Effect of Extended-Release Niacin on High-Density Lipoprotein (HDL) Functionality, Lipoprotein Metabolism, and Mediators of Vascular Inflammation in Statin-Treated Patients

Rahul Yadav, Yifen Liu, See Kwok, Salam Hama, Michael France, Ruth Eatough, Phil Pemberton, Jonathan Schofield, Tarza J Siahmansur, Rayaz Malik, Basil A Ammori, Basil Issa, Naveed Younis, Rachelle Donn, Adam Stevens, Paul Durrington, Handrean Soran, Rahul Yadav, Yifen Liu, See Kwok, Salam Hama, Michael France, Ruth Eatough, Phil Pemberton, Jonathan Schofield, Tarza J Siahmansur, Rayaz Malik, Basil A Ammori, Basil Issa, Naveed Younis, Rachelle Donn, Adam Stevens, Paul Durrington, Handrean Soran

Abstract

Background: The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment.

Methods and results: In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity.

Conclusions: ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL-C-raising effect.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054508.

Keywords: HDL functionality; LDL quality; cholesterol efflux; extended‐release niacin; inflammation; laropiprant; oxidation.

© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Study overview. Patients randomized to placebo during the first period received extended-release niacin/laropiprant (ERN/LRP) in the second period and vice versa. In each period, the ERN/LRP dose was increased from 1 g/20 mg to 2 g/40 mg after 4 weeks. SC indicates screening visit.
Figure 2
Figure 2
LPO generated over 3 hours on incubating LDL or LDL+HDL with CuSO4 on treatment with ERN/LRP and placebo. HDL on both placebo and ERN/LRP markedly decreased generation of lipid peroxides, *P<0.0001. However, this antioxidant property of HDL was not enhanced by ERN/LRP therapy. Values are in median (interquartile range). ERN/LRP indicates extended release niacin/laropiprant; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LPO, lipid peroxides.
Figure 3
Figure 3
Effect of extended-release niacin/laropiprant (ERN/LRP) (treatment) and placebo on % cholesterol efflux from J774A.1 cells over 4 hours (when control is subtracted), *P=0.045. Control is percent efflux to serum-free media.

References

    1. Miller GJ, Miller NE. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet. 1975;1:16–19.
    1. Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk. Ann Intern Med. 2010;153:800–808.
    1. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–1310.
    1. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267.
    1. HPS2 THRIVE Group. Landray MJ, Haynes R. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–212.
    1. Yadav R, France M, Younis N, Hama S, Ammori BJ, Kwok S, Soran H. Extended-release niacin with laropiprant: a review on efficacy, clinical effectiveness and safety. Expert Opin Pharmacother. 2012;13:1345–1362.
    1. Soran H, Hama S, Yadav R, Durrington PN. HDL functionality. Curr Opin Lipidol. 2012;23:353–366.
    1. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–135.
    1. Patel PJ, Khera AV, Wilensky RL, Rader DJ. Anti-oxidative and cholesterol efflux capacities of high-density lipoprotein are reduced in ischaemic cardiomyopathy. Eur J Heart Fail. 2013;15:1215–1219.
    1. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099.
    1. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–924.
    1. Soran H, Durrington PN. Susceptibility of LDL and its subfractions to glycation. Curr Opin Lipidol. 2011;22:254–261.
    1. Rizos E, Tambaki AP, Gazi I, Tselepis AD, Elisaf M. Lipoprotein-associated PAF-acetylhydrolase activity in subjects with the metabolic syndrome. Prostaglandins Leukot Essent Fatty Acids. 2005;72:203–209.
    1. Thompson A, Gao P, Orfei L, Watson S, Di Angelantonio E, Kaptoge S, Ballantyne C, Cannon CP, Criqui M, Cushman M, Hofman A, Packard C, Thompson SG, Collins R, Danesh J. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet. 2012;375:1536–1544.
    1. Stafforini DM, Tjoelker LW, McCormick SP, Vaitkus D, McIntyre TM, Gray PW, Young SG, Prescott SM. Molecular basis of the interaction between plasma platelet-activating factor acetylhydrolase and low density lipoprotein. J Biol Chem. 1999;274:7018–7024.
    1. Steinbrecher UP, Pritchard PH. Hydrolysis of phosphatidylcholine during LDL oxidation is mediated by platelet-activating factor acetylhydrolase. J Lipid Res. 1989;30:305–315.
    1. Benitez S, Sanchez-Quesada JL, Ribas V, Jorba O, Blanco-Vaca F, Gonzalez-Sastre F, Ordonez-Llanos J. Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction. Circulation. 2003;108:92–96.
    1. Vickers KC, Castro-Chavez F, Morrisett JD. Lyso-phosphatidylcholine induces osteogenic gene expression and phenotype in vascular smooth muscle cells. Atherosclerosis. 2010;211:122–129.
    1. Goncalves I, Edsfeldt A. Evidence supporting a key role of Lp-PLA2 generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol. 2012;32:1505–1512.
    1. Niu N, Yu YH, Wang Y, Wang LJ, Li Q, Guo LM. Combined effects of niacin and chromium treatment on vascular endothelial dysfunction in hyperlipidemic rats. Mol Biol Rep. 2009;36:1275–1281.
    1. Kuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 2006;98:743–745.
    1. Wu BJ, Yan L, Charlton F, Witting P, Barter PJ, Rye KA. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol. 2010;30:968–975.
    1. Christian JB, Olson EJ, Allen JK, Lowe KA. HDL-C response variability to niacin ER in US adults. Cholesterol. 2013 .
    1. Charlton-Menys V, Chobotova J, Durrington PN. Use of the TLX ultracentrifuge for the isolation of different density lipoproteins and effects of freeze/thawing of human plasma before ultracentrifugation. Clin Chem Lab Med. 2008;46:1285–1288.
    1. Charlton-Menys V, Liu Y, Durrington PN. Semiautomated method for determination of serum paraoxonase activity using paraoxon as substrate. Clin Chem. 2006;52:453–457.
    1. Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345–1353.
    1. Brown RE, Jarvis KL, Hyland KJ. Protein measurement using bicinchoninic acid: elimination of interfering substances. Anal Biochem. 1989;180:136–139.
    1. el-Saadani M, Esterbauer H, el-Sayed M, Goher M, Nassar AY, Jurgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent. J Lipid Res. 1989;30:627–630.
    1. de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol. 2010;30:796–801.
    1. Mackness MI, Abbott C, Arrol S, Durrington PN. The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J. 1993;294:829–834.
    1. 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. Biochem Pharmacol. 2004;67:411–419.
    1. Yvan-Charvet L, Kling J, Pagler T. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30:1430–1438.
    1. van der Hoorn JW, de Haan W, Berbee JF, Havekes LM, Jukema JW, Rensen PC, Princen HM. Niacin increases HDL by reducing hepatic expression and plasma levels of cholesteryl ester transfer protein in APOE*3Leiden.CETP mice. Arterioscler Thromb Vasc Biol. 2008;28:2016–2022.
    1. Franceschini G, Favari E, Calabresi L, Simonelli S, Bondioli A, Adorni MP, Zimetti F, Gomaraschi M, Coutant K, Rossomanno S, Niesor EJ, Bernini F, Benghozi R. Differential effects of fenofibrate and extended-release niacin on high-density lipoprotein particle size distribution and cholesterol efflux capacity in dyslipidemic patients. J Clin Lipidol. 2013;7:414–422.
    1. Khera AV, Patel PJ, Reilly MP. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62:1909–1910.
    1. Mackey RH, Greenland P, Goff DCJ. High density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis) J Am Coll Cardiol. 2012;60:508–516.
    1. Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, Digby JE, Neubauer S, Choudhury RP. 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;54:1787–1794.
    1. Hamoud S, Kaplan M, Meilin E. Niacin administration significantly reduces oxidative stress in patients with hypercholesterolemia and low levels of high-density lipoprotein cholesterol. Am J Med Sci. 2013;345:195–199.
    1. Albers JJ, Slee A, Kevin DO. Relationships of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH Trial. J Am Coll Cardiol. 2013;62:1575–1579.
    1. Lamon-Fava S, Diffenderfer MR, Barrett PH, Buchsbaum A, Nyaku M, Lichtenstein AH, Dolnikowski GG, Schaefer EJ. Extended-release niacin alters the metabolism of plasma apolipoprotein (Apo) A-I and ApoB-containing lipoproteins. Arterioscler Thromb Vasc Biol. 2008;28:1672–1678.
    1. Morgan JM, Capuzzi DM, Baksh RI, Intenzo C, Carey CM, Reese D, Walker K. Effects of extended-release niacin on lipoprotein subclass distribution. Am J Cardiol. 2003;91:1432–1436.
    1. Caslake MJ, Stewart G, Day SP, Daly E, McTaggart F, Chapman MJ, Durrington P, Laggner P, Mackness M, Pears J, Packard CJ. Phenotype-dependent and -independent actions of rosuvastatin on atherogenic lipoprotein subfractions in hyperlipidaemia. Atherosclerosis. 2003;171:245–253.
    1. Younis N, Charlton-Menys V, Sharma R, Soran H, Durrington PN. Glycation of LDL in non-diabetic people: small dense LDL is preferentially glycated both in vivo and in vitro. Atherosclerosis. 2009;202:162–168.
    1. Younis NN, Soran H, Sharma R, Charlton-Menys V, Greenstein A, Elseweidy MM, Durrington PN. Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes. Diab Vasc Dis Res. 2010;7:289–295.
    1. Digby JE, Martinez F, Jefferson A. Anti-Inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109a dependent mechanisms. Arterioscler Thromb Vasc Biol. 2012;32:669–676.
    1. Huang PH, Lin CP, Wang CH. Niacin improves ischemia-induced neovascularization in diabetic mice by enhancement of endothelial progenitor cell functions independent of changes in plasma lipids. Angiogenesis. 2012;15:377–389.
    1. Soran H, France MW, Kwok S, Dissanayake S, Charlton-Menys V, Younis NN, Durrington PN. Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients. Ann Clin Biochem. 2011;48:566–571.
    1. Brown BG, Zhao XQ, Chait A, Fisher LD, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–1592.
    1. Maccubbin D, Bays HE, Olsson AG, Elinoff V, Pasternak RC, Paolini JF. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract. 2008;62:1959–1970.
    1. Paolini JF, Mitchel YB, Reyes R, Kher U, Bays HE, Davidson M, Ballantyne CM. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 2008;101:625–630.
    1. Lai E, Wenning LA, Crumley TM, De Lepeleire I, Liu F, Gottesdiener KG, Wagner JA. Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist. Clin Pharmacol Ther. 2008;83:840–847.
    1. Lai E, Schwartz JI, Dallob A, Jumes P, Liu F, McCrary Sisk C, Radziszewski W, Wagner JA. Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects. Platelets. 2010;21:191–198.
    1. McKenney J, Bays H, Koren M, Ballantyne CM, Paolini JF, Mitchel Y, Sisk CM, Maccubbin D. Safety of extended-release niacin/laropiprant in patients with dyslipidemia. J Clin Lipidol. 2010;4:105–112.e101.
    1. Lauring B, Dishy V, Luo WL, Laterza O, Patterson J, Cote J, Chao A, Larson P, Gutierrez M, Wagner JA, Lai E. Laropiprant in combination with extended-release niacin does not alter urine 11-dehydrothromboxane B2, a marker of in vivo platelet function, in healthy, hypercholesterolemic, and diabetic subjects. J Clin Pharmacol. 2009;49:1426–1435.
    1. Dallob A, Luo WL, Luk JM, Ratcliffe L, Johnson-Levonas AO, Lepeleire ID, Radziszewski W, Wagner JA, Lai E. The effects of laropiprant, a selective prostaglandin D(2) receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin. Platelets. 2011;22:495–503.
    1. Song WL, Stubbe J, Ricciotti E. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest. 2012;122:1459–1468.

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