Discussion on use of Niacin

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Discussion on use of Niacin

Niacin

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Evidence for effectiveness:

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Natural Medicines. (2016). Niacin. Retrieved from https://naturalstandardce.therapeuticresearch.com/monographs/html/niacin.html#effectivenessBriefBackground (Links to an external site.)

Synonyms/Common Names/Related Substances

· 2-Pyridone, 3-pyridine carboxamide, acipomox, Acipimox®, acipimox (5-methylpyrazinecarboxylic acid 4-oxide), antiblacktongue factor, antipellagra factor, B vitamin, B-complex vitamin, benicot, B-vitamin, chromium polynicotinate (niacin-bound chromium), coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)), crystalline niacin, dihydropyridines, Efacin®, Endur-Acin® (sustained-release niacin (nicotinic acid)), Enduramide®, ER niacin, ER niacin monotherapy, ER niacin therapy, esters of niacin, extended-release niacin, extended-release niacin monotherapy, extended-release niacin therapy, Hexopal®, immediate-release niacin, immediate-release niacin, inositol hexaniacinate, inositol hexanicotinate, inositol nicotinate, kynurenine (KYN), low-dose sustained-release nicotinic acid (Tri-B3), meso-inositol hexanicotinate, methyl niacinamide, Nature’s Bounty® Flush Free Niacin Inositol Hexanicotinate 500mg Dietary Supplement, NIAC®, niacin, niacin, niacin equivalents, niacin ER, niacinamide, niacinamide adenine dinucleotide (NAD), niacinamide adenine dinucleotide phosphate (NADP), niacin-colestipol therapy, niacine, Niacor®, Niaspan® (prolonged-release nicotinic acid), Niaspan® (sustained-release nicotinic acid), Nicalex®, nicamid, Nicamin®, Nicangin®, Niceritrol, Nico-400®, Nicobid® (sustained-released niacin), Nicobid® (time-release niacin), Nicolar® (unmodified niacin), nicosedine, Nico-Span®, nicotinamide, nicotinate, Nicotinex®, nicotinic acid, nicotinic acid adenine, nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinic acid amide, nicotinic acid analog (low plasma free fatty acid trial, LFA), nicotinic acid analogue, nicotinic amide, nicotinuric acid, nicotylamidum, nutrient supplements, Papulex®, pellagra-preventing factor, pentaerythritoltetranicotinate, perycit, PR nicotinic acid, prolonged-release nicotinic acid (niacine), pyridine-3-carboxylic acid, Slo-Niacin® (sustained-release niacin), sustained-release nicotinic acid (Nico-Span®), Tega-Span®, time-release niacin, Tri-B3®, trigonelline, tryptophan, vitamin B-3, vitamin B3, vitamin B3 derivative, vitamin B complex (vit-B), Wampocap®, wax-matrix sustained-release niacin (Endur-Acin®). Discussion on use of Niacin

· Combination product examples: ADVICOR® (niacin extended-release/lovastatin tablets), CordaptiveTM (niacin/laropiprant).

Clinical Bottom Line/Effectiveness

Brief Background

· Vitamin B3 is composed of niacin (nicotinic acid) and its amide, niacinamide, and may be found in many foods, including yeast, meat, fish, milk, eggs, green vegetables, and cereal grains. Dietary tryptophan, found in protein-containing foods such as red meat, poultry, eggs, and dairy products, is also converted to niacin after ingestion. Vitamin B3 is frequently found in combination with other B vitamins, including thiamine, riboflavin, pantothenic acid, pyridoxine, cyanocobalamin, and folic acid.

· According to numerous clinical trials, niacin (not niacinamide) appears to be a relatively safe, inexpensive, and effective treatment for hyperlipidemia. Niacin supplementation is a lipid-modifying therapy that specifically addresses the triglyceride/high-density lipoprotein cholesterol axis (1). Niacin is also a widely used lipid-regulating agent in dyslipidemic patients (2;3;4;5). Niacin elicits significant increases in HDL, up to 20-30% at doses of 1-2g daily, with greater effects than other drugs (including 3-hydroxy 3-methylglutarylCoA; HMG-CoA reductase inhibitors/statins) (6;7;8;9). Niacin also causes mild reductions (~5-20%) in low-density lipoproteins (LDL), with stronger effects occurring at higher doses (3-4.5g daily) (10;11;12;13;14). Additional decreases in LDL levels may be achieved by combining niacin with an HMG-CoA reductase inhibitor or bile acid sequestrant (9). Preliminary evidence suggests that niacin therapy may reduce the incidence of atherosclerosis and secondary cardiovascular events (15). Niacin decreases lipoprotein (a) and fibrinogen levels; both have been associated with a decreased risk of coronary artery disease (16;17;18;4). Niacin may also decrease the carotid intima-media thickness (4;9). However, niacin therapy has also been found to increase plasma homocysteine levels by up to 55% (19;20), possibly negating any positive effects on serum lipids and increasing the risk of adverse cardiac events. Due to the adverse effects associated with niacin use, it is not often used in the treatment of pediatric dyslipidemia (21).

· Niacin therapy has a high incidence of initial minor adverse events, including cutaneous flushing, pruritus, and gastrointestinal upset (22;23;24;25;26;27;28;29;30;31;32;33;34;35;36). Concomitant NSAIDs or aspirin are often recommended during the first 1-2 weeks to reduce flushing (likely prostaglandin mediated); aspirin (325mg), ibuprofen (200mg), naproxen, indomethacin, and laropiprant have been shown to significantly reduce the incidence of flushing experienced after niacin administration (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52;3;53). Use of an antihistamine 15 minutes prior to a niacin dose may also suppress cutaneous flushing (54;55). The flushing response often spontaneously diminishes after 1-2 weeks of therapy. Numerous case reports have been published concerning the development of hepatotoxicity following niacin therapy, ranging from elevated aminotransferase levels to jaundice, ascites, and hepatitis (56;57;58;39;59;60;61;62;63;64;65;66;67;68;69;70;71;72;31;73;74;75;76;77;78;79;80;81). Concomitant use of niacin or niacinamide and other agents that elevate transaminases or elicit hepatotoxicity may have additive hepatotoxic effects. Both niacin and HMG-CoA reductase inhibitors may elevate liver function tests or result in hepatotoxicity, and transaminase levels should be monitored. Immediate-release nicotinic acid may pose less risk of hepatotoxicity than extended-release formulations. Niacin, particularly in large doses, may cause insulin resistance, hyperglycemia, and hyperinsulinemia (82;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;91;32;92;93;94;95;96;97;98;99).

· Niacinamide (not niacin) has been investigated for the prevention and delay of type 1 diabetes mellitus, possibly mediated through the protection and preservation of pancreatic beta-islet cell function. Initial human research has been equivocal. Preliminary evidence suggests potential for niacinamide as a treatment for osteoarthritis. Discussion on use of Niacin

· In preliminary studies, inositol hexanicotinate, an ester of niacin and inositol, has also been shown to share some beneficial effects with niacin without causing the adverse effects associated with niacin administration (100;101).

· Nicotinic analog hypolipidemic medications, such as 5-methylpyrazine carboxylic acid 4-oxide (Acipimox®), have been developed for lipid modification in individuals with hyperlipoproteinemia and cardiovascular disease (102;103;104;105;106). Acipimox® is not available in the United States. Skin rash, headache, transient low blood pressure, altered thyroid hormone levels, and elevated blood levels of uric acid have also been noted with nicotinic acid therapy.

· Niacin consumption for treatment of a condition should be monitored by a healthcare professional (107).

Scientific evidence for Common/Studied Uses

Indication	Grade
Hyperlipidemia	A
Pellagra	A
Atherosclerosis (as adjunct therapy; niacin)	B
Cardiovascular disease (niacin)	B
Age-related macular degeneration	C
Alzheimer’s disease/ cognitive decline	C
Erectile dysfunction	C
Headaches	C
Hepatitis C	C
High blood phosphorous level	C
Osteoarthritis (niacinamide)	C
Skin conditions (topical)	C
Type 1 diabetes mellitus: preservation of beta-islet cell function (niacinamide)	C
Type 2 diabetes	C
Type 1 diabetes mellitus prevention (niacinamide)	D

Historical or Theoretical Uses That Lack Sufficient Evidence

· Alcohol dependence (108), anemia (109;110), angina (105), anti-aging (111;112;113;114), antioxidant (115;116), anxiety, arthritis (117;118;119), Bell’s palsy (120), bone marrow suppression, breast cancer (121;122), bursitis, cancer prevention (123;114), cataract prevention (124;125), central nervous system disorders, chemotherapy-induced bone marrow suppression (126), choleric diarrhea (127;128;129), chronic diarrhea/hypokalemia (related to pancreatic islet cell dysplasia) (130), circulation improvement, coronary artery disease (131;132;133;134;135;136;137;138;139;140;141;142;143;15;26), cosmetic uses (144), dementia (confusion) (145;139), depression (146), dermatitis (101;147;148), diabetes mellitus (type 1) treatment (149;150;151;152;153;154;155;156;157;114;158;94), diabetic complications (lipid abnormalities) (159;160;14;161;162;138;163;164), diarrhea, digestion improvement, dizziness, drug-induced hallucinations, dysmenorrhea (165), edema (166), encephalopathy, erythema induratum, glossitis (167), growth (168), hearing loss (169), heart attack prevention (170;171;172), helminthic infections (173), hepatic encephalopathy (174), human immunodeficiency virus (175;176;177;178;179;180), hyperactivity, hyperkinesis, hypertension (181;14;182), insomnia, intermittent claudication (183;184;185;186;187), ischemia-reperfusion injury prevention (188;189;190;114;137), leprosy, liver disease (179;67;189), liver cancer (191), lupus (lipid abnormalities) (192), memory enhancement (193), Meniere’s syndrome (endolymphatic hydrops) (194;195;196), menstrual pain, metabolic syndrome (197;160;198), migraine headache (199;200;201), motion sickness, multiple sclerosis (202), nutrition supplementation (110), obesity (14;203), pain (sympathicolysis) (204), pancreatitis (205), Parkinson’s disease (114), peripheral vascular disease, photoprotection, platelet aggregation inhibition (206), polymorphous light eruption (207), pregnancy (208), premenstrual syndrome (209), prostate cancer (210), pruritus (chloroquine-induced) (211), psoriasis (101), psychosis, Raynaud’s phenomenon (212;213;214;101;215;216;217;218;219;220;221;222;223;224;225;226), schizophrenia (diagnostic) (215;216;217;218;219;220;221;222;223;224;225;47;227;228;229;230;231;232;233;234), scleroderma, sedative, seizure disorder (235), sexual arousal (orgasm improvement), sleep quality (235), smoking cessation, stroke (139), tardive dyskinesia, taste disturbances (236), thyroid disorders, tinnitus (237), tuberculosis, ulcers (238), vascular spasm (blood vessels) (239), vasculitis (erythema diutinum), vertigo, wound healing (240). Discussion on use of Niacin

Expert Opinion & Historic/Folkloric Precedent

· The dietary reference intake established by the Food and Nutrition Board for niacin (in the form of niacin equivalents, 1mg of niacin=60mg of tryptophan) is 14-18mg daily for adults (males and females), with an upper intake level set at 35mg daily (241).

· Data from dietary surveys in adults conducted in Germany, the United States, the Netherlands, and the United Kingdom report that suboptimal intake of vitamins, including niacin, still exist in affluent countries despite intake recommendations and access to diverse foods. However, inadequate intake of niacin is not considered to be critical (242). Women in resource-poor settings were shown in a systematic review of 52 studies from 1988-2008, were reported to have and intake of niacin that was 34% lower than the estimated average requirement (243). Several authors have evaluated the validity of food frequency questionnaires in different settings (244;245;246;247).

· The U.S. Food and Drug Administration (FDA) has approved niacin for use in treating vitamin B3 deficiency (pellagra), which may be characterized by dermatitis, dementia, and diarrhea. Niacin and niacinamide are generally considered as safe (GRAS) and may be added to certain foods, including cereal flours, macaroni and noodle products, and enriched bread, according to the FDA.

· Niacin has been studied in combination with oxycodone to help deter abuse. Pain reduction was superior when compared to placebo for bunionectomy surgery (248). However, the FDA did not approve the combination drug Acurox® in 2010.

· There are strong clinical data to support the safety and efficacy of niacin, alone or in combination with other medications, for the treatment of hypercholesterolemia and possibly the prevention of cardiovascular events and disease. Its use in the treatment of schizophrenia and osteoarthritis has also been explored, with few positive results.

· A sustained-release form of low-dose niacin may be suitable if a patient is using niacin for the first time (249). Changing niacin products may affect the dose needed.

Brief Safety Summary

· Likely Safe: When niacin is used orally in daily recommended intakes under the supervision of a qualified healthcare provider (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81). Periodic monitoring of liver function tests is recommended (every three months initially) (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81). Homocysteine levels should also be monitored. The adverse effects profile of niacin at therapeutic doses may limit patient compliance: most patients experience initial flushing, and concomitant NSAIDs or aspirin are often recommended to reduce flushing; antihistamines may also be effective. Taking with food or milk may also be suggested. Gastrointestinal distress may also occur, and taking niacin with food may decrease stomach upset and the risk of peptic ulcer. Immediate release of (crystalline) niacin is sometimes preferred to sustained-release formulations, due to reports of superior HDL effects and a lower incidence of hepatotoxicity and gastrointestinal side effects. Some sustained-release products, such as Niaspan®, may be associated with a lower incidence of flushing than immediate-release niacin.

· Possibly Safe: When used in patients with diabetes, according to emerging clinical evidence in humans, despite original findings of increased glucose levels (252;143); monitoring of glucose levels is suggested. Extended-release niacin up to 2g daily for up to 44 weeks was found to be safe in patients with HIV infection (253).

· Possibly Unsafe: When used in higher-than-recommended doses without supervision of a qualified healthcare provider or when taken by subjects with diabetes mellitus who are not monitored by a qualified healthcare provider. Niacin has been shown to raise serum glucose levels and may interfere with glycemic control (58;24;25;83;254;255;86;29;87;90;12;93;256;257;96;98). Caution is also warranted in patients with gout. Niacin has been shown to increase plasma uric acid levels and may exacerbate gout symptoms (54;58;25;24;26;254;255;84;85;86;29;12;258;259;260;261;257;98;262). Concerns about the use of lipid-lowering agents in children have been raised, and close medical monitoring is merited in children with dyslipidemias. Due to the adverse effects associated with niacin use, it is not frequently used in the treatment of pediatric dyslipidemia (21). Caution is advised when used in patients with bleeding disorders or those taking anticoagulants (263). In addition, thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88).

· Likely Unsafe: When used in patients with known allergies or hypersensitivities to niacin, niacinamide, or any product containing one or both of these agents. When used in patients with hepatic disease or dysfunction. Niacin has been implicated as a cause of hepatotoxicity in humans (56;58;39;60;61;62;63;64;68;65;66;67;69;70;71;74;76;77;78;79;80;81). When used in patients with peptic ulcer disease, as it has been reported to induce or reactivate peptic ulcer disease at therapeutic doses (250;265). When used in patients with arterial bleeding, according to secondary sources.

Dosing/Toxicology

General

· Doses may be based on those most commonly used in available trials, or on historical practice. However, with natural products it is often not clear what the optimal doses are to balance efficacy and safety. Preparation of products may vary from manufacturer to manufacturer, and from batch to batch within one manufacturer. Because it is often not clear what the active component(s) of a product is, standardization may not be possible, and the clinical effects of different brands may not be comparable.

· Notes on niacin dosing: Taking niacin with food may decrease stomach upset and the risk of peptic ulcer (39). Doses are usually started low and gradually increased to decrease the adverse effect of facial flushing (57;39;398;37;38;40;41;43;44;46;47;50;51;52;42;45;48;49). Concomitant NSAIDs or aspirin are often recommended during the first 1-2 weeks to reduce flushing (likely prostaglandin mediated); aspirin (325mg), ibuprofen (200mg), naproxen, indomethacin, and laropiprant have been shown to significantly reduce the incidence of flushing experienced after niacin administration (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52;3;53). Use of an antihistamine 15 minutes prior to a niacin dose may also suppress cutaneous flushing (54;55). The flushing response often spontaneously diminishes after 1-2 weeks of therapy. A once-daily extended-release niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin (675), although extended-release niacin products may be associated with an increased incidence of gastrointestinal upset, transaminitis, and hepatitis (57;69;70;71;72;31;73;75;76;59). Not all niacin products are equivalent, and patients switching from one product to another have reported an increase in adverse effects (676). Combining niacin with other lipid-modifying medications may increase the risk of adverse events (677). Older individuals appear to be at no greater risk for adverse events from a wax-matrix sustained-release form of niacin (324). Patients advised to use niacin should be carefully screened and monitored (678).

Standardization

· Niacinamide (nicotinamide) and niacin (nicotinic acid) are used in cosmetics as hair and skin conditioning agents (144). Niacinamide and niacin may be found in cosmetic formulations such as shampoos, hair tonics, skin moisturizers, and cleansing formulations. The concentration of niacinamide varies from a low of 0.0001% in night preparations to a high of 3% in body and hand creams, lotions, powders, and sprays. Niacin concentrations range from 0.01% in body and hand creams, lotions, powders, and sprays to 0.1% in paste masks (mud packs).

Adults (age ≥ 18)

Oral:

· Dietary intake: The dietary reference intake established by the Food and Nutrition Board for niacin (in the form of niacin equivalents, 1mg of niacin=60mg of tryptophan) is 14-18mg daily for adults, with an upper intake level set at 35mg daily (241).

· Age-related macular degeneration: A single dose of 500mg of immediate-release niacin has been used (266).

· Atherosclerosis: In a meta-analysis of 14 trials, niacin doses were 3,000-4,000mg daily alone or in combination with any statin, ezetimibe plus simvastatin, gemfibrozil plus cholestyramine, colestipol, clofibrate, or colestipol for 0.5-6.2 years (267).

· 1,000mg of extended-release niacin has been used (15). In trials in which niacin is combined with other agents, up to 4.2g of niacin has been used, for up to 2.5 years, in combination with colestipol (10g three times daily) and/or lovastatin (20mg two times daily) (59;26;268;269;270;271;272;19;273;274). 0.25-4g of niacin has been used daily for an unknown duration (275).

· Cardiovascular disease: In meta-analysis and systematic reviews, niacin was administered at doses of 0.125-12g daily for up to three years (275;276;277).

· 1,000mg of extended-release niacin in addition to statin therapy has been used (15). 4g of immediate-release niacin has been used daily for five years (96). Dosages of up to 3g daily have been evaluated in the treatment of patients with cardiovascular disease (278;172;279;268). At 3g daily, niacin has been used in combination with clofibrate, gemfibrozil, and cholestyramine, as well as pravastatin, gemfibrozil, and cholestyramine, for up to five years (269;280;281;282;172).

· Erectile dysfunction: An initial dose of 500mg of Niaspan® (Abbott Laboratories, Abbott Park, IL) has been used nightly, with a dose escalation of 500mg every two weeks until a maximum of 1,500mg was reached. The tolerable dose was administered for a total trial duration of 12 weeks (283).

· Hyperlipidemia: In a systematic review of four trials using wax-matrix niacin, dosages were 1,000-2,000mg of niacin daily (in divided doses) for 20-44 weeks (284). In a systematic review of five trials, participants in the included studies were administered 750-4,500mg of niacin daily; however, the duration was unclear (285). Clinical trials have most commonly administered immediate-release (crystalline) niacin at doses of 500-3,000mg daily (286;27;250;287;288;254;88;289;290;31;258;291;292;293;294;295;296;297;298;299). Dosing may be initiated at 100mg three times daily and increased gradually to an average of 1,000mg three times daily, as tolerated (286;27;250;287;288;254;88;289;290;31;258;291;292;293;294;295;296;297;298). Significant increases in high-density lipoproteins (HDL), up to 30%, may occur at doses of 1-2g daily (300;301;292;302;10;262;11;12;303;304;305;75;31;306). Mild reductions in low-density lipoprotein (LDL) levels may occur at these doses, with stronger effects (up to 20%) occurring at higher doses (3-4.5g daily) (307;300;10;11;12;305;304;308;75;31;306), or when used in combination with an HMG-CoA reductase inhibitor or bile acid sequestrant. Plasma concentrations of lipoprotein (a) and apolipoproteins are also affected by niacin administration. At a dose of 4g daily for six weeks, niacin significantly decreased lipoprotein (a) levels (18). Doses of 4-12g daily of nicotinic acid have been used for reduction of apolipoproteins C-I, C-II, C-III, and E, which correlated to a reduction of very-low-density lipoprotein triglyceride levels (309;310). 0.25-4g of niacin has been used daily for an unknown duration (275).

· Combination HMG-CoA reductase inhibitor or bile acid sequestrant: In a systematic review of 28 trials, participants were administered 500-2,000mg of extended-release niacin plus 20-40mg of lovastatin or 10-40mg of simvastatin (NER/S) daily for a mean treatment duration of 8-16 weeks (311). In a meta-analysis of 14 trials, niacin doses were 3,000-4,000mg daily alone or in combination with any statin, ezetimibe plus simvastatin, gemfibrozil plus cholestyramine, colestipol, clofibrate, or colestipol for 0.5-6.2 years (267). In a systematic review, doses used in the included studies were 1-4g of niacin daily in combination with statin treatment for 1-3 years (312). 500-2,000mg of niacin twice daily for up to 28 weeks in combination with an HMG-CoA reductase inhibitor (pravastatin, lovastatin, rosuvastatin) was more effective than niacin alone (313;314;315;316;317;318). The U.S. Food and Drug Administration (FDA) has approved a combination tablet (Advicor®) containing lovastatin (10mg) and niacin (500mg) for the treatment of hypercholesterolemia, based on the results of an open-label study that found the combination tablet to be effective at decreasing LDL, triglyceride, and lipoprotein (a) levels, and at increasing HDL levels, with few adverse effects (319).

· Extended-release: Extended- or sustained-release niacin may be initiated at a dose of 500mg daily (or nightly) and titrated up to 3g daily. Up to 3g of extended-release niacin daily for up to 26 weeks has been used (29;86;320;321;322;323;324;325;326;327;99). The duration of the above-noted studies has been up to 60 weeks.

· Maximum dose: The maximum recommended daily dose is 3g, although a number of clinical trials have used 4.5-12g daily (286;23;24;255;98;276). Multiple trials have found that niacin (not niacinamide) administration causes significant decreases in serum cholesterol (328;329;330;24;250;331;332;92;333;334;257;335;336;10).

· Hyperlipidemia (in HIV-infected patients) : Up to 2,000mg of extended-release niacin has been taken daily for up to 44 weeks (253). Patients received 500mg (Niaspan; Abbott Laboratories, Abbott Park, IL) at bedtime for two weeks, increasing by 500mg biweekly to a maximum of 2g for two years(337).

· High blood phosphorus level: A single 375mg dose of extended-release nicotinic acid has been used (338).

· Osteoarthritis (niacinamide): 3g of niacinamide daily for 12 weeks has been used (339).

· Pellagra: The available evidence regarding dosing of niacin in the treatment of pellagra specifies dosing in the range of 50mg to 1g daily (340;341;342). Supplementation during pregnancy is not required; the catabolism of tryptophan is accelerated during pregnancy, resulting in increased niacin production (343).

· Type 1 diabetes mellitus prevention (niacinamide): Niacinamide has been used for the preservation of beta-islet cell function in patients with newly diagnosed diabetes mellitus (type 1), at doses of 200mg and up to 3g daily for up to one year (344;152;345;346;347;348;349;350;351). Not all studies show evidence of benefit. For instance, 20-40mg/kg daily for up to one year has not shown evidence of benefit (352;353;354;355;356).

· Type 2 diabetes: 0.5g of nicotinamide three times daily for six months has been used (357).

Topical:

· General: According to various websites, niacinamide (nicotinamide) and niacin (nicotinic acid) are used in cosmetics, as well as hair and skin conditioning agents. The concentration of niacinamide varies from a low of 0.0001% in night preparations to a high of 3% in body and hand creams, lotions, powders, and sprays. Niacin concentrations range from 0.01% in body and hand creams, lotions, powders, and sprays to 0.1% in paste masks (mud packs).

· Skin conditions: 2-5% of niacinamide cream for up to 12 weeks has been used (358;113).

Parenteral (Intravenous/Intramuscular):

· Hyperlipidemia: Continuous intravenous infusion of 2g of niacin over 11 hours at night resulted in significant decreases in plasma triglyceride levels not seen when the same infusion was administered during the day (359).

Children (age < 18)

Oral:

· Note: There are insufficient safety data available to recommend niacin for any indication in children in amounts greater than found in foods. Niacin is not recommended because of potential side effects (360). There are concerns about the lack of evidence regarding treatment of childhood lipid disorders, including the long-term psychological and metabolic effects. Due to the adverse effects associated with niacin use, it is not frequently used in the treatment of pediatric dyslipidemia (21). Diet alteration is considered acceptable first-line treatment, without the use of lipid-lowing drugs, until adulthood is reached.

· Type 1 diabetes mellitus prevention (niacinamide): Niacinamide has been used for the preservation of beta-islet cell function in patients with newly diagnosed diabetes mellitus (type 1) at doses of 200mg and up to 3g daily for up to one year, or 25mg/kg daily for the prevention of type 1 diabetes mellitus in “high-risk” individuals for up to five years (361;344;362;363;153;152;345;346;347;348;349;350;351). Several studies specifically mentioned patients under the age of 18 (152;354;344). However, not all studies showed evidence of benefit (364;363;361). Doses of 20-40mg/kg daily for up to one year have not shown evidence of benefit (352;353;354;355;356).

Toxicology

· The toxicity of nicotinic acid and some of its derivatives has been reviewed (365;366;367;368). In humans, the incidence of side effects and toxicity of sustained-release niacin was no greater in older subjects compared to younger (324). Safety and tolerability of niacin formulations may differ (141). Rogovik et al. concluded in a systematic review that niacin may have significant adverse effects or toxicities and should be relabeled as an over-the-counter medication (369).

· Carcinogenic effects: Topical agents containing niacinamide were not mutagenic in Ames tests (144). Niacinamide and niacin at 2mg/mL were negative in a chromosome aberration test in Chinese hamster ovary cells but did produce large structural chromosome aberrations at 3mg/mL. Oral niacinamide (1%) was not carcinogenic in mice. Niacinamide in combination with streptozotocin or heliotrine produced pancreatic islet tumors.

· Dermatologic effects: Animal testing of topical niacinamide-containing agents suggested only negative or some marginally skin-irritating responses. Clinical testing of niacinamide produced no stinging sensation at concentrations up to 10% and no irritation at concentrations up to 5%. Niacinamide was not found to be a sensitizer or a photosensitizer (144).

· Developmental effects: In vitro, niacinamide affected development but reduced the reproductive and developmental toxicity of 2-aminonicotinamide-amino-1,3,4-thiadiazole hydrochloride and urethane (144).

· Hepatotoxicity: Numerous case reports have been published concerning the development of hepatotoxicity following niacin therapy, ranging from elevated aminotransferase levels to jaundice, ascites, and hepatitis (57;56;58;39;59;60;61;62;63;64;68;65;66;67;69;70;71;72;31;73;74;75;76;77;78;79;80;81). Concomitant use of niacin or niacinamide and other agents that elevate transaminases or elicit hepatotoxicity may have additive hepatotoxic effects. Both niacin and HMG-CoA reductase inhibitors may elevate liver function tests or result in hepatotoxicity, and transaminase levels should be monitored. However, observations of hepatic toxicity with immediate-release and extended-release niacin used in combination with statins have been minimal, although transaminase elevations were shown to occur with the use of sustained-release niacin (136). Concomitant use of niacin and ethanol, two potential hepatotoxic agents, reportedly caused elevated liver enzymes in a 44 year-old man with normal liver function (370).

· Lactic acidosis: Case reports have been published detailing the development of lactic acidosis after ingestion of sustained-release niacin, one involving concurrent ethanol ingestion (371;370). Rapid recovery followed treatment with hydration and administration of thiamine and magnesium (370).

· Ocular effects: Toxic amblyopia has been associated with the administration of nicotinic acid (372). In vitro, niacinamide was not considered to be an acute ocular hazard (144).

· Lethal dose: Animal studies have found the minimal lethal dose of niacin to be 4,500mg/kg in mice and 3,500mg/kg in both rats and guinea pigs (366). The LD50 of a niacinamide subcutaneous injection was found to be 1.68g/kg in rats, while that of niacin was found to be 5g/kg, and the LD50 of orally administered niacin in mice and rats was found to be 5-7g/kg (365;373).

Precautions/Contraindications

Allergy

· Avoid with known allergy or hypersensitivity to niacin, niacinamide, or any product containing one or both of these agents.

· Development of anaphylactic shock was reported in a 32 year-old male who was prescribed niacin 150mg three times daily (374). Anaphylactic shock necessitating the administration of epinephrine has also been described in two women receiving intravenous niacin subsequent to sensitization with oral niacin (375). A 65 year-old male developed shock after an intravenous infusion of niacin, which was reversed with intramuscular epinephrine (376).

Adverse Effects/Post-Market Surveillance

· General: Niacin therapy has a high incidence of minor initial adverse events, including cutaneous flushing, pruritus, and gastrointestinal upset; however, these effects often diminish after 1-2 weeks of continued use (22;23;24;25;26;27;28;29;30;31;32;33;34;35;36). Niacin-induced cutaneous flushing may limit patient acceptance (377;378;379;96). Rogovik et al. concluded in a systematic review that niacin may have significant adverse effects or toxicities and should be relabeled as an over-the-counter medication (369). In a systematic review of 17 trials for hyperlipidemia, the rates of adverse effects were reported as being rather low (312). Approximately 10-20% of all patients discontinued the study drug due to flushing; other reasons for discontinuation included gastrointestinal upset, pruritus, rash, and headache (312). Slow-release niacin products have been shown through comparative trials to produce a lower incidence of flushing than conventional niacin preparations (59;380;321). However, in a recent study designed to examine the safety and tolerability of prolonged-release nicotinic acid (Niaspan®), flushing occurred in 42% of patients, and 9.7% withdrew for this reason (381). Studies have also found that sustained-release niacin delays the appearance of cutaneous flushing but accentuates gastrointestinal or hepatic adverse effects (25;382;383). Concomitant treatment with prostaglandin inhibitors (e.g., NSAIDs) is often recommended to reduce the incidence of flushing (which is likely prostaglandin mediated) (228); aspirin (325mg), ibuprofen (200mg), naproxen, indomethacin, and laropiprant have been shown to significantly reduce the incidence of flushing experienced after niacin administration (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52;3;53). More serious adverse effects have included the development of hepatotoxicity or lactic acidosis, the activation of peptic ulcer disease, and the elevation of serum glucose and uric acid concentrations. Inositol hexanicotinate, an ester of inositol and niacin, has been suggested to be a preferable source of niacin in terms of reduced adverse effects (100;101). Niacinamide is generally not associated with adverse events (384). Only scant clinical evidence has implicated niacinamide as the cause of increased glucose intolerance (385). Due to side effects, niacin products for lipid lowering may not be recommended in children (360).

· Cardiovascular: Niacin therapy has been shown to increase plasma homocysteine levels by up to 55% from baseline, possibly increasing the risk of adverse cardiac events (19;20). Circulatory collapse following intravenous administration of nicotinic acid has been reported in a patient who was suspected of being chronically ill and poorly nourished (376). Abnormal heart rhythms and heart palpitations have occurred in niacin studies, according to secondary sources.

· Dermatologic: The majority (>80%) of subjects taking niacin experience cutaneous flushing and warm sensations, especially of the face, neck, and ears, upon initial ingestion and with dose escalation. This flushing and cutaneous warmth is usually mild in severity but has been reported intolerable enough to cause withdrawal of up to 50% of participants in clinical trials (386;286;56;328;278; 320;22;23;24;26;27;250;287;288;387;313;28;86;29;388;88;12;30;389;306;31;32;390;33;34;35;379;96;36;98;391;392;281;381;316; 303;317;314;62;300;393;394;395). Males appear to display a significantly weaker flush response than females (396). Dry skin, pruritus, and cutaneous itching are also commonly experienced with niacin administration (56;278;320;22;24;250;287;60;62;313;28;388;88;12;306;92;397;98;381). Concomitant treatment with prostaglandin inhibitors (e.g., NSAIDs) is often recommended to reduce the incidence of flushing (which is likely prostaglandin mediated) (228); aspirin (325mg), ibuprofen (200mg), indomethacin, and laropiprant have been shown to significantly reduce the incidence of flushing experienced after niacin administration (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52;3;53) Use of an antihistamine 15 minutes prior to a niacin dose may also suppress cutaneous flushing (54;55). The flushing response is typically transient and often spontaneously diminishes after 1-2 weeks of therapy. Dosing of niacin is usually started low and gradually increased to decrease the adverse effect of facial flushing (57;39;398). Extended-release niacin products tend to cause less flushing than immediate-release (crystalline) formulations, but they may be associated with an increased incidence of gastrointestinal upset, transaminitis, and hepatitis (57;69;70;71;72;31;73;75;76;59). A newly formulated extended-release niacin resulted in a decrease in flush intensity, duration, and incidence (399). Medications to suppress niacin-induced flushing are under development (400;401). CordaptiveTM is an investigational new drug developed by Merck & Co. that contains niacin and laropiprant, a novel flushing pathway inhibitor. However, in April 2008, the U.S. Food and Drug Administration (FDA) rejected the drug. Experts speculate that the drug was “not approvable” because the FDA needs to see more safety data. Rash has been reported in secondary sources. Pruritus has been reported in clinical trials in a small number of patients (338;393). In animals, topical application of niacinamide-based products resulted in nonirritant reactions or marginally irritating responses (144).

· Endocrine: Niacin may cause significant increases in blood glucose concentrations, glucose intolerance, and insulin resistance, necessitating monitoring of niacin therapy, especially in diabetic patients, as insulin or hypoglycemic medications may require dosing alterations (285;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;91;32;92;93;94;95;96;98). Despite its use to help reduce the risk of type 2 diabetes, niacinamide has been shown to cause a significant increase in insulin resistance in subjects at high risk for developing diabetes mellitus (type 1) (385). Elevated serum uric acid levels have been observed with niacin therapy (54;58;24;25;26;398;250;60;254;255;84;85;28;86;29;88;12;258;259;260;261;257;98;262). The development of gout has reportedly occurred in some patients due to hyperuricemia following high doses of niacin (54;278;398;250;259;390). Hypothyroidism and its associated alterations in thyroid hormone and binding globulin tests (such as decreased total serum thyroxine, increased triiodothyronine, decreased thyroxine-binding globulin levels, and increased triiodothyronine uptake) have been observed with niacin therapy (22;25;402;403;264;404).

· Gastrointestinal: Dyspepsia, nausea, vomiting, abdominal pain, and diarrhea are common complaints upon the initiation of niacin therapy in clinical trials (286;56;278;320;24;22;250;387;313;28;86;388;389;31;390;96;281;381). This discomfort is usually mild and subsides with continued use. Taking niacin with food may decrease stomach upset and the risk of peptic ulcer (39). The development or activation of peptic ulcer disease has also been reported in subjects receiving niacin therapy (250;265). One subject taking 3-6g of niacin daily as part of a 1961 prospective cohort study developed an esophageal hiatal hernia during treatment that resolved upon reduction of the niacin dose (24). In a systematic review of four clinical trials using wax-matrix niacin, adverse events included elevation of some liver enzymes (alkaline phosphatase (AP) and aspartate transaminase (AST)), and one subject who experienced a reversible increase in liver enzymes also reported severe gastrointestinal symptoms with liver involvement (284). Niacin administration has been reported to cause significant but reversible elevation of serum transaminase concentrations in clinical trials (56;320;24;25;26;250;60;387;62;313;65;254;28;86;29;251;388;90;71;306;389;258;75;260;261;257;79;96;98;81;316;393;327). Numerous case reports detail the development of hepatotoxicity, including jaundice, hepatitis, ascites, fulminant hepatic failure, and liver structural changes after niacin administration (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81;405;60;62;69). Periodic monitoring of liver function tests, especially transaminase values, is recommended (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81).

· Hematologic: There are three published case reports of patients who developed a reversible coagulopathy while taking sustained-release niacin (263). O’Brien et al. reported on the development of leukopenia in two patients taking niacin for the treatment of hypercholesterolemia (264). Mild eosinophilia was observed in six of seven subjects given sustained-release niacin (1g three times daily) for a period of two weeks (406). Thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88). Treatment with niacin has been shown to cause a significant decrease in plasma fibrinogen levels (16;17).

· Musculoskeletal: Elevated creatine kinase levels have been reported in subjects taking niacin (313;88;390;98). Two case reports of niacin-induced myopathy have been reported in a 67 year-old male and 87 year-old female taking 1,500mg and 1,000mg of niacin three times daily, respectively (407). Litin et al. reported development of myopathy in three patients taking niacin for the treatment of hypercholesterolemia (408). Concomitant administration of niacin and HMG-CoA reductase inhibitors may increase the risk of myopathy and rhabdomyolysis (409;313;410;411;412); patients should be monitored closely.

· Neurologic/CNS: Headache has been reported by a number of subjects participating in clinical trials. Two 65 year-old males taking niacin for the treatment of dyslipidemias developed, after five months of therapy, severe dental and gingival pain that was relieved by the discontinuation of niacin (413). Fainting, migraine, and tension-type headaches have also been reported in secondary sources (200).

· Ocular/Otic: Secondary sources report that niacin has been associated with ocular side effects (cystoid macular edema, blurred vision, discoloration, edema, proptosis, keratitis, loss of eyebrows and eyelashes, and dry eyes), which have been reported to the National Registry of Drug-Induced Ocular Side Effects (414;415). Ocular side effects may be seen with as little as 1.5g of niacin daily but are reportedly more common at the 3g daily dose. Side effects usually resolve once niacin is discontinued. Macular edema, maculopathy, and toxic amblyopia have been noted in association with nicotinic acid in case reports and secondary sources (166;416;372;417;418). In patients with age-related macular degeneration, niacin increased choroidal blood volume (266).

· Psychiatric: Dizziness and panic attacks have been reported in secondary sources.

· Renal: One case report has been published detailing the development of lactic acidosis after ingestion of sustained-release niacin (371). A second case report details the development of lactic acidosis in a 44 year-old male on niacin therapy for hypercholesterolemia after the ingestion of a large quantity of wine (370). Glycosuria and ketonuria were observed in five subjects receiving 1.5g of niacin three times daily (85). Glycosuria and impaired glucose tolerance have also been described in three patients taking 4g of niacin daily for hypercholesterolemia (95).

Precautions/Warnings/Contraindications

· Use cautiously in patients with diabetes mellitus who are not monitored by a qualified healthcare provider, as niacin may cause insulin resistance, hyperglycemia, and hyperinsulinemia (82;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;91;32;92;93;94;95;96;97;98;99). Caution is also warranted with the use of niacinamide, as it has been shown to cause a significant increase in insulin resistance in subjects at high risk for developing type 1 diabetes mellitus (385).

· Use niacin cautiously in patients with gout. Niacin therapy has been shown to increase serum uric acid levels (54;58;24;25;26;398;250;60;254;255;84;85;28;86;29;88;12;258;259;260;261;257;98;262).

· Use cautiously in patients with renal impairment. Cases of lactic acidosis, glycosuria, and ketonuria have been reported (371;370;85;95).

· Use cautiously in patients with bleeding disorders or those taking anticoagulants (263). In addition, thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88).

· Use cautiously in children. Concerns have been raised about the use of lipid-lowering agents in children. Due to the adverse effects associated with niacin use, it is not frequently used in the treatment of pediatric dyslipidemia (21). Close medical monitoring is merited in children with dyslipidemias.

· Avoid in patients with allergy or hypersensitivity to niacin, niacinamide, or any of their components.

· Avoid in patients with hepatic dysfunction or liver disease. Niacin has been observed to cause elevations in liver enzymes (56;320;24;25;26;250;60;387;62;313;65;254;28;86;29;251;388;90;71;306;389;258;75;260;261;257;79;96;98;81). Periodic monitoring of liver function tests, especially transaminase values, is recommended (every three months initially) (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81).

· Avoid in patients with peptic ulcer disease, due to the potential risk for development of ulcers (54;250;265;97).

· Avoid in patients with arterial bleeding, according to secondary sources.

· Periodic monitoring of homocysteine levels may be warranted (20).

· Be aware that niacin may cause flushing and a warm sensation in the skin, particularly upon initial ingestion and dose escalation (386;286;56;328;278;320;22;23;24;26;27;250;287;288;387;313;28;86;29;388;88;12;30;389;306;31;32;390;33;34;35;379;96;36;98;391; 392;281;381;316;303;317;314;62;300;393;394). Flushing may be reduced with pretreatment of aspirin or nonsteroidal anti-inflammatory agents(37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52;3).

Pregnancy & Lactation

· Pregnancy: Niacin (Niaspan®) has been assigned to pregnancy category C by the U.S. Food and Drug Administration (FDA). There is a lack of animal and human studies regarding the use of niacin during pregnancy. If a woman with primary hypercholesterolemia (types IIa or IIb) becomes pregnant, niacin should be discontinued. If a woman being treated for hypertriglyceridemia (types IV or V) becomes pregnant, the drug may be continued only if the benefits outweigh the risks. Niacin is converted to niacinamide, and niacinamide may cross the human placenta; however, there is a lack of reports of adverse effects on the human fetus.

· According to secondary sources, the need for niacin increases by 3mg of niacin equivalents daily, particularly in the second and third trimesters, to cover increased energy utilization and maternal and fetal growth. The recommended dietary allowance (RDA) for niacin in pregnant women is 18mg daily. The tolerable upper intake level of niacin in pregnant women is 35mg daily.

· Supplementation during pregnancy is generally not thought to be required; the catabolism of tryptophan is accelerated during pregnancy, indicating that pregnancy would not be an etiology of pellagra and niacin supplementation is not needed (343). On the other hand, it has been suggested that pregnancy may predispose individuals to the development of pellagra.

· Niacinamide has been shown to increase the solubility of 17-beta-estradiol, progesterone, and testosterone in vitro, which may affect the toxicity or efficacy of these agents (419). Interactions may theoretically occur between niacin or niacinamide and herbs or supplements with phytoestrogenic constituents. It is not known if this would lead to a potential negative impact on the developing fetus. Female sex hormones may also increase niacin-induced prostaglandin release and vasodilation (396).

· Supplementation of HIV-infected women, during and after pregnancy, with multivitamins, including niacin, increased weight gain in offspring (168).

· Lactation: Niacin is reportedly excreted in breast milk. The benefits and risks of potential serious adverse effects in the nursing infant should be weighed when deciding if to discontinue the drug or if to discontinue nursing the infant. According to secondary sources, the amount of niacin needed is 2.4mg daily for breastfeeding women, to account for preformed niacin secreted daily during lactation. The daily reference intake (DRI) for niacin in pregnant women is 17mg daily. The tolerable upper intake level of niacin in pregnant women is 35mg daily.

· Information on niacin’s effects on lactation is lacking in the National Institute of Health’s Lactation and Toxicology Database (LactMed).

Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

Niacin/Drug Interactions

· Alcohol: According to numerous clinical trials, niacin treatment frequently produces cutaneous flushing (386;286;56;328;278; 320;22;23;24;26;27;250;287;288;387;313;28;86;29;388;88;12;30;389;306;31;32;390;33;34;35;379;96;36;98;391;392;281;381;316; 303;317;314;62;300;393;394;395); theoretically, niacin-induced flushing may be magnified by concomitant ingestion of alcohol (420). According to a case report, coadministration of alcohol and niacin may increase the risk of hepatotoxicity (370)

· Androgens: Niacinamide has been shown to increase the solubility of testosterone in vitro (419), which may affect the toxicity or efficacy of testosterone administration in vivo (419).

· Antibiotics: According to secondary sources, antibiotics may lead to decreased production of B vitamins through the destruction of normal gastrointestinal flora.

· Anticoagulants and antiplatelets: According to case reports, niacin therapy may increase the risk of bleeding (263). In addition, thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88).

· Anticonvulsant agents: According to animal and human evidence, niacinamide may increase plasma levels of anticonvulsants, including carbamazepine, diazepam, and sodium valproate (421). In patients with epilepsy, nicotinamide increased the half-life of carbamazepine (422).

· Antidiabetic agents: In numerous human studies, niacin increased blood glucose levels (82;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;32;92;93;94;95;96;97;98). On the contrary, the concomitant administration of niacinamide and insulin has been shown to lead to a reduction in insulin requirements in children newly diagnosed with type 1 diabetes mellitus (152;347;346). Some studies have found no difference (423;347;345). Dosing adjustments of antidiabetic agents may be needed.

· Antigout agents: In clinical research, niacin therapy has been shown to increase serum uric acid levels (54;58;24;25;26;398;250;60;254;255;84;85;28;86;29;88;12;258;259;260;261;257;98;262).

· Antihistamines: In human research, use of an antihistamine 15 minutes prior to a niacin dose suppressed cutaneous flushing (54;55). The flushing response often spontaneously diminishes after 1-2 weeks of therapy.

· Antihypertensives: In human evidence, nicotinic acid lowered blood pressure values in patients with hypertension (181). Nicotinic acid may act similarly to calcium channel blockers, according to principal component analysis and factor analysis of molecular properties (424).

· Antilipemic agents, bile acid sequestrants: In human research, concomitant administration of niacin and bile acid sequestrants (cholestyramine, colestipol) enhanced lipid-lowering effects, reduced niacin absorption, and increased the risk of adverse effects, such as myopathy (408;135;330;271;272;19;26;425;426;427;274;390;428;429;430).

· Antilipemic agents: In humans, taking niacin and fibrates, such as gemfibrozil, clofibrate, or fenofibrate, increased the risk of adverse effects (408), altered the pharmacokinetics of either agent (431), or enhanced the cholesterol-lowering effects of the antilipemic (171;172;280;330;432;298;433).

· Antilipemic agents, HMG-CoA reductase inhibitors: In humans, taking niacin and HMG-CoA reductase inhibitors, such as pravastatin, lovastatin, and atorvastatin, increased the risk of adverse effects, namely myopathy and rhabdomyolysis (409;313;410;411;412). This combination may also elevate liver function tests, result in hepatotoxicity, enhance the reduction of serum cholesterol levels (270;434;313;435;436;388;437;438;30;319;390;293;318;35;15;439;440;441;442), or increase plasma HDL levels (436;388;35;440;442).

· Antithyroid agents: Decreases in total serum thyroxine and free thyroxine levels and increases in triiodothyronine uptake ratios have been reported in humans after niacin therapy (22;25;402;403;264;404).

· Aspirin: Concurrent use of aspirin has been shown to reduce the tingling, itching, flushing, and warmth associated with oral niacin administration in humans (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52).

· Benzodiazepines: Niacinamide has been shown to increase the solubility of diazepam in vitro, which may or may not affect the toxicity or efficacy of diazepam and possibly other benzodiazepines (419).

· Calcium channel blockers: Nicotinic acid is similar to medications in the class of drugs known as dihydropyridine calcium channel blockers, according to principal component analysis and factor analysis of molecular properties (424).

· Cardiovascular agents: In humans, niacin therapy increased plasma homocysteine levels by up to 55% from baseline, possibly increasing the risk of adverse cardiac events (19;20). Circulatory collapse following intravenous administration of nicotinic acid has been reported in one patient who was suspected of being chronically ill and poorly nourished (376). Abnormal heart rhythms and heart palpitations have occurred in niacin studies, according to unconfirmed reports.

· Contraceptives: Niacinamide has been shown to increase the solubility of 17-beta-estradiol in vitro, which may affect the toxicity or efficacy of 17-beta-estradiol and possibly other estrogens (419). Oral contraceptives may stimulate tryptophan oxygenase and increase the amount of tryptophan that is converted into niacin, thus lowering the doses of niacin that may be necessary to attain a specific clinical effect (443;428).

· Cytochrome P450 metabolized agents: Nicotinamide decreased the conversion of primidone to phenobarbital in both animals and epileptic patients, likely due to the inhibition of cytochrome P450 (422).

· Epinephrine: Anaphylactic shock necessitating the administration of epinephrine has been described in two women and one man after receiving intravenous niacin (375;376). The subcutaneous administration of a single 250mg/kg dose of niacin in rats inhibited normal fasting epinephrine, norepinephrine, and theophylline-induced free fatty acid release (444).

· Estrogens: Niacinamide has been shown to increase the solubility of 17-beta-estradiol in vitro (419), which may affect the toxicity or efficacy of 17-beta-estradiol and possibly other estrogens. Oral contraceptives may stimulate tryptophan oxygenase and increase the amount of tryptophan that is converted into niacin (443;428), thus theoretically lowering the doses of niacin that may be necessary to attain a specific clinical effect.

· Ganglionic blocking drugs: In human research, nicotinic acid had ganglionic-like effects (445), and theoretically it may potentiate the effects of ganglionic blocking agents, thereby resulting in postural hypotension.

· Griseofulvin: Niacinamide has been shown to increase the solubility of griseofulvin in vitro (419), which may theoretically affect the toxicity or efficacy of griseofulvin administration in vivo.

· Hepatotoxic agents: Niacin administration has been reported to cause significant but reversible elevation of serum transaminase concentrations in clinical trials (56;320;24;25;26;250;60;387;62;313;65;254;28;86;29;251;388;90;71;306;389;258;75;260;261;257;79;96;98;81;316;393;327). Numerous case reports detail the development of hepatotoxicity, including jaundice, hepatitis, ascites, fulminant hepatic failure, and liver structural changes after niacin administration (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81;405;60;62;69). Theoretically, concomitant use of niacin with other hepatotoxic agents may increase the risk of liver damage.

· Neomycin: Concomitant use of neomycin and niacin may result in additive effects on the lowering of lipoprotein (a), low-density lipoprotein, and total cholesterol levels (446;289).

· Nicotine: Worsening of flushing and dizziness has been reported in humans with the use of transdermal nicotine and niacin (447).

· Nonsteroidal antiinflammatory agents (NSAIDs): In humans, use of aspirin or other NSAIDs reduced the tingling, itching, flushing, and warmth associated with oral niacin administration (37;38;39;40;41;43;44;46;47;50;51;52;42;45;48;49;3).

· Primidone: In animals, nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively (422). Nicotinamide also decreased the conversion of primidone to phenobarbital in patients with epilepsy.

· Probucol: Concomitant administration of niacin and probucol in patients resulted in enhanced cholesterol-lowering effects and may allow lower doses of each medication to be used (448).

· Procetofene: In humans, a combination of procetofene and niacin normalized triglyceride levels (449).

· Progestins: Niacinamide has been shown to increase the solubility of progesterone in vitro (419), which may affect the toxicity or efficacy of progesterone administration in vivo.

· Pyrazinamide: In humans, pellagra occurred with use of pyrazinamide and niacin due to structural similarities between pyrazinamide and nicotinamide (450). The administration of a diet rich in pyrazinamide has been shown to significantly increase the metabolism of tryptophan to niacin in rats (451), which may have implications for the concurrent use of niacin and pyrazinamide in humans.

· Theophylline: The subcutaneous administration of a single 250mg/kg dose of niacin in rats inhibited normal fasting epinephrine, norepinephrine, and theophylline-induced free fatty acid release (444).

· Thyroid hormones: Decreases in total serum thyroxine and free thyroxine levels and increases in triiodothyronine uptake ratios have been reported in humans after niacin therapy (22;25;402;403;264;404).

· Vasodilators: Niacin induces a vasodilatory response in humans (386;286;56;328;278;320;22;23;24;26;27;250; 287;288;387;313;28;86;29;388;88;12;30;389;306;31;32;390;33;34;35;379;96;36;98;391;392;281;381;316;303;317;314;62;300;393;394).

Niacin/Herb/Supplement Interactions

· Amino acids: Basic scientific research has revealed that interactions among certain amino acids, such as lysine and tryptophan, may play a role in niacin synthesis (452)

· Androgens: Niacinamide increases the solubility of testosterone in vitro (419), which may affect the toxicity or efficacy of testosterone administration in vivo.

· Antibacterials: According to secondary sources, antibacterial herbs or supplements may lead to a decreased production of B vitamins through the destruction of normal gastrointestinal flora.

· Anticoagulants and antiplatelets: In theory, niacin therapy may increase the risk of bleeding (263). In addition, thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88).

· Anticonvulsants: According to animal and human research, niacinamide may alter plasma levels of anticonvulsants (421).

· Antigout herbs and supplements: In clinical research, niacin therapy has been shown to increase serum uric acid levels (54;58;24;25;26;398;250;60;254;255;84;85;28;86;29;88;12;258;259;260;261;257;98;262).

· Antihistamines: In human research, use of an antihistamine 15 minutes prior to a niacin dose may also suppress cutaneous flushing (54;55). The flushing response often spontaneously diminishes after 1-2 weeks of therapy.

· Antilipemics: In humans, niacin increased the risk of side effects (409;313;410;408;411;412) and increase lipid-lowering effects (453;434;409;313;436;410;388;437;438;30;319;390;318;293;35;411;15;439;440;441;442;412;454) when used with antilipemic agents.

· Antioxidants: In human research, there is conflicting evidence as to whether antioxidants decrease niacin’s beneficial effects on cholesterol levels and heart disease (455;270;454;453;456;457;458).

· Cardiovascular herbs and supplements: Niacin therapy has been shown to increase plasma homocysteine levels by up to 55% from baseline in humans, possibly increasing the risk of adverse cardiac events (19;20). Circulatory collapse following intravenous administration of nicotinic acid has been reported in one patient who was suspected of being chronically ill and poorly nourished (376). Abnormal heart rhythms and heart palpitations have occurred in niacin studies, according to unconfirmed reports.

· Chromium: In humans, chromium and nicotinic acid had synergistic effects on blood glucose control in the elderly (459;460).

· Cytochrome P450 metabolized herbs and supplements: Nicotinamide decreases the conversion of primidone to phenobarbital in both animals and epileptic patients, likely due to inhibition of cytochrome P450 (422).

· Contraceptives: Niacinamide has been shown to increase the solubility of 17-beta-estradiol in vitro (419), which may affect the toxicity or efficacy of 17-beta-estradiol and possibly other estrogens. Oral contraceptives may stimulate tryptophan oxygenase and increase the amount of tryptophan that is converted into niacin, thus lowering the doses of niacin that may be necessary to attain a specific clinical effect (443;428).

· Grape: Concomitant administration of chromium polynicotinate (niacin-bound chromium) and grape seed proanthocyanidin has been shown to result in greater improvements in the lipid profile of hypercholesterolemic subjects than either agent alone (461), suggesting an additive effect.

· Hepatotoxic herbs and supplements: Niacin administration has been reported to cause significant but reversible elevation of serum transaminase concentrations in clinical trials (56;320;24;25;26;250;60;387;62;313;65;254;28;86;29;251;388;90;71;306;389;258;75;260;261;257;79;96;98;81;316;393;327). Numerous case reports detail the development of hepatotoxicity, including jaundice, hepatitis, ascites, fulminant hepatic failure, and liver structural changes after niacin administration (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81;405;60;62;69). Theoretically, concomitant use of niacin with other hepatotoxic agents may increase the risk of liver damage.

· Hypoglycemics: In human research, niacin has been shown to increase blood glucose levels and may require dosing adjustments of hypoglycemic agents (82;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;32;92;93;94;95;96;97;98). On the contrary, the concomitant administration of niacinamide and insulin has been shown to lead to a reduction in insulin requirements in children newly diagnosed with type 1 diabetes mellitus (152;347;346). Some studies have found no difference (423;82;56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;32;92;93;94;95;96;97;98).

· Hypotensives: In patients with hypertension, nicotinic acid lowers blood pressure values (181). Thus, additive effects with hypotensive agents are possible. Nicotinic acid may act similarly to calcium channel blockers, according to principal component analysis and factor analysis of molecular properties (424).

· Inositol hexanicotinate: Inositol hexanicotinate may be a source of nicotinic acid therapy (101).

· Kava: It has been suggested that kava-induced dermopathy is due to niacin deficiency in humans (462).

· Minerals: Oral administration of zinc sulfate to alcoholics with pellagra has been shown to increase the urinary excretion of niacin metabolites, suggesting its ability to affect the metabolism of tryptophan to niacin; this has possible implications for the concurrent administration of zinc and niacin (463).

· Pantothenic acid: The results of one crossover study in adolescents found that supplementation with pantothenic acid increased urinary secretion of niacin and may have implications for the concomitant use of the two B-complex vitamins (464).

· Phytoestrogens: Interactions may theoretically occur between estrogens and niacin or niacinamide, but it is not clear if these interactions apply to herbs or supplements with phytoestrogenic constituents (chemical components that possess estrogen receptor agonist or antagonist properties, or exert estrogen-like effects clinically but may not be structurally similar to estrogens). Niacinamide has been shown to increase the solubility of 17-beta-estradiol in vitro (419), which may affect the toxicity or efficacy of 17-beta-estradiol and possibly other estrogens. Oral contraceptive drugs may stimulate tryptophan oxygenase and increase the amount of tryptophan that is converted into niacin, thus lowering the doses of niacin that may be necessary to attain a specific clinical effect (443;428).

· Phytoprogestins: Niacinamide has been shown to increase the solubility of progesterone in vitro (419), which may affect the toxicity or efficacy of progesterone administration in vivo.

· Salicylate containing herbs: Concurrent use of aspirin has been shown to reduce the tingling, itching, flushing, and warmth associated with oral niacin administration in humans (37;38;39;40;41;42;43;44;45;46;47;48;49;50;51;52), an effect that may also result from use of salicylate-containing herbs. Aspirin significantly reduced the intensity and duration of niacin-induced flushing, using a specially formulated low-flushing niacin. However, levels of salicylates in herbs may vary or be too low to attain desired clinical effects.

· Plant Sterols: In humans, concomitant administration of niacin and a 20% suspension of beta-sitosterol and dihydro-beta-sitosterol resulted in an additive decrease in plasma cholesterol compared to each agent alone (22).

· Thyroid agents: Decreases in total serum thyroxine and free thyroxine levels and increases in triiodothyronine uptake ratios have been reported in humans after niacin therapy (22;25;402;403;264;404).

· Tryptophan: As a precursor to niacin, supplementation with tryptophan may theoretically increase niacin levels. During pregnancy, the catabolism of tryptophan is accelerated, and niacin supplementation may not be needed (343).

· Vasodilator herbs and supplements: Niacin induces a vasodilatory response in humans (386;286;56;328;278;320;22;23;24; 26;27;250;287;288;387;313;28;86;29;388;88;12;30;389;306;31;32;390;33;34;35;379;96;36;98;391;392;281;381;316;303;317;314;62; 300;393;394). Theoretically, the vasodilatory effects of niacin by other vasodilatory agents.

· Vitamins: In clinical research, concomitant administration of vitamin E and niacin may have additive effects on the lowering of serum cholesterol levels (465). The addition of vitamin A to this combination may also contribute (458). However, a number of studies have demonstrated no benefits of antioxidants (vitamin E) on cardiovascular outcomes (466;467;468;469). In addition, it has been suggested that antioxidants may blunt niacin’s beneficial effects on cholesterol levels and heart disease, possibly by interfering with niacin’s effects on proteins involved with the formation of high-density lipoproteins (HDL) (454;453;456;458;465). Niacin in combination with vitamin A has been suggested as a possible therapy to ameliorate dysgeusia (loss of taste or a metallic taste) (236). The results of one crossover study in adolescents found that supplementation with pantothenic acid increased urinary secretion of niacin and may have implications for the concomitant use of the two B-complex vitamins (464). Supplementary vitamin B6 may interfere with niacin metabolism.

Niacin/Food Interactions

· General: Taking niacin with food may decrease stomach upset and the risk of peptic ulcer in humans (39).

· Coffee: Coffee is a source of niacin (470). Concomitant use may increase levels of niacin.

· Hot beverages: Niacin has been shown to induce flushing (420); theoretically, hot beverages ingested concomitantly may magnify niacin-induced flushing (420).

· Oat bran: One trial involving combination treatment found no added effect with the use of oat bran and niacin therapy (389).

· Sorghum: Human niacin status may be affected by eating sorghum (Sorghum gramineae) grain in ready-to-eat breakfast cereals (471).

· Tryptophan-containing foods: As the precursor to niacin, supplementation with tryptophan may increase niacin levels. During pregnancy, the catabolism of tryptophan is accelerated, and niacin supplementation may not be needed (343).

Niacin/Lab Interactions

· Apolipoproteins: In clinical trials, niacin was shown to reduce apolipoprotein C-I, C-II, C-III, and E levels (309;310).

· Blood pressure: In hypertensive individuals, nicotinic acid lowered blood pressure values (181).

· Coagulation panel: There are three published case reports of patients who developed a reversible coagulopathy while taking sustained-release niacin (263). O’Brien et al. reported on the development of leukopenia in two patients taking niacin for the treatment of hypercholesterolemia (264). Mild eosinophilia was observed in six of seven subjects given sustained-release niacin (1g three times daily) for a period of two weeks (406). Thrombocytopenia has been observed in clinical trials of niacin therapy (264;27;88). Treatment with niacin has been shown to cause a significant decrease in plasma fibrinogen levels in humans (16;17). Niacin therapy may also lead to clotting factor synthesis deficiency and coagulopathy, which may result in prolonged prothrombin times (263). In clinical trials, treatment with niacin has been shown to cause a significant decrease in plasma prothrombin levels (279).

· Cortisol: Intravenous niacin administration caused a significant increase in plasma cortisol in healthy male volunteers (472).

· Creatine kinase: In humans, niacin therapy has been associated with increases in creatine kinase levels (313;88;390;98;316).

· Fibrinogen levels: Treatment with niacin has been shown to cause a significant decrease in plasma fibrinogen levels in humans (16;17;279).

· Glucagon: Intravenous niacin administration caused a significant increase in plasma glucagon in healthy male volunteers (472).

· Glucose levels: Niacin may cause significant increases in blood glucose concentrations, glucose intolerance, and insulin resistance, necessitating monitoring of niacin therapy, especially in diabetic patients, as insulin or hypoglycemic medications may require dosing alterations (56;58;24;25;83;60;84;85;28;86;29;87;88;89;90;12;91;32;92;93;94;95;96;98). Niacinamide was shown to cause a significant 23.6% increase in insulin resistance in a group of eight subjects at high risk of developing diabetes mellitus (type 1) (385). Seven of 11 subjects were glucose-intolerant after extended-release (ER) niacin therapy; for three of these subjects, this was a new finding (99). In a clinical trial, nicotinic acid increased plasma glucose levels in both those with or without a family history of type 2 diabetes (473).

· Homocysteine levels: Concomitant administration of colestipol and niacin therapy as part of the Cholesterol Lowering Atherosclerosis Study (CLAS) resulted in increased homocysteine levels in humans, which may also be attributable to niacin therapy alone (19). An analysis of 52 participants in the Arterial Disease Multiple Intervention Trial (ADMIT) also showed niacin therapy to cause a 55% increase in plasma homocysteine levels from baseline (p=0.001) (20). Periodic monitoring of homocysteine levels may be warranted (20).

· Human growth hormone: Nicotinic acid has been shown to increase human growth hormone levels (474).

· Lactic acid test: Two case reports have been published detailing the development of lactic acidosis after ingestion of sustained-release niacin, one involving concurrent ethanol ingestion (371;370).

· Lipid profile: At a dose of 2g daily, Niaspan® was shown to cause a significant decrease in serum lipoprotein (a) and triglyceride concentrations in humans (321;322;18). Niacin induced a small but significant increment in hepatic secretion of biliary cholesterol (11). Significant increases in high-density lipoproteins (HDL) have been shown in clinical trials using niacin (300;301;292;302;10;262;11;12;303;304;305). In clinical trials, niacin reduced low-density lipoprotein (LDL) levels (307;300;10;11;12;305;304). In clinical trials, niacin administration caused significant decreases in serum cholesterol (328;329;330;24;250;331;332;92;333;334;257;335;336;10). In clinical trials, niacin reduced very-low-density lipoprotein (VLDL) and small LDL (308;305;307) and increased HDL (305).

· Liver function tests: Niacin and niacinamide administration may increase human serum bilirubin, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase concentrations (56;320;24;25;26;250;60;387;62;313;65;254;28;86;29;251;388;90;71;306;389;258;75;260;261;257;79;96;98;81;316). One patient receiving 2,000mg of niacin plus 40mg of lovastatin experienced reversible elevations in liver transaminases (314). Periodic monitoring of liver function tests, especially transaminase values, is recommended (every three months initially) (58;24;250;61;63;64;66;67;68;251;87;70;90;71;46;74;76;77;78;79;96;80;81;475).

· Plasma uric acid: Elevated serum uric acid levels have been observed with niacin therapy in humans (54;58;24;25;26;398;250;60;254;255;84;85;28;86;29;88;12;258;259;260;261;257;98;262;476). The development of gout has reportedly occurred in some patients due to hyperuricemia following high doses of niacin (54;278;398;250;259;390).

· Thyroid function tests: Decreases in total serum thyroxine and free thyroxine levels and increases in triiodothyronine uptake ratios have been reported after niacin therapy in humans (22;25;402;403;264;404).

Niacin/Nutrient Depletion

· 5-Fluorouracil: According to human case reports and secondary sources, 5-fluorouracil may cause niacin deficiency (477;478;479).

· Azathioprine: According to human case report and secondary sources, azathioprine may cause niacin deficiency (480).

· Chloramphenicol: According to secondary sources, chloramphenicol may cause niacin deficiency (477).

· Cycloserine: According to human case report, cycloserine may cause niacin deficiency (481).

· Decarboxylase inhibitors (e.g., benserazide, carbidopa): According to human case reports, decarboxylase inhibitors may cause niacin deficiency (482). These agents inhibit the enzyme involved in the conversion of tryptophan to niacin (482).

· Ethionamide: According to human case report, chloramphenicol may cause niacin deficiency (481).

· Isoniazid: Isoniazid may cause a deficiency of pyridoxine, which is necessary for the conversion of tryptophan to niacin, thus inducing pellagra or niacin deficiency in poorly nourished patients (483;484;428;450).

· Mercaptopurine: According to human case report and secondary sources, 6-mercaptopurine may cause niacin deficiency, likely due to 6-mercaptopurine interfering with the synthesis of adenine dinucleotide (480).

· Minerals (: zinc sulfate): Oral administration of zinc sulfate to alcoholics with pellagra has been shown to increase the urinary excretion of niacin metabolites, suggesting its ability to affect the metabolism of tryptophan to niacin, and having possible implications for the concurrent administration of zinc and niacin (463).

· Pantothenic acid: The results of one crossover study in adolescents found that supplementation with pantothenic acid increased urinary secretion of niacin; this may have implications for the concomitant use of the two B-complex vitamins (464).

· Phenobarbital: According to secondary sources, phenobarbital may cause niacin deficiency (478).

· Phenytoin: According to human case reports and secondary sources, phenytoin may cause niacin deficiency (485;478).

· Pyrazinamide: According to human research, pellagra may occur with concomitant use of pyrazinamide and niacin due to structural similarities between pyrazinamide and nicotinamide (450). The administration of a diet rich in pyrazinamide has been shown to significantly increase the metabolism of tryptophan to niacin in rats (451), which may have implications for the concurrent use of niacin and pyrazinamide in humans.

· Valproic acid: According to human case reports and secondary sources, valproic acid may cause niacin deficiency (485;478).

Mechanism of Action

Pharmacology

· Niacin is metabolized to form niacinamide adenine dinucleotide (NAD), niacinamide adenine dinucleotide phosphate (NADP), and nicotinuric acid, all coenzymes necessary for cell function (420;486;487;384;488;489;490). According to a review, nicotinic acid adenine dinucleotide phosphate (NAADP) action is a potent Ca2+ mobilizing messenger (491).

· Kynurenine is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid (492). It is formed in the mammalian brain and taken up from the periphery. In the brain, kynurenine may be converted to two other components of the pathway, quinolinic acid and kynurenic acid.

· Niceritrol is an ester product of nicotinic acid and pentaerythritol or meso-inositol that is hydrolyzed by enzymes in plasma and tissues of humans, rats, and dogs, resulting in increases of nicotinic acid (493).

· Niacin deficiency: The niacin deficiency syndrome pellagra has been reviewed by Pitche (478). Pellagra is rarely seen in Europe and North America, although it still exists in some developing countries. Nutritional niacin deficiency is the principal cause of pellagra, although chronic alcoholism, malabsorption syndromes, and some medications (5-fluorouracil, isoniazid, pyrazinamide ethionamide, 6-mercaptopurine, hydantoins, phenobarbital, and chloramphenicol) may also play a role. The diagnosis of pellagra is based on the patient’s nutritional and medication history and the presence of dermatitis, diarrhea, and dementia. Low levels of urinary excretion of N-methylnicotinamide and pyridone are also indications of niacin deficiency.

· Antiacne effects: Secondary information suggests that potential antiacne mechanisms of nicotinamide may include anti-inflammatory effects via inhibition of leukocyte chemotaxis, lysosomal enzyme release, lymphocytic transformation, mast cell degranulation, bacteriostatic effect against Propionibacterium acnes, inhibition of vasoactive amines, preservation of intracellular coenzyme homeostasis, decreased sebum production, suppression of vascular permeability, and protection against DNA damage (494).

· Antiaging effects: In vitro, nicotinamide inhibited the activity of sirtuins, NAD(+)-dependent protein deacetylases involved in transcriptional regulation, metabolism, apoptosis, differentiation, and aging (495). Li et al. reviewed the role of mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation in the role of niacinamide and cellular integrity and longevity (114). Each of these cellular targets may play a role in niacinamide-induced antiaging effects in the cell.

· Antibacterial effects: In isolated rabbit jejunum, nicotinic acid demonstrated prevention and reversal of cholera enterotoxin effects (128). Cholera-induced fluid movement and unidirectional sodium fluxes in rabbit jejunum were affected (129).

· Anticancer effects: Li et al. reviewed the role of mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation in the role of niacinamide and cellular integrity and longevity (114). Each of these cellular targets may play a role in niacinamide-induced anticancer effects in the cell. Supplemental nicotinic acid has not been found to reduce cytogenic damage in peripheral blood lymphocytes of smokers (496)

· Antioxidant effects: Niacinamide has been shown to decrease recombinant interleukin-1-beta-induced nitrite production dose-dependently in vitro, possibly through the inhibition of the inducible form of nitric oxide synthase (497). The addition of niacinamide has been shown to inhibit the release of reactive oxygen intermediates from a xanthine oxidase-hypoxanthine system in vitro, protecting rat islet cells from oxidative damage (115).

· Cardiovascular effects: Niacin treatment has been shown to significantly decrease fibrinogen levels in subjects with peripheral artery disease after one year of therapy, a condition which may produce favorable cardiovascular outcomes (279;17). Changes in fibrinolytic parameters with niacin treatment also occurred in hyperlipidemic lupus (SLE)-membranous nephropathy (MN) patients (192). A significant decrease in prothrombin F1.2 has also been observed in response to niacin (279). Niacin significantly inhibited beta-oxidation during preischemia and reperfusion, prevented the degradation of membrane phospholipids, reduced free fatty acid accumulation, and stimulated glycolysis in arrested-reperfused pig hearts (498). Animal experiments suggest that niacin administration causes a decrease in serum cholesterol and prevents experimentally induced atherosclerosis (499). In combination with colestipol, niacin therapy increased nonatherosclerosis progression and atherosclerosis regression (500). Treatment benefit of colestipol and niacin on coronary atherosclerosis was shown best using visual panel assessments (501). Niacin oral treatment has been associated with an increase in exogenous glucose utilization by cardiac tissue, as seen in five healthy volunteers (502).

· Cholesterol and lipid effects: The mechanism of action by which niacin alters lipid profiles is not well understood. Niacin has also been associated with reductions (5-20%) in low-density lipoprotein (LDL) levels, with stronger effects generally occurring at higher doses than required for raising HDL levels (up to 3-4.5g daily) (10;11;12). Niacin exerted additive effects on LDL lowering when used concomitantly with HMG-CoA reductase inhibitors or bile acid sequestrants (315). Suggested mechanisms include decreased hepatic synthesis of very-low-density lipoprotein levels (VLDL), the precursor of LDL, which may occur as a result of niacin-induced reductions in free fatty acids (FFA) mobilized from peripheral adipose tissues and lower plasma FFA concentrations (204;83;503;504;505;474;506;507;508;509;510). Niacin was also associated with an increase in LDL particle size and a shift from small LDL to the less atherogenic, large LDL subclasses (315;511). Treatment with niacin has also been shown, through randomized controlled trials, to cause a significant conversion of LDL subclass patterns (512;430). Treatment with niacin has also been shown to decrease serum triglyceride levels by reducing the size of VLDL particles (309). Niacin was found to increase large HDL particles (H5 and H4, corresponding to the HDL[2ab] fraction) without having a net effect on small HDL particles (H3, H2, and H1, corresponding to the HDL[3abc] fraction), and to decrease smaller, denser LDL particles (L1 and L2) and increase the larger, more buoyant L3 subclass (305). The inhibitory effect of niacin on VLDL lipoprotein was evident on the larger particles (V6, V5, V4, and V3 subclasses) rather than the smaller ones (V2 and V1). Reductions in hepatic cholesterol synthesis have also been demonstrated in human studies (11;507;256). Niacin selectively and directly inhibited hepatic diacylglycerol acyltransferase 2, but not diacylglycerol acyltransferase 1, thus inhibiting hepatic triglyceride synthesis and VLDL (252).

· Treatment with niacin was shown to result in significant increases in high-density lipoproteins (HDL), up to 30%, at doses of 1-1.5g daily (301;292;302;10;262;11;12;513;514). Multiple mechanisms have been suggested based on the results of clinical research, including delayed clearance of HDL and decreased cholesterol transfer from HDL to VLDL. Niacin-associated elevations in HDL cholesterol likely stem from differential drug effects on subclasses, producing favorable changes in levels of HDL2 and apolipoprotein A1 (315). In vitro studies have shown niacin to increase apoprotein A1 levels in a culture medium without increasing the de novo synthesis of apoprotein A1, but rather by reducing HDL protein uptake and HDL apoprotein A1 uptake by hepatic cells (515).

· Treatment with daily oral niacin has been shown to significantly decrease serum concentrations of apolipoproteins C-I, C-II, C-III, and E, which correlated to a reduction of VLDL triglyceride levels (309;310). Combination treatment has also been associated with significant reductions in apolipoprotein B levels (516;135;446).

· Niacin increases the lipoprotein subfraction A1 (517). Administration of niacin and simvastatin has been shown to increase lipoprotein A independently of phospholipid transfer protein (454).

· Acyl CoA:diacylglycerol acyltransferase (DGAT) is a microsomal enzyme that plays a key role in the esterificationof fatty acids to form triglycerides (518). DGAT catalyzes the acylation of DAG in the synthesis of triglycerides (519). Niacin has been found to noncompetitivelyand directly inhibit the activity of DGAT2 but not DGAT1, which may result in a decreasedrate of triglyceride synthesis and its availability for intracellular apo B lipidation and translocation across the endoplasmic reticulum membrane, resultingin increased apo B degradation (2)

· The mechanism of action of nicotinic acid on serum lipids has been investigated in early studies (328;520;329;334;257;521;522). Nicotinic acid is has been found to exert antilipolytic effects via a distinct G-protein coupled receptor (506). Nicotinic acid has been shown to increase the lipoprotein lipase activity of adipose tissue in an animal study (523).

· CNS effects: In vitro, niacinamide displayed low potency inhibition of the 3H-diazepam binding site (235).

· Cytochrome P450 effects: Nicotinamide decreased the conversion of primidone to phenobarbital in both animals and epileptic patients, likely due to inhibition of cytochrome P450 (422).

· Dermatological effects: In vitro, niacinamide inhibited melanosome transfer in a melanocyte-keratinocyte coculture system (524). This may play a role in reduced hyperpigmentation of skin.

· Endocrine effects: Niacinamide (200-600mg daily) and insulin therapy together resulted in significantly lower mean postprandial glucose and HbA1c levels, lower insulin requirements, and longer remission duration than insulin alone in newly diagnosed children with type 1 diabetes (152). In human research, nicotinic acid reduced insulin sensitivity in young and older individuals with normal glucose tolerance and older individuals with impaired glucose tolerance (525). Animal research has found that niacinamide (not niacin) delays the development of diabetes mellitus (type 1) (526;487;527;528;529). Given the proposed development of type 1 diabetes mellitus through beta-cell destruction caused partially by depletion of niacinamide adenine dinucleotide (NAD), activation of poly(ADP-ribose) polymerase (PARP) and free radical damage, and niacinamide’s ability to protect against these stimuli, it has been postulated that niacinamide may play a role in the prevention of type 1 diabetes mellitus in “high-risk” individuals (defined as those with afflicted first-degree relatives with or without the presence of islet cell antibodies) (530). Niacinamide has been reported in numerous in vitro and animal studies to have significant protective effects toward pancreatic beta-islet cells (158;531). According to animal research, niacinamide may protect beta-islet cells through an increase in NAD levels (532;156). Niacinamide has been shown to have no effect on insulin secretion or glucose kinetics, unlike niacin, which increases insulin resistance (533;91).

· Niacinamide administered by injection at a dosage of 500mg/kg also increased the cell replication rate of transplanted pancreatic beta-islet cells in mice (534). Niacinamide has been reported to decrease islet cell inflammation (526) and to significantly increase C-peptide release in subjects with diabetes mellitus (type 2) (357;345;535). Niacinamide has been shown to partially reverse the inhibition of glucose-induced insulin release of pancreatic islet cells caused by interleukin-1beta in vitro (536). At a concentration of 20mM, niacinamide inhibited cytokine-induced expression of major histocompatibility complex (MHC) class II molecules on mouse pancreatic islet cells (537).

· It has been found that niacinamide inhibits poly(ADP-ribose) polymerase; in vitro studies examining the effect of niacinamide on single-strand DNA breaks caused by streptozocin and alloxan have found that niacinamide increases the number of single strand breaks induced by streptozocin, consistent with the inhibition of poly(ADP-ribose) synthetase. Niacinamide also reduces the number of single-strand DNA breaks induced by alloxan, consistent with the scavenging of hydroxyl free radicals induced by alloxan (538;539). Niacinamide has been shown to induce beta-cell differentiation in porcine islet-like cell clusters in vitro, leading to an increased number of insulin-positive cells (540). Niacinamide was also shown to block nitric oxide toxicity on beta-islet cells in vitro (154). Niacinamide inhibited ADP-ribosylation and prevented beta-islet cell lysis due to nitric oxide toxicity (541). The addition of niacinamide has been shown to inhibit the release of reactive oxygen intermediates from a xanthine oxidase/hypoxanthine system in vitro, protecting rat islet cells from oxidative damage (115)

· The protective effect of nicotinamide on preservation of mouse islet function and morphology has also been shown (542). In vitro, nicotinamide did not directly affect human beta-cell function or the cell replicatory rate (543).

· The influence of nicotinic acid on insulin secretion in vivo and in vitro was examined in early studies (544). Nicotinic acid, or its analogs, seems to alleviate insulin resistance in the short term, whereas, paradoxically, the long-term effect is often the opposite (506). Suppression of lipolysis by nicotinic acid gave rise to a prominent rebound, and the degree to which this occurs might explain this paradox.

· Nicotinic acid resulted in an increase in transcription of the genes PPAR-alpha, PPAR-delta, and PPAR coactivator-1alpha (PGC-1alpha) in human skeletal muscle; lipid regulatory genes were unaffected (545).

· Metabolic effects: Niacin has demonstrated inhibition of lipolysis in vitro (546;547;505;548;549;550;551). The effect of chronic treatment with nicotinic acid on lipoprotein lipase has also been investigated in humans (552;83). Nocturnal inhibition of lipolysis in humans has been demonstrated (553).

· Niacin has been shown to inhibit stimulated adenyl cyclase activity in vitro and to prevent the accumulation of 3H-labeled cyclic-AMP in fat cells (546).

· Vascular effects: It has been observed that niacin administration initially causes cutaneous flushing in most subjects (>80%). Multiple explanations have been postulated, primarily regarding the release of prostaglandins and local vasodilation. Age and sex (gender) considerably influence niacin sensitivity, possibly due to the effects of sex hormones on vasomotor function and prostaglandin metabolism (396). Research has shown that niacin inhibits the formation of thromboxane-A2 in rat platelets, while increasing the synthesis of prostaglandin-E2 and prostaglandin-E2alpha and inhibiting collagen-induced platelet aggregation (554). In vitro and in vivo research has demonstrated niacin-induced flush to be caused by an increase in the formation of prostaglandins and the subsequent formation of cyclic adenosine monophosphate (37;38). In humans, the administration of oral niacin has been shown to increase the release of prostaglandin-D2 (PGD2), prostacyclins, PGF2alpha, and 6-keto-PGF1alpha, which did not persist with continued treatment, as shown through urinary analysis of eight women taking rapidly increasing oral doses of niacin (555;556;557). Niacin administration to seven healthy fasting volunteers led to increased forearm blood flow, which was inhibited by the administration of indomethacin, suggesting a role of prostaglandins in this phenomenon (45). The cutaneous flushing caused by niacin was found not to be due to a change in metabolic rate but rather to local vasodilatory action in the skin (558). The tolerance to flushing observed in subjects after continued use of niacin appears to be due to a reduction in the release of PGD2 with continued niacin administration (559).

· As reviewed by Offermanns, a G-protein-coupled receptor that binds to nicotinic acid has been identified by three separate scientific groups (560). This receptor is known as GPR109A (HM74A in humans and PUMA-G in mice) and is expressed mainly in adipocytes and immune cells. This receptor is thought to mediate the flushing effects of nicotinic acid.

Pharmacodynamics/Kinetics

· General: Weiner suggested that pharmacological effects of niacin may be dependant on prolonged exposure as opposed to high doses (561). Few or no discernible changes in blood levels of the drug may be needed for pharmacological effects.

· Onset: A single 1g dose of niacin was shown to reach peak plasma levels in 60 minutes after oral ingestion and to decrease to normal after six hours postingestion (503;522).

· Concentration levels: Niacin Cmax and AUC(0-t) values were highest at 9.3mcg/mL and 26.2mcg per hour per mL, respectively (562). Peak niacin and nicotinuric acid occurred at 4.6 hours, as opposed to 8.6 hours for nicotinamide and 11.1 hours for nicotinamide N-oxide.

· Absorption: According to secondary sources, niacin is rapidly absorbed from the stomach and intestine (approximately 60-70% of the dose when administered orally). Esters between nicotinic acid and pentaerythritol or meso-inositol are readily absorbed from the gastric mucosa and hydrolyzed to niacin, causing a significant increase in serum niacin levels four hours after ingestion, as shown in rats, dogs, and humans (563;493). At low concentrations, absorption is mediated by sodium ion-depended facilitated diffusion, but at high concentrations, absorption is by passive diffusion. In humans, absorption of niacin from commercial vitamin water or a standardized mixed meal was reported to be similar in regard to five-hour area under the curve and maximum concentration (564).

· Bioavailability: The bioavailability of unchanged niacin from a single 500mg dose was 1% from two slow-release formulations and 25% from a rapid-release formulation tested in a randomized crossover study in seven healthy volunteers (382). Niacin and nicotinuric acid levels in plasma increased with an increasing dosing rate; nicotinamide and nicotinamide N-oxide did not (565). According to secondary sources, niacin should be taken with food to maximize bioavailability.

· Distribution: According to product information from Niaspan®, niacin is stored in various tissues, particularly the liver, kidney, and adipose tissues. The coenzymes of niacin, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), are synthesized in body tissues from nicotinamide or nicotinic acid (503;522;384). Free nicotinic acid has been isolated in plasma (566).

· Metabolism: According to product information from Niaspan®, niacin is rapidly metabolized in the liver to the metabolites nicotinamide adenine dinucleotide (NAD), nicotinamide (inactive), and nicotinuric acid (inactive). NAD is then catabolized to release niacinamide. NAD is a coenzyme involved in tissue respiration and is required for DNA synthesis and for the activity of poly(ADP-ribose) polymerase (420;486;487;488;343). Niacinamide degradation has been determined to follow a third-order rate equation in vitro (567). The requirements of niacin are met by both the presence of nicotinic acid and nicotinamide in the diet as well as the conversion from dietary protein containing tryptophan.

· Elimination: According to product information from Niaspan®, approximately 60-76% is excreted by the kidneys. Urinary excretion of the metabolites trigonelline, methyl niacinamide, niacin, niacinamide, 2-pyridone, and nicotinuric acid have been shown to peak within the first seven hours of niacinamide or niacin administration in three healthy volunteers, with excretion of methyl niacinamide, niacinamide 2-pyridone, and niacinamide being greater after ingestion of 1g of niacinamide, and excretion of niacin and trigonelline being greater after ingestion of 1g of niacin (568;569). Regular niacin preparations resulted in higher 24-hour urinary concentrations of nicotinuric acid, the metabolite of niacin excreted in the urine, than controlled-release preparations (570). A study of urinary excretion after both immediate- and sustained-release niacin found that the renal excretion of nicotinuric acid is four times greater with the ingestion of immediate-release niacin compared with sustained-release niacin, suggesting a difference in the metabolism of each compound. Urinary recovery of niacin and metabolites account for approximately 69.5% of the administered dose, 3.2% as niacin (562). The highest recovery was for N-methyl-2-pyridone-5-carboxamide (37.9%), followed by N-methylnicotinamide (16.0%) and nicotinuric acid (11.6%). Half-lives for N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide were 12.6 hours and 12.8 hours, respectively. Urinary niacin metabolite levels were not dependent on dosing (565). Urinary output and biosynthesis of nicotinamide from tryptophan increase from stress from cold exposure increased urinary excretory output of niacin in women (571). An ion-selective piezoelectric sensor has been used to determine the level of niacinamide in serum and urine (572).

· Elimination half-life: The mean plasma terminal half-life for niacin (0.9 hours) and nicotinuric acid (1.3 hours) were shorter than that of nicotinamide (4.3 hours) (562). Niacinamide is reported to have a plasma half-life up to nine hours and reaches peak plasma levels within 10 minutes of niacinamide ingestion, and metabolites of niacinamide are detected in the urine after 30 minutes (384).

· Other: Animal research has found that continuous duodenal infusion of niacin has significantly greater lipid-lowering effects than either oral or continuous infusion of equivalent doses, suggesting that the site of action of niacin may be located presystemically (573). As reviewed by Offermanns, a G-protein-coupled receptor that binds to nicotinic acid has been identified by three separate scientific groups (560). This receptor is known as GPR109A (HM74A in humans and PUMA-G in mice) and is expressed mainly in adipocytes and immune cells. This receptor is thought to mediate the antilipolytic and flushing effects of nicotinic acid.

History

· Niacin was originally reported to have applications for the treatment of hyperlipidemic states in a landmark study from 1966 to 1975, the Coronary Drug Project (278;574;575). Since that time, there have been multiple controlled trials of niacin alone and in combination with other medications for hyperlipidemia. Both immediate-release and sustained-release forms have been investigated.

· Niacin deficiency, or pellagra, was a common ailment in the early 20th Century due to the introduction of maize (576). This syndrome, affecting the gastrointestinal tract, skin, and central nervous system, is characterized by dermatitis, dementia, and diarrhea. Pellagra has now been virtually eliminated in the United States due to the niacin fortification of foods, except in some cases of chronic alcoholism (576). The treatment of cerebral pellagra by nicotinic acid first took place in the first half of the 20th Century (577;576).

· Niacinamide, a derivative of niacin, was reportedly isolated in the early 1930s (576). The application of niacinamide for the treatment of arthritis was first begun in the 1940s and 1950s by a Connecticut physician.

Evidence Table

Condition	Study Design	Author, Year	N	Statistically Significant	Quality Of Study 0-2=poor 3-4=good 5=excellent	Magnitude of Benefit	ARR	NNT	Comments
Hyperlipidemia	Meta-analysis	Robinson, 2012	Five studies	Yes	NA	Small	NA	NA	Meta-analysis with niacin used in combination.
Hyperlipidemia	Meta-analysis	Robinson, 2009	7 studies	Yes	NA	Small	NA	NA	Meta-analysis of effect on coronary heart disease and HDL.
Hyperlipidemia	Meta-analysis	Sharma, 2009	15 studies	No	NA	NA	NA	NA	Meta-analysis of niacin alone and in combination.
Hyperlipidemia	Meta-analysis	Goldberg, 2004	432	Yes	NA	Large	NA	NA	Five trials showed greater decreases in LDL and TG; effects were slightly better in women.
Hyperlipidemia	Systematic review	Dunatchik, 2012	Four studies	NA	NA	NA	NA	NA	Review of safety and efficacy of wax-matrix niacin.
Hyperlipidemia	Systematic review	Ito, 2012	Five studies	NA	NA	NA	NA	NA	Systematic review on cholesterol, carotid intima-media thickness, and cardiovascular events.
Hyperlipidemia	Systematic review	Brooks, 2010	17 Studies	NA	NA	NA	NA	NA	Systematic review using niacin in combination with statins.
Hyperlipidemia	Systematic review	Charland, 2010	28 studies	NA	NA	NA	NA	NA	Systematic review using niacin in combination with statins.
Hyperlipidemia	Systematic review	Gupta, 2010	Five studies	NA	NA	NA	NA	NA	Systematic review of niacin on cholesterol levels.
Hyperlipidemia	Systematic review and meta-regression	Labreuche, 2010	Eight studies	NA	NA	NA	NA	NA	The authors reported a decrease in risk of stroke due to decrease triglyceride levels.
Hyperlipidemia	Systematic review	Reiner, 2010	20 studies	NA	NA	NA	NA	NA	Systematic review of combination treatments.
Hyperlipidemia	Systematic review	Schectman, 1996	Six studies	NA	NA	NA	NA	NA	Three trials of niacin monotherapy demonstrated efficacy; three trials combining niacin with statins found additive effects.
Atherosclerosis (as adjunct therapy; niacin)	Meta-analysis	Robinson, 2012	Five studies	Yes	NA	Small	NA	NA	Meta-analysis with niacin used in combination.
Atherosclerosis (as adjunct therapy; niacin)	Meta-analysis	Bruckert, 2010	14 Studies	Yes	NA	Medium	NA	NA	Meta-analysis with a significant reduction in coronary events.
Cardiovascular disease (niacin)	Meta-analysis	Robinson, 2012	Five studies	Yes	NA	Small	NA	NA	Meta-analysis of niacin used in combination.
Cardiovascular disease (niacin)	Meta-analysis	Bruckert, 2010	14 studies	Yes	NA	Medium	NA	NA	Meta-analysis with a significant reduction in cardiovascular events.
Cardiovascular disease (niacin)	Meta-analysis	Duggal, 2010	Seven studies	Yes	NA	Small	NA	NA	A significant decrease reported in some ischemic events but not mortality.
Cardiovascular disease (niacin)	Meta-analysis	Robinson, 2009	Seven studies	Yes	NA	Small	NA	NA	Meta-analysis with effect on coronary heart disease and HDL.
Cardiovascular disease (niacin)	Meta-analysis	Sharma, 2009	15 studies	No	NA	NA	NA	NA	Meta-analysis of niacin alone and in combination.
Cardiovascular disease (niacin)	Meta-analysis	Birjmohun, 2005	4,749	Yes	NA	Small	NA	NA	30 trials; limited data on cardiovascular event rate. 10 trials included Acipimox®.
Cardiovascular disease (niacin)	Systematic review	Ito, 2012	Five studies	NA	NA	NA	NA	NA	Systematic review of cholesterol, carotid intima-media thickness, and cardiovascular events.
Cardiovascular disease (niacin)	Systematic review	Charland, 2010	28 studies	NA	NA	NA	NA	NA	Systematic review using niacin in combination with statins.
Cardiovascular disease (niacin)	Systematic review and meta-regression	Labreuche, 2010	Eight studies	NA	NA	NA	NA	NA	The authors reported a decrease in risk of stroke due to decreased triglyceride levels.
Cardiovascular disease (niacin)	Systematic review	Studer, 2005	97 studies (only two niacin trials)	No (mortality)	NA	NA	NA	NA	Risk ratio for overall mortality (95% CI: 0.86-1.08), cardiac mortality, and noncardiovascular mortality indicated no benefit from niacin.
Cardiovascular disease (niacin)	Systematic review	Bucher, 1999	59 studies; two studies on niacin	No (mortality)	NA	NA	NA	NA	Review of mortality and all cholesterol-lowering treatments. Included two trials of niacin therapy. Pooled results showed a nonsignificant risk ratio of 0.95 for cardiac mortality, 0.96 for all-cause mortality, and 0.9 for noncardiac mortality.
Headaches	Systematic review	Prousky, 2005	Nine case series or case reports	NA	NA	NA	NA	NA	Overall evidence from case series and case reports suggested that niacin is of benefit for headaches.
Type 1 diabetes mellitus: preservation of beta-islet cell function (niacinamide)	Meta-analysis	Pozzilli, 1996	10 studies; 211 subjects	Yes	NA	Medium	NA	NA	Significantly higher baseline C-peptide levels in niacinamide-treated patients vs. controls at one year.

Evidence Discussion

Discussion on use of Niacin

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