treatment of hyperlipidemias in light of new clinical trials: Has niacin lost its place?, Med. Sci. Monit. 21 (2015) 2156-2162; DOI: 10.12659/MSM.893619.

24. J. T. Chai, J. E. Digby and R. P. Choudhury, GPR109A and vascular inflammation, Curr. Atheroscler. Rep. 15 (2013) 325 (10 pages); DOI: 10.1007/s11883-013-0325-9.

25. M. Lukasova, J. Hanson, S. Tunaru and S. Offermanns, Nicotinic acid (niacin): new lipid-independent mechanisms of action and therapeutic potential, Trends Pharmacol. Sci. 32 (2011) 700-707; DOI: 10.1016/

26. L-H. Zhang, V. S. Kamanna, M. C. Zhang and M. L. Kashyap, Niacin inhibits surface expression of ATP synthase b chain in HepG2 cells: implications for raising HDL, J. Lipid Res. 49 (2008) 1195-1201; DOI: 10.1194/jlr.M700426-JLR200.

27. S. H. Ganji, S. Tavintharan, D. Zhu, Y. Xing, V. S. Kamanna and M. L. Kashyap, Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells, J. Lipid Res. 45 (2004) 1835-1845; DOI: 10.1194/jlr.M300403-JLR200.

28. B. J. Wu, L. Yan, F. Charlton, P. Witting, P. J. Barter and K. A. Rye, Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 968-975; DOI: 10.1161/ATVBAHA.109.201129.

29. J. E. Digby, E. McNeill, O. J. Dyar, V. Lam, D. R. Greaves and R. P. Choudhury, Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, rantes, and mcp-1 and upregulation of adiponectin, Atherosclerosis 209 (2010) 89-95; DOI: 10.1016/j.atherosclerosis.2009.08.045.

30. J. E. Digby, F. Martinez, A. Jefferson, N. Ruparelia, J. Chai, M. Wamil, D. R. Graves and R. P. Choudhury, Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms, Arterioscl. Thromb. Vas. Biol. 32 (2012) 669-676; DOI: 10.1161/ ATVBAHA.111.241836.

31. D. H. Endemann and E. L. Schiffrin, Endothelial dysfunction, J. Am. Soc. Nephrol. 15 (2004) 1983-1992; DOI: 10.1097/01.ASN.0000132474.50966.DA.

32. H. N. Siti, Y. Kamisah and J. Kamsiah, The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review), Vascul. Pharmacol. 71 (2015) 40-56; DOI: 10.1016/j. vph.2015.03.005.

33. B. Chen, Y. Lu, Y. Chen and J. Cheng, The role of Nrf2 in oxidative stress-induced endothelial injuries, J. Endocrinol. 225 (2015) R83-R99; DOI: 10.1530/JOE-14-0662.

34. S. H. Ganji, S. Qin, L. Zhang, V. S. Kamanna and M. L. Kashyap, Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells, Atherosclerosis 202 (2009) 68-75; DOI: 10.1016/j.atherosclerosis.2008.04.044.

35. S. Tavintharan, S. C. Lim and C. F. Sum, Effects of niacin on cell adhesion and early atherogenesis: biochemical and functional findings in endothelial cells, Basic Clin. Pharmacol. Toxicol. 104 (2009) 206-210; DOI: 10.1111/j.1742-7843.2008.00364.x.

36. E. P. Plaisance, M. Lukasova, S. Offermanns, Y. Zhang, G. Cao and R. L. Judd, Niacin stimulates adiponectin secretion through the GPR109A receptor, Am. J. Physiol. Endocrinol. Metab. 296 (2009) E549-E558; DOI: 10.1152/ajpendo.91004.2008.

37. M. Iantorno, U. Campia, N. Di Daniele, S. Nistico, G. B. Forleo, C. Cardillo and M. Tesauro, Obesity, inflammation and endothelial dysfunction, J. Biol. Regul. Homeost. Agents 28 (2014) 169-176.

38. A. Warnholtz, P. Wild, M. A. Ostad, V. Elsner, F. Stieber, R. Schinzel, U. Walter, D. Peetz, K. Lackner, S. Blankenberg and T. Munzel, Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study, Atherosclerosis 204 (2009) 216-221; DOI: 10.1016/j.atherosclerosis.2008.08.003.

39. S. Sahebkar, Effect of niacin on endothelial function: A systematic review and meta-analysis of randomized controlled trials, Vasc. Med. 19 (2014) 54-66; DOI: 10.1177/1358863X13515766.

40. S. Westphal, K. Borucki, C. Luley, J. Martens-Lobenhoffer and S. M. Bode-Böger, Treatment with niacin lowers ADMA, Atherosclerosis 184 (2006) 448-450; DOI: 10.1016/j.atherosclerosis.2005.11.018.

41. B. J. Wu, K. Chen, P. J. Barter and K. A. Rye, Niacin inhibits vascular inflammation via the induction of heme oxygenase-1, Circulation 125 (2012) 150-158; DOI: 10.1161/CIRCULATIONAHA.111.053108.

42. K. H. Cho, H. J. Kim, B. Rodriguez-Iturbe and N. D. Vaziri, Niacin ameliorates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure, Am. J. Physiol. Renal Physiol. 297 (2009) F106-F113; DOI: 10.1152/ajprenal.00126.2009.

43. A. El Atrash, L. Dawood, E. Tousson and A. Salama, Neuroprotective role of vitamin B3 in experimentally induced oxidative stress, Int. J. Clin. Exp. Neurol. 3 (2015) 21-25; DOI: 10.12691/ijcen-3-1-4.

44. S. Hamoud, M. Kaplan, E. Meilin, A. Hassan, R. Torgovicky, R. Cohen and T. Hayek, Niacin administration significantly reduces oxidative stress in patients with hypercholesterolemia and low levels of high-density lipoprotein cholesterol, Am. J. Med. Sci. 345 (2013) 195-199; DOI: 10.1097/ MAJ.0b013e3182548c28.

45. A. Kei, C. Tellis, E. Liberopoulos, A. Tselepis and M. Elisaf, Effect of switch to the highest dose of rosuvastatin versus add-on-statin fenofibrate versus add-on-statin nicotinic acid/laropiprant on oxidative stress markers in patients with mixed dyslipidemia, Cardiovasc. Ther. 32 (2014) 139-146; DOI: 10.1111/1755-5922.12072.

46. M Lukasova, C. Malaval, A. Gille, J. Kero and S. Offermanns, Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells, J. Clin. Invest. 121 (2011) 1163-1173; DOI: 10.1172/JCI41651.

47. W. Y. Kwon, G. J. Suh, K. S. Kim and Y. H. Kwak, Niacin attenuates lung inflammation and improves survival during sepsis by downregulating the nuclear factor-kB pathway, Crit. Care Med. 39 (2011) 328-334; DOI: 10.1097/CCM.0b013e3181feeae4.

48. Y. Si, Y. Zhang, J. Zhao, S. Guo, L. Zhai, S. Yao, H. Sang, N. Yang, G. Song, J. Gu and S. Qin, Niacin inhibits vascular inflammation via downregulating nuclear transcription factor-kB signaling pathway, Mediators Inflamm. 2014 (2014) article ID 263786 (12 pages); DOI: 10.1155/2014/263786.

49. J. T. Kuvin, D. M. Dave, K. A. Sliney, P. Mooney, A. R. Patel, C. D. Kimmelstiel and R. H. Karas, Effects of extended release niacin on lipoprotein particle size, distribution, an inflammatory markers in patients with coronary artery disease, Am. J. Cardiol. 98 (2006) 743-745; DOI:10.1016/j. amjcard.2006.04.011.

50. M. Thoenes, A. Oguchi, S. Nagamia, C. S. Vaccari, R. Hammoud, G. E. Umpierrez and B. V. Khan, 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. 61 (2007) 1942-1948; DOI: 10.1111/j.1742-1241.2007.01597.x.

51. P. M. Ridker, M. J. Stampfer and N. Rifai, Novel risk factors for systemic atherosclerosis. A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease, JAMA 285 (2001) 2481-2485; DOI: 10.1001/ jama.285.19.2481.

52. N. Singh, A. Gurav, S. Sivaprakasam, E. Brady, R. Padia, H. Shi, M. Thangaraju, P. D. Prasad, S. Manicassamy, D. H. Munn, J. R. Lee, S. Offermanns and V. Ganapathy, Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis, Immunity 40 (2014) 128-139; DOI: 10.1016/j.immuni.2013.12.007.

53. J. O. Johansson, N. Egberg, A. Asplund-Carlson and L. A. Carlson, Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men, J. Cardiovasc. Risk 4 (1997) 165-171; DOI: 10.1177/174182679700400302.

54. S. Tavintharan, M. Sivakumar, S. C. Lim and C. F. Sum, Niacin affects cell adhesion molecules and plasminogen activator inhibitor-1 in HepG2 cells, Clin. Chim. Acta 376 (2007) 41-44; DOI: 10.1016/j. cca.2006.07.009.

55. R. S. Rosenson, Antiatherothrombotic effects of nicotinic acid, Atherosclerosis 171 (2003) 87-96; DOI: 10.1016/j.atherosclerosis.2003.07.003.

56. G. Lowe, A. Rumley, J. Norrie, I. Ford, J. Shepherd, S. Cobbe, P. Macfarlane and C. Packard, Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study, Thromb. Haemost. 84 (2000) 553-558. Erratum in: Thromb. Haemost. 85 (2001) 946.

57. L. Wilhelmsen, K. Svärdsudd, K. Korsan-Bengtsen, B. Larsson, L. Welin and G. Tibblin, Fibrinogen as a risk factor for stroke and myocardial infarction, N. Engl. J. Med. 311 (1984) 501-505; DOI: 10.1056/NEJM198408233110804.

58. W. B. Kannel, P. A. Wolf, W. P. Castelli and R. B. D‘Agostino, Fibrinogen and risk of cardiovascular disease. The Framingham Study, JAMA 258 (1987) 1183-1186; DOI:10.1001/jama.1987.03400090067035.

59. J. Ma, C. H. Hennekens, P. M. Ridker and M. J. Stampfer, A prospective study of fibrinogen and risk of myocardial infarction in the physicians‘ health study, J. Am. Coll. Cardiol. 33 (1999) 1347-1352; DOI:10.1016/S0735-1097(99)00007-8.

60. P. Y. Scarabin, D. Arveiler, P. Amouyel, C. Dos Santos, A. Evans, G. Luc, J. Ferrières and I. Juhan- Vague, Prospective epidemiological study of myocardial infarction. Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study, Atherosclerosis 166 (2003) 103-109; DOI: 10.1016/S0021-9150(02)00309-X.

61. A. Kei and M. Elisaf, Nicotinic acid/laropiprant reduces platelet count but increases mean platelet volume in patiens with primary dyslipidemia, Arch. Med. Sci. 3 (2014) 439-444; DOI: 10.5114/ aoms.2014.43738.

62. K. Stach, F. Zaddach, X. D. Nguyen, E. Elmas, S. Kralev, C. Weiß, M. Borggrefe and T. Kälsch, Effects of nicotinic acid on endothelial cells and platelets, Cardiovasc. Pathol. 21 (2012) 89-95; DOI: 10.1016/j.carpath.2011.04.002.

63. A. M. Gotto and H. Pownall, Manual of Lipid Disorders, 3rd ed., Lippincott Williams & Wilkins, Philadelphia 2003.

64. L. A. Carlson, Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review, J. Intern. Med. 258 (2005) 94-114; DOI: 10.1111/j.1365-2796.2005.01528.x.

65. [The Emerging Risk Factors Collaboration] S. Erqou, S. Kaptoge, P. L. Perry, E. A. Di Angelantonio, I. R. Thompson, S. M. White, R. Marcovina, R. Collins, S. G. Thompson and J. Danesh, Lipoprotein(a) concentration and the risk of coronary heart disease, stroke and nonvascular mortality, JAMA 302 (2009) 412-423; DOI: 10.1001/jama.2009.1063.

66. M. L. Koschinsky and S. M. Marcovina, Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity, Curr. Opin. Lipidol. 15 (2004) 167-167; DOI: 10.1097/

67. S. Tsimikas, L. D. Tsironis and A. D. Tselepis, New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 2094-2099; DOI: 10.1161/01.ATV.0000280571.28102.d4..

68. S. Tsimikas, J. Willeit, M. Knoflach, M. Mayr, G. Egger, M. Notdurfter, J. L. Witztum, C. J. Wiedermann, Q. Xu and S. Kiechl, Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study, Eur. Heart J. 30 (2009) 107-115; DOI: 10.1093/eurheartj/ehn502.

69. V. Serebruany, A. Malinin, D. Aradi, W. Kuliczkowski, N. B. Norgard and W. E. Boden, The in vitro effects of niacin on platelet biomarkers in human volunteers, Thromb. Haemost. 104 (2010) 311-317; DOI: 10.1160/TH10-01-0015.

70. M. Liu and F. Liu, Transcriptional and post-translational regulation of adiponectin, Biochem. J. 425 (2009) 41-52; DOI: 10.1042/BJ20091045.

71. H. Kobayashi, N. Ouchi, S. Kihara, K. Walsh, M. Kumada, Y. Abe, T. Funahashi and Y. Matsuzawa, Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin, Circ. Res. 94 (2004) e27-e31; DOI: 10.1161/01.RES.0000119921.86460.37.

72. M. Kumada, S. Kihara, S. Sumitsuji, T. Kawamoto, S. Matsumoto, N. Ouchi, Y. Arita, Y. Okamoto, I. Shimomura, H. Hiraoka, T. Nakamura, T. Funahashi, Y. Matsuzawa and Osaka CAD Study Group. Coronary artery disease, Association of hypoadiponectinemia with coronary artery disease in men, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 85-89; DOI: 10.1161/01.ATV.0000048856.22331.50.

73. F. Otsuka, S. Sugiyama, S. Kojima, H. Maruyoshi, T. Funahashi, K. Matsui, T. Sakamoto, M. Yoshimura, K. Kimura, S. Umemura and H. Ogawa, Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease, J. Am. Coll. Cardiol. 48 (2006) 1155-1162; DOI: 10.1016/j.jacc.2006.05.054.

74. T. Pischon, C. J. Girman, G. S. Hotamisligil, N. Rifai, F. B. Hu and E. B. Rimm, Plasma adiponectin levels and risk of myocardial infarction in men, JAMA 291 (2004) 1730-1737; DOI: 10.1001/ jama.291.14.1730.

75. W. Koenig, N. Khuseinova, J. Baumert, C. Meisinger and H. Löwel, Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany, J. Am. Coll. Cardiol. 48 (2006) 1369-1377; DOI: 10.1016/j.jacc.2006.06.053.

76. C. Kistorp, J. Faber, S. Galatius, F. Gustafsson, J. Frystyk, A. Flyvbjerg and P. Hildebrandt, Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure, Circulation 112 (2005) 1756-1762; DOI: 10.1161/CIRCULATIONAHA.104.530972.

77. T. Nakamura, H. Funayama, N. Kubo, T. Yasu, M. Kawakami, M. Saito, S. Momomura and S. E. Ishikawa, Association of hyperadiponectinemia with severity of ventricular dysfunction in congestive heart failure, Circ. J. 70 (2006) 1557-1562; DOI: 10.1253/circj.70.1557.

78. T. Tamura, Y. Furukawa, R. Taniguchi, Y. Sato, K. Ono, H. Horiuchi, Y. Nakagawa, T. Kita and T. Kimura, Serum adiponectin level as an independent predictor of mortality in patients with congestive heart failure, Circ. J. 71 (2007) 623-630; DOI: 10.1253/circj.71.623.

79. L. Chen, W. Y. So, S. Y. Li, Q. Cheng, B. J. Boucher and P. S. Leung, Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets, Mol. Cell. Endocrinol. 404 (2015) 56-66; DOI: 10.1016/j.mce.2015.01.029.

80. T. E. Graham, Q. Yang, M. Blüher, A. Hammarstedt, T. P. Ciaraldi, R. R. Henry, C. J. Wason, A. Oberbach, P. A. Jansson, U. Smith and B. B. Kahn, Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects, N. Engl. J. Med. 354 (2006) 2552-2563; DOI: 10.1056/NEJMoa054862.

81. Q. Yang, T. E. Graham, N. Mody, F. Preitner, O. D. Peroni, J. M. Zabolotny, K. Kotani, L. Quadro and B. B. Kahn, Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes, Nature 436 (2005) 356-362; DOI: 10.1038/nature03711.

82. V. C. Luft, M. Pereira, J. S. Pankow, C. Ballantyne, D. Couper, G. Heiss and B. B. Duncan, Retinol binding protein 4 and incident diabetes - the Atherosclerosis Risk in Communities Study (ARIC Study), Rev. Bras. Epidemiol. 16 (2013) 388-397; DOI: 10.1590/S1415-790X2013000200014.

83. B. Vergès, B. Guiu, J. P. Cercueil, L. Duvillard, I. Robin, P. Buffier, B. Bouillet, S. Aho, M. C. Brindisi and J. M. Petit, Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus, Arterioscler. Thromb. Vasc. Biol. 32 (2012) 3050-3057; DOI: 10.1161/ATVBAHA.112.255190.

84. D. Wanders, Novel Pleiotropic Effects of Niacin, Ph. D. Thesis, Auburn University, Auburn (AL, USA) 2012.

85. M. M. Heemskerk, H. K. Dharuri, S. A. van den Berg, H. S. Jónasdóttir, D. P. Kloos, M. Giera, K. W. van Dijk and V. van Harmelen, Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile, J. Lipid Res. 55 (2014) 2532-2540; DOI: 10.1194/jlr.M051938.

86. R. Fischer, A. Konkel, H. Mehling, K. Blossey, A. Gapelyuk, N. Wessel, C. von Schacky, R. Dechend, D. N. Muller, M. Rothe, F. C. Luft, K. Weylandt and W. H. Schunck, Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway, J. Lipid Res. 55 (2014) 1150-1164; DOI: 10.1194/jlr.M047357.

87. S. H. Ganji, G. D. Kukes, N. Lambrecht, M. L. Kashyap and V. S. Kamanna, Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease, Am. J. Physiol. Gastrointest. Liver Physiol. 306 (2014) G320-G327; DOI: 10.1152/ajpgi.00181.2013.

88. M. Hara, M. Kurano, K. Tsuneyama, K. Kikuchi, A. Takai, T. Matsushima and K. Tsukamoto, Nicotinic acid prevents and restores steatohepatitis together with amelioration of postprandial dyslipidemia, Arterioscler. Thromb. Vasc. Biol. 34 (2014) A601. American Heart Association (AHA) Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2014 Spring Conference, Toronto, Canada, May 1-3, 2014.

89. T. H. Grahn, R. Kaur, J. Yin, M. Schweiger, V. M. Sharma, M. J. Lee, Y. Ido, C. M. Smas, R. Zechner, A. Lass and V. Puri, Fat-specific protein 27 (FSP27) interacts with adipose triglyceride lipase (ATGL) to regulate lipolysis and insulin sensitivity in human adipocytes, J. Biol. Chem. 289 (2014) 12029-12039; DOI: 10.1074/jbc.M113.539890.

90. E. Fabbrini, B. S. Mohammed, K. M. Korenblat, F. Magkos, J. McCrea, B. W. Patterson and S. Klein, Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease, J. Clin. Endocrinol. Metab. 95 (2010) 2727-2735; DOI: 10.1210/jc.2009-2622.

91. M. Hu, W. C. Chu, S. Yamashita, D. K. Yeung, L. Shi, D. Wang, D. Masuda, Y. Yang and B. Tomlinson, Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients, J. Lipid Res. 53 (2012) 802-809; DOI: 10.1194/jlr.P023614.

92. R. N. Foley, P. S. Parfrey and M. J. Sarnak, Epidemiology of cardiovascular disease in chronic renal disease, J. Am. Soc. Nephrol. 9 (Suppl. 12) (1998) S16-S23.

93. A. S. Go, G. M. Chertow, D. Fan, C. E. McCulloch and C. Y. Hsu, Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization, N. Engl. J. Med. 351 (2004) 1296-1305; DOI: 10.1056/NEJMoa041031.

94. M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B. Culleton, L. L. Hamm, P. A. McCullough, B. L. Kasiske, E. Kelepouris, M. J. Klag, P. Parfrey, M. Pfeffer, L. Raij, D. J. Spinosa and P. W. Wilson, Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention, Circulation 108 (2003) 2154–2169; DOI: 10.1161/01.CIR.0000095676.90936.80.

95. J. Omran, A. Al-Dadah and K. C. Dellsperger, Dyslipidemia in patients with chronic and endstage kidney disease, Cardiorenal Med. 3 (2013) 165–177; DOI: 10.1159/000351985.

96. N. D. Vaziri, Causes of dysregulation of lipid metabolism in chronic renal failure, Semin. Dial. 22 (2009) 644–651; DOI: 10.1111/j.1525-139X.2009.00661.x.

97. V. Tsimihodimos, Z. Mitrogianni and M. Elisaf, Dyslipidemia associated with chronic kidney disease, Open Cardiovasc. Med. J. 5 (2011) 41–48.

98. E. A. Friedman, Consequences and management of hyperphosphatemia in patients with renal insufficiency, Kidney Int. Suppl. 95 (2005) S1-S7; DOI: 10.1111/j.1523-1755.2005.09500.x.

99. M. Tonelli, N. Pannu and B. Manns, Oral phosphate binders in patients with kidney failure, N. Engl. J. Med. 362 (2010) 1312–1324; DOI: 10.1056/NEJMra0912522.

100. H. J. Kang, D. Y. Kim, S. M. Lee, K. H. Kim, S. H. Han, H. K. Nam, K. H. Kim, S. E. Kim, Y. K. Son and W. S. An, Effect of low-dose niacin on dyslipidemia, serum phosphorus levels and adverse effects in patients with chronic kidney disease, Kidney Res. Clin. Pract. 32 (2013) 21–26; DOI: 10.1016/j.krcp.2012.12.001.

101. D. Maccubbin, D. Tipping, O. Kuznetsova, W. A. Hanlon and A. G. Bostom, Hypophosphatemic effect of niacin in patients without renal failure: a randomized trial, Clin. J. Am. Soc. Nephrol. 5 (2010) 582–589; DOI: 10.2215/CJN.07341009.

102. P. Aramwit, R. Srisawadwong and O. Supasyndh, Effectiveness and safety of extended-release nicotinic acid for reducing serum phosphorus in hemodialysis patients, J. Nephrol. 25 (2012) 354–362; DOI: 10.5301/jn.5000011.

103. K. Kitai, H. Tanaka, S. Tatsymi, Y. Fukunaga, K. Genjida, K. Morita, N. Kuboyama, T. Suzuki, T. Akita, K. Miyamoto and E. Takeda, Nicontinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestine, Nephrol. Dial. Transplant. 14 (1999) 1195–1201; DOI: 10.1093/ndt/14.5.1195.

104. S. Shin and S. Lee, Niacin as a drug repositioning candidate for hyperphosphatemia management in dialysis patients, Ther. Clin. Risk Manag. 10 (2014) 875–883; DOI: 10.2147/TCRM.S71559.

105. M. H. Ahmed, Niacin as potential treatment for dyslipidemia and hyperphosphatemia associated with chronic renal failure: the need for clinical trials, Renal Failure. 32 (2010) 642–646; DOI: 10.3109/08860221003753323.

106. E. Streja, C. P. Kovesdy, D. A. Streja, H. Moradi, K. Kalantar-Zadeh and M. L. Kashyap, Niacin and progression of CKD, Am. J. Kidney Dis. 65 (2015) 785–798; DOI: 10.1053/j.ajkd.2014.11.033.

107. M. Al-Hijji, S. S. Martin, P. H. Joshi and S. R. Jones, Effect of equivalent on-treatment apolipoprotein levels on outcomes (from the AIM-HIGH and HPS2-THRIVE), Am. J. Cardiol. 112 (2013) 1697–1700; DOI: 10.1016/j.amjcard.2013.07.030.

108. A. Owada, S. Suda and T. Hata, Antiproteinuric effect of niceritrol, a nicotinic acid derivative, in chronic renal disease with hyperlipidemia: a randomized trial, Am. J. Med. 114 (2003) 347–353; DOI: 10.1016/S0002-9343(02)01567-X.

109. H. Goel and R. L. Dunbar, Niacin alternatives for dyslipidemia: Fool’s gold or gold mine? Part II: Novel niacin mimetics, Curr. Atheroscler. Rep. 18 (2016) article 17 (13 pages); DOI: 10.1007/s11883-016-0570-9.

110. R. S. Birjmohun, B. A. Hutten, J. J. P. Kastelein and E. S. G. Stroes, Efficacy and safety of highdensity lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials, J. Am. Coll. Cardiol. 45 (2005) 185–197; DOI: 10.1016/j.jacc.2004.10.031.

111. J. Hanson, A. Gille, S. Zwykiel, M. Lukasova, B. E. Clausen, K. Ahmed, S. Tunaru, A. Wirth and S. Offermanns, Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice, J. Clin. Invest. 120 (2010) 2910-2919; DOI: 10.1172/JCI42273.

112. R. H. Stern, J. D. Spence, D. J. Freeman and A. Parbtani, Tolerance to nicotinic acid flushing, Clin. Pharmacol. Ther. 50 (1991) 66-70; DOI: 10.1038/clpt.1991.104.

113. S. Andersson, L. A. Carlson, L. Orö and E. A. Richards, Effect of nicotinic acid on gastric secretion of acid in human subjects and in dogs, Scand. J. Gastroenterol. 6 (1971) 555-559; DOI: 10.3109/00365527109179938.

114. J. McKenney, New perspectives on the use of niacin in the treatment of lipid disorders, Arch. Intern. Med. 164 (2004) 697-705; DOI: 10.1001/archinte.164.7.697.

115. S. S. Bhardwaj and N. Chalasani, Lipid-lowering agents that cause drug-induced hepatotoxicity, Clin. Liver Dis. 11 (2007) 597-613; DOI: 10.1016/j.cld.2007.06.010.

116. J. R. Guyton and H. E. Bays, Safety considerations with niacin therapy, Am. J. Cardiol. 99 (6, Suppl. 1) (2007) S22-S31; DOI: 10.1016/j.amjcard.2006.11.018.

117. J. R. Guyton, S. Fazio, A. J. Adewale, E. Jensen, J. E. Tomassini, A. Shah and A. M. Tershakovec, Effect of extended-release niacin on new-onset diabetes among hyperlipidemic patients treated with ezetimibe/simvastatin in a randomized controlled trial, Diabetes Care 35 (2012) 857-860; DOI: 10.2337/dc11-1369.

118. A. M. Poynten, S. K. Gan, A. D. Kriketos, A. O’Sullivan, J. J. Kelly, B. A. Ellis, D. J. Chisholm and L. V. Campbell, Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content, Metabolism 52 (2003) 699-704; DOI: 10.1016/ S0026-0495(03)00030-1.

119. L. A. Carlson and L.Oro, The effect of nicotinic acid on the plasma free fatty acid; demonstration of a metabolic type of sympathicolysis, Acta Med. Scand. 172 (1962) 641-645; DOI: 10.1111/j.0954-6820.1962.tb07203.x.

120. M. M. Heemskerk, S. A. A. van den Berg, A. C. M. Pronk, J.-B. van Klinken, M. R. Boon, L. M. Havekes, P. C. N. Rensen, K. W. van Dijk and V. van Harmelen, Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B, Am. J. Physiol. Endocrinol. Metabol. 306 (2014) E808-E813; DOI:10.1152/ ajpendo.00641.2013.

121. L. Chen, W. Y. So, S. Y. T. Li, Q. Cheng, B. J. Boucher and P. S. Leung, Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets, Mol. Cell. Endocrinol. 404 (2015) 56-66; DOI: 10.1016/j.mce.2015.01.029.

122. T. P. Wong, L. K. Y. Chan and P. S. Leung, Involvement of the niacin receptor GPR109a in the local control of glucose uptake in small intestine of type 2 diabetic mice, Nutrients 7 (2015) 7543-7561; DOI: 10.3390/nu7095352.

123. C. Goldie, A. J. Taylor, P. Nguyen, C. McCoy, X.-Q. Zhao and D. Preiss, Niacin therapy and the risk of new-onset diabetes: A meta-analysis of randomised controlled trials, Heart 102 (2016) 198-203; DOI: 10.1136/heartjnl-2015-308055.

124. P. L. Canner, C. D. Furberg, M. L. Terrin and M. E. McGovern, Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project), Am. J. Cardiol. 95 (2005) 254-257; DOI: 10.1016/j.amjcard.2004.09.013.

125. S. L.Gershon and I. H. Fox, Pharmacologic effects of nicotinic acid on human purine metabolism, J. Lab. Clin. Med. 84 (1974) 179-186.

126. Z. N. Gaut, R. Pocelinko, H. M. Solomon and G. B. Thomas, Oral glucose tolerance, plasma insulin, and uric acid excretion in man during chronic administration of nicotinic acid, Metabolism 20 (1971) 1031-1035; DOI: 10.1016/0026-0495(71)90026-6.

127. D. Domanico, F. Verboschi, S. Altimari, L. Zompatori and E. M. Vingolo, Ocular effects of niacin: A review of the literature, Med. Hypothesis Discov. Innov. Ophthalmol. 4 (2015) 64–71.

128. H. Stals, C. Vercammen, C. Peeters and M. A. Morren, Acanthosis nigricans caused by nicotinic acid: case report and review of the literature, Dermatology 189 (1994) 203–206; DOI: 10.1159/000246834.

129. A. G. Gharavi, J. A. Diamond, D. A. Smith and R. A. Phillips, Niacin-induced myopathy, Am. J. Cardiol. 74 (1994) 841–842; DOI: 10.1016/0002-9149(94)90453-7.

130. A. Pandian, A. Arora, L. S. Sperlinga and B. V. Khan, Targeting mulitple dyslipidemias with fixed combinations – focus on extended release niacin and simvastatin, Vasc. Health Risk Manag. 4 (2008) 1001–1009; DOI: 10.2147/VHRM.S3460.

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