Safety of extended-release niacin/laropiprant in patients with dyslipidemia

Published:February 15, 2010DOI:


      To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program.


      Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931).


      The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin.


      The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.


      To read this article in full you will need to make a payment


      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Gotto A.M.
        High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease.
        Am Heart J. 2002; 144: S33-S42
        • Shah P.K.
        • Kaul S.
        • Nilsson J.
        • Cercek B.
        Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins—an idea whose time for testing is coming, Part I.
        Circulation. 2001; 104: 2376-2383
      1. 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; 106: 3143-3421
        • Anon
        The coronary drug project.
        JAMA. 1972; 221: 918
        • Brown B.G.
        • Zhao X.Q.
        • Chait A.
        • et al.
        Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
        N Engl J Med. 2001; 345: 1583-1592
        • Brown B.G.
        • Hillger L.
        • Zhao X.Q.
        • Poulin D.
        • Albers J.J.
        Types of change in coronary stenosis severity and their relative importance in overall progression and regression in coronary disease. Observations from the FATS trial. Familial Atherosclerosis Treatment study.
        Ann NY Acad Sci. 1995; 748: 407-417
        • Brown B.G.
        • Bardsley J.
        • Poulin D.
        • et al.
        Moderate dose, 3-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: 111-115
        • The Coronary Drug Project Research Group
        Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • Canner P.L.
        • Berge K.G.
        • Wenger N.K.
        • et al.
        Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
        J Am Coll Cardiol. 1986; 8: 1245-1255
        • Guyton J.R.
        • Bays H.E.
        Safety considerations with niacin therapy.
        Am J Cardiol. 2007; 99: 22C-31C
        • Knopp R.H.
        • Ginsberg J.
        • Albers J.J.
        • 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: 642-650
        • Birjmohun R.S.
        • Hutten B.A.
        • Kastelein J.J.
        • Stroes E.S.
        Increasing HDL cholesterol with extended-release nicotinic acid: from promise to practice.
        Neth J Med. 2004; 62: 229-234
        • Illingworth D.R.
        • Stein E.A.
        • Mitchel Y.B.
        • et al.
        Comparative effects of lovastatin and niacin in primary hypercholesterolemia: a prospective trial.
        Arch Intern Med. 1994; 154: 1586-1595
        • Mills E.
        • Prousky J.
        • Raskin G.
        • et al.
        The safety of over-the-counter niacin. A randomized placebo-controlled trial.
        BMC Clin Pharmacol. 2003; 3: 4-11
        • Kamal-Bahl S.J.
        • Burke T.
        • Watson D.
        • Wentworth C.
        Discontinuation of lipid modifying drugs among commercially insured United States patients in recent clinical practice.
        Am J Cardiol. 2007; 99: 530-534
        • Kamal-Bahl
        • Burke T.
        • Watson D.
        Dosage, titration, and gaps in treatment with extended release niacin in clinical practice.
        Curr Med Res Opin. 2008; 24: 1817-1821
        • Cheng K.
        • Wu T.J.
        • Wu K.K.
        • et al.
        Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.
        Proc Natl Acad Sci U S A. 2006; 103: 6682-6687
        • Kaijser L.
        • Eklund B.
        • Olsson A.G.
        • Carlson L.A.
        Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man.
        Med Biol. 1979; 57: 114-117
        • Negishi M.
        • Sugimoto Y.
        • Ichikawa A.
        Prostanoid receptors and their biological actions.
        Prog Lipid Res. 1993; 32: 417-434
        • Sturino C.F.
        • O'Neill G.
        • Lachance N.
        • et al.
        Discovery of a potent and selective prostaglandin D(2) receptor antagonist, [(3R)-4-(4-Chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid (MK-0524).
        J Med Chem. 2007; 50: 794-806
        • Maccubbin D.
        • Bays H.E.
        • Olsson A.G.
        • et al.
        Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesteroaemia or mixed dyslipidaemia.
        Int J Clin Pract. 2008; 62: 1959-1970
        • Paolini J.F.
        • Mitchel Y.B.
        • Reyes R.
        • et al.
        Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia.
        Am J Cardiol. 2008; 101: 625-630
        • Van Hecken A.
        • Depré M.
        • De Lepeleire I.
        • et al.
        The effect of MK-0524, a prostaglandin D2 receptor antagonist, on prostaglandin D2-induced nasal airway obstruction in healthy volunteers.
        Eur J Pharmacol. 2007; 63: 135-141
        • Lai E.
        • Wenning L.A.
        • Crumley T.M.
        • et al.
        Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist.
        Clin Pharacol Ther. 2008; 83: 840-847
        • Gleim G.
        • Ballantyne C.M.
        • Liu N.
        • et al.
        Efficacy and safety profile of co-administered ER niacin/laropiprant and simvastatin in dyslipidaemia.
        Br J Cardiol. 2009; 16: 90-97
        • Koren M.J.
        • Maccubbin D.
        • Davidson M.
        • et al.
        Flushing profile of extended release niacin/laropiprant versus gradually titrated Niaspan™ in patients with dyslipidemia.
        J Am Coll Cardiol. 2008; 51 ([abstract]): A324
        • Tatò F.
        • Vega G.L.
        • Grundy S.M.
        Effects of crystalline nicotinic acid-induced hepatic dysfunction of serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase.
        Am J Cardiol. 1998; 81: 805-807
        • Rader J.I.
        • Calvert R.J.
        • Hathcock J.N.
        Hepatic toxicity of unmodified and time-release preparations of niacin.
        Am J Med. 1992; 92: 77-81
        • Grundy S.M.
        • Vega G.L.
        • McGovern M.E.
        • et al.
        • Diabetes Multicenter Research Group
        Efficacy, safety, and tolerability of once-daily niacin for the treatment of dysplipidemia associated with type 2 diabetes—results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial.
        Arch Intern Med. 2002; 162: 1568-1576
        • Elam M.B.
        • Hunninghake D.B.
        • Davis K.B.
        • et al.
        Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease.
        JAMA. 2000; 284: 1263-1270
        • Knopp R.H.
        • 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; 47: 1097-1104