Safety Considerations with Niacin Therapy

Published:November 29, 2006DOI:
      Niacin has beneficial effects on plasma lipoproteins and has demonstrated clinical benefits in reducing cardiovascular events and atherosclerosis progression. The side effects of niacin, however, have limited its use in general clinical practice. An understanding of cutaneous flushing based on the best available evidence should enhance patient education efforts and improve adherence. Although serious hepatic toxicity from niacin administration has been reported, it is largely confined to the use of slow-release formulations given as unregulated nutritional supplements. Niacin has been shown to induce insulin resistance in short-term trials, but the glycemic response in subjects with and without diabetes is usually minor. Niacin can be used safely in patients with diabetes. Despite a few case reports of myopathy associated with niacin-statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) combination therapy, 2 decades of clinical evidence since the introduction of statins do not support a general myopathic effect of niacin either alone or in combination with statins. Rare, less well-defined side effects of niacin include blurred vision due to cystoid macular edema, nausea and vomiting, and the exacerbation of peptic ulcers. Laboratory abnormalities that are usually small (≤10%) and clinically unimportant include increased prothrombin time, increased uric acid, and decreases in platelet count and serum phosphorus. Overall, the perception of niacin side effects is often greater than the reality. As a result, a valuable medication for cardiovascular risk is underused.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


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


        • Knopp R.H.
        • Ginsberg J.
        • Albers J.J.
        • Hoff C.
        • Ogilvie J.T.
        • Warnick G.R.
        • Burrows E.
        • Retzlaff B.
        • Poole M.
        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
        • Gibbons L.W.
        • Gonzalez V.
        • Gordon N.
        • Grundy S.
        The prevalence of side effects with regular and sustained-release nicotinic acid.
        Am J Med. 1995; 99: 378-385
        • McKenney J.M.
        • Proctor J.D.
        • Harris S.
        • Chinchili V.M.
        A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.
        JAMA. 1994; 271: 672-677
        • Coronary Drug Project Research Group
        Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • Goldberg A.
        • Alagona Jr, P.
        • Capuzzi D.M.
        • Guyton J.
        • Morgan J.M.
        • Rodgers J.
        • Sachson R.
        • Samuel P.
        Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
        Am J Cardiol. 2000; 85: 1100-1105
        • Guyton J.R.
        • Blazing M.A.
        • Hagar J.
        • Kashyap M.L.
        • Knopp R.H.
        • McKenney J.M.
        • Nash D.T.
        • Nash S.D.
        Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.
        Arch Intern Med. 2000; 160: 1177-1184
        • Knopp R.H.
        • Alagona P.
        • Davidson M.
        • Goldberg A.C.
        • Kafonek S.D.
        • Kashyap M.
        • Sprecher D.
        • Superko H.R.
        • Jenkins S.
        • Marcovina S.
        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
        • Morgan J.M.
        • Capuzzi D.M.
        • Guyton J.R.
        • Centor R.M.
        • Goldberg R.
        • Robbins D.C.
        • DiPette D.
        • Jenkins S.
        • Marcovina S.
        Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemia: a placebo-controlled trial.
        J Cardiovasc Pharmacol Ther. 1996; 1: 195-202
        • Morrow J.D.
        • Awad J.A.
        • Oates J.A.
        • Roberts II, L.J.
        Identification of skin as a major site of prostaglandin D2 release following oral administration of niacin in humans.
        J Invest Dermatol. 1992; 98: 812-815
        • Stern R.H.
        • Spence J.D.
        • Freeman D.J.
        • Parbtani A.
        Tolerance to nicotinic acid flushing.
        Clin Pharmacol Ther. 1991; 50: 66-70
        • Oberwittler H.
        • Baccara-Dinet M.
        Clinical evidence for use of acetyl salicylic acid in control of flushing related to nicotinic acid treatment.
        Int J Clin Pract. 2006; 60: 707-715
        • Cheng K.
        • Wu T.J.
        • Wu K.K.
        • Sturino C.
        • Metters K.
        • Gottesdiener K.
        • Wright S.D.
        • Wang Z.
        • O’Neill G.
        • Lai E.
        • Waters M.G.
        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
        • Meyers C.D.
        • Carr M.C.
        • Park S.
        • Brunzell J.D.
        Varying cost and free nicotinic acid content in over-the-counter niacin preparations for dyslipidemia.
        Ann Intern Med. 2003; 139: 996-1002
        • Guyton J.R.
        Extended-release niacin for modifying the lipoprotein profile.
        Expert Opin Pharmacother. 2004; 5: 1385-1398
        • Altschul R.
        • Hoffer A.
        • Stephen J.D.
        Influence of nicotinic acid on serum cholesterol in man.
        Arch Biochem. 1955; 54: 558-559
        • Christensen N.A.
        • Achor R.W.
        • Berge K.G.
        • Mason H.L.
        Nicotinic acid treatment of hypercholesterolemia: comparison of plain and sustained-action preparations and report of two cases of jaundice.
        JAMA. 1961; 177: 76-80
        • Patterson D.J.
        • Dew E.W.
        • Gyorkey F.
        • Graham D.Y.
        Niacin hepatitis.
        South Med J. 1983; 76: 239-241
        • Tato F.
        • Vega G.L.
        • Grundy S.M.
        Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesteryl acyl transferase.
        Am J Cardiol. 1998; 81: 805-807
        • Henkin Y.
        • Oberman A.
        • Hurst D.C.
        • Segrest J.P.
        Niacin revisited: clinical observations on an important but underutilized drug.
        Am J Med. 1991; 91: 239-246
        • Henkin Y.
        • Johnson K.C.
        • Segrest J.P.
        Rechallenge with crystalline niacin after drug-induced hepatitis from sustained-release niacin.
        JAMA. 1990; 264: 241-243
        • Capuzzi D.M.
        • Guyton J.R.
        • Morgan J.M.
        • Goldberg A.C.
        • Kreisberg R.A.
        • Brusco O.A.
        • Brody J.
        Efficacy and safety of an extended-release niacin (Niaspan); a long-term study.
        Am J Cardiol. 1999; 82: 74U-81U
      1. Advicor® (niacin extended-release/lovastatin tablets) [prescribing information]. Cranbury, NJ: Kos Pharmaceuticals, Inc.; 2005. Available at: Accessed July 20, 2006.

        • Dearing B.D.
        • Lavie C.J.
        • Lohmann T.P.
        • Genton E.
        Niacin-induced clotting factor synthesis deficiency with coagulopathy.
        Arch Intern Med. 1992; 152: 861-863
        • Gentile S.
        • Tiribelli C.
        • Persico M.
        • Bronzino P.
        • Marmo R.
        • Orzes N.
        • Orlando C.
        • Rubba P.
        • Coltorti M.
        Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert’s syndrome.
        J Lab Clin Med. 1986; 107: 166-171
        • Guyton J.R.
        • Goldberg A.C.
        • Kreisberg R.A.
        • Sprecher D.L.
        • Superko H.R.
        • O’Connor C.M.
        Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia.
        Am J Cardiol. 1998; 82: 737-743
        • Kelly J.J.
        • Lawson J.A.
        • Campbell L.V.
        • Storlien L.H.
        • Jenkins A.B.
        • Whitworth J.A.
        • O’Sullivan A.J.
        Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects.
        J Hum Hypertens. 2000; 14: 567-572
        • Alvarsson M.
        • Grill V.
        Impact of nicotinic acid treatment on insulin secretion and insulin sensitivity in low and high insulin responders.
        Scand J Clin Lab Invest. 1996; 56: 563-570
        • Rasouli N.
        • Hale T.
        • Kahn S.E.
        • Spencer H.J.
        • Elbein S.C.
        Effects of short-term experimental insulin resistance and family history of diabetes on pancreatic beta-cell function in nondiabetic individuals.
        J Clin Endocrinol Metab. 2005; 90: 5825-5833
        • Chang A.M.
        • Smith M.J.
        • Galecki A.T.
        • Bloem C.J.
        • Halter J.B.
        Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance.
        J Clin Endocrinol Metab. 2006; 91: 3303-3309
        • Kahn S.E.
        • Beard J.C.
        • Schwartz M.W.
        • Ward W.K.
        • Ding H.L.
        • Bergman R.N.
        • Taborsky Jr, G.J.
        • Porte Jr, D.
        Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance.
        Diabetes. 1989; 38: 562-568
        • Poynten A.M.
        • Gan S.K.
        • Kriketos A.D.
        • O’Sullivan A.
        • Kelly J.J.
        • Ellis B.A.
        • Chisholm D.J.
        • Campbell L.V.
        Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content.
        Metabolism. 2003; 52: 699-704
        • Vega G.L.
        • Cater N.B.
        • Meguro S.
        • Grundy S.M.
        Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia.
        Am J Cardiol. 2005; 95: 1309-1313
        • Adler A.I.
        • Neil H.A.
        • Manley S.E.
        • Holman R.R.
        • Turner R.C.
        Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom Prospective Diabetes Study (UKPDS 47).
        Am Heart J. 1999; 138: S353-S359
        • Garg A.
        • Grundy S.M.
        Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus.
        JAMA. 1990; 264: 723-726
        • Elam M.B.
        • Hunninghake D.B.
        • Davis K.B.
        • Garg R.
        • Johnson C.
        • Egan D.
        • Kostis J.B.
        • Sheps D.S.
        • Brinton E.A.
        Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT [Arterial Disease Multiple Intervention Trial] study.
        JAMA. 2000; 284: 1263-1270
        • Grundy S.M.
        • Vega G.L.
        • McGovern M.E.
        • Tulloch B.R.
        • Kendall D.M.
        • Fitz-Patrick D.
        • Ganda O.P.
        • Rosenson R.S.
        • Buse J.M.
        • Robertson D.D.
        • Sheehan J.P.
        • Diabetes Multicenter Research Group
        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.
        Arch Intern Med. 2002; 162: 1568-1576
        • Canner P.L.
        • Furberg C.D.
        • Terrin M.L.
        • McGovern M.E.
        Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project).
        Am J Cardiol. 2005; 95: 254-257
        • Bays H.
        Statin safety: an overview and assessment of the data—2005.
        Am J Cardiol. 2006; 97: 6C-26C
        • Carlson L.A.
        • 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: 405-418
        • Blankenhorn D.H.
        • Nessim S.A.
        • Johnson R.L.
        • Sanmarco M.E.
        • Azen S.P.
        • Cashin-Hemphill L.
        Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
        JAMA. 1987; 257: 3233-3240
        • Bays H.E.
        Extended-release niacin/lovastatin: the first combination product for dyslipidemia.
        Expert Rev Cardiovasc Ther. 2004; 2: 485-501
        • McKenney J.
        New perspectives on the use of niacin in the treatment of lipid disorders.
        Arch Intern Med. 2004; 164: 697-705
      2. Niaspan (niacin extended-release tablets) [prescribing information]. Cranbury, NJ: Kos Pharmaceuticals, Inc.; 2005. Available at: Accessed July 20, 2006.

        • Reaven P.
        • Witztum J.L.
        Lovastatin, nicotinic acid, and rhabdomyolysis.
        Ann Intern Med. 1988; 109: 597-598
        • Ratz Bravo A.E.
        • Tchambaz L.
        • Krahenbuhl-Melcher A.
        • Hess L.
        • Schlienger R.G.
        • Krahenbuhl S.
        Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy.
        Drug Saf. 2005; 28: 263-275
        • Bottorff M.B.
        Statin safety and drug interactions: clinical implications.
        Am J Cardiol. 2006; 97: 27C-31C
        • Bays H.
        • Stein E.A.
        Pharmacotherapy for dyslipidaemia—current therapies and future agents.
        Expert Opin Pharmacother. 2003; 4: 1901-1938
        • Davidson M.H.
        Combination therapy for dyslipidemia: safety and regulatory considerations.
        Am J Cardiol. 2002; 90: 50K-60K
        • Bays H.E.
        • Dujovne C.A.
        • McGovern M.E.
        • White T.E.
        • Kashyap M.L.
        • Hutcheson A.G.
        • Crouse J.R.
        Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]).
        Am J Cardiol. 2003; 91: 667-672
        • Bays H.E.
        • McGovern M.E.
        Once-daily niacin extended release/lovastatin combination tablet has more favorable effects on lipoprotein particle size and subclass distribution than atorvastatin and simvastatin.
        Prev Cardiol. 2003; 6: 179-188
        • Brown B.G.
        • Zhao X.Q.
        • Chait A.
        • Fisher L.D.
        • Cheung M.C.
        • Morse J.S.
        • Dowdy A.A.
        • Marino E.K.
        • Bolson E.L.
        • Alaupovic P.
        • Frohlich J.
        • Albers J.J.
        Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
        N Engl J Med. 2001; 345: 1583-1592
      3. Trial finds that simvastatin plus niacin is safe in people with coronary artery disease and low HDL cholesterol.
        Evid Based Cardiovasc Med. 2004; 8: 171-176
        • Zhao X.Q.
        • Morse J.S.
        • Dowdy A.A.
        • Heise N.
        • DeAngelis D.
        • Frohlich J.
        • Chait A.
        • Albers J.J.
        • Brown B.G.
        Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (the HDL Atherosclerosis Treatment Study).
        Am J Cardiol. 2004; 93: 307-312
        • Kashyap M.L.
        • McGovern M.E.
        • Berra K.
        • Guyton J.R.
        • Kwiterovich P.O.
        • Harper W.L.
        • Toth P.D.
        • Favrot L.K.
        • Kerzner B.
        • Nash S.D.
        • Bays H.E.
        • Simmons P.D.
        Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia.
        Am J Cardiol. 2002; 89: 672-678
        • Hunninghake D.B.
        • McGovern M.E.
        • Koren M.
        • Brazg R.
        • Murdock D.
        • Weiss S.
        • Pearson T.
        A dose-ranging study of a new, once-daily, dual-component drug product containing niacin extended-release and lovastatin.
        Clin Cardiol. 2003; 26: 112-118
        • Wolfe M.L.
        • Vartanian S.F.
        • Ross J.L.
        • Bansavich L.L.
        • Mohler III, E.R.
        • Meagher E.
        • Friedrich C.A.
        • Rader D.J.
        Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia.
        Am J Cardiol. 2001; 87: 476-479
        • Rubenfire M.
        Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study.
        Am J Cardiol. 2004; 94: 306-311
        • Taylor A.J.
        • Sullenberger L.E.
        • Lee H.J.
        • Lee J.K.
        • Grace K.A.
        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: 3512-3517
        • Fraunfelder F.W.
        Ocular side effects from herbal medicines and nutritional supplements.
        Am J Ophthalmol. 2004; 138: 639-647
        • Bressler N.M.
        Cystoid macular edema from niacin typically is not accompanied by fluorescein leakage on angiography.
        Am J Ophthalmol. 2005; 139 ([letter]): 951
        • Mosher L.R.
        Nicotinic acid side effects and toxicity: a review.
        Am J Psychiatry. 1970; 126: 1290-1296
        • Gershon S.L.
        • Fox I.H.
        Pharmacologic effects of nicotinic acid on human purine metabolism.
        J Lab Clin Med. 1974; 84: 179-186