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Niacin and Hyperlipidemia: Which Form is Best?

Niacin and Hyperlipidemia: Which Form is Best?

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Niacin therapy has long been recognized as a treatment option in addressing hyperlipidemia.[1],[2] Niacin is inexpensive and therapeutically comparable with statin drugs in cases of hyperlipidemia.[3],[4] However, not all niacin forms are biological equivalents.[5] Care should be taken when choosing niacin preparations for patients to ensure efficacy, tolerance, and safety, depending on the therapeutic goal. In this article, we will explore four different forms of niacin and the best way to utilize each of them in practice when optimizing cholesterol levels.

Nicotinic Acid (NA)

Nicotinic acid (NA) is probably the most well-known and most researched form of niacin. Marketed as both a dietary supplement and a prescription drug, NA is one of the few lipid-altering agents that has also been shown to decrease mortality in cases of cardiac arrest.[6] NA is rapidly and almost completely absorbed.[7],[8] NA reaches peak plasma concentrations as quickly as 30 minutes to one hour after oral supplementation.[9]

NA fully supports the coenzyme functions needed from NAD.5 At much higher intakes, NA is an effective lipid-lowering agent.8 Numerous studies have shown that NA successfully lowers low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and triglycerides.[10] NA also increases serum high-density lipoprotein cholesterol (HDL-C), commonly referred to as “good cholesterol,” leading to a more desirable cholesterol ratio in the hyperlipidemic patient.5 Data reveals NA’s lipid-lowering effects, showing a reduction in total triglyceride levels by 20 to 50%, a reduction in LDL-C levels by 10 to 25% (which includes a preferential reduction of the small, dense LDL particles associated with more atherogenicity), and an increase in HDL-C levels by 10 to 30%.[11],[12],[13],[14],[15] Because NA has been so widely studied, the dosage response for this particular form of niacin is well known,[16] with 15 to 18 mg/day being sufficient for enzymatic nutritional functions.9 To achieve beneficial effects on serum lipid values, much higher intakes (500 to 3,000 mg/day) are needed.5

The research consistently shows NA to be an effective and inexpensive option for patients with hyperlipidemia; however, it is still not recommended as the initial drug therapy for these individuals due to possible adverse effects.[17] The most famous of these is the “niacin flush” that occurs as a result of rapid vasodilation following dosage of NA. This gives the patient a sensation of intense burning or itching and visibly red skin when plasma levels are at their peak, approximately 30 minutes to one hour following ingestion.[18] Flushing is generally regarded as a nuisance effect that serves no major risk to the patient, but the sensation is markedly unpleasant enough to make patient adherence difficult to achieve.[19] Some patients can experience a flush at intakes as low as 50 mg/day.5 The effects of flushing can be mitigated by starting at a lower dose of NA and titrating up slowly toward therapeutic ranges as a tolerance is built.[20] Taking 150 to 300 mg of quercetin with NA, or 30 to 60 minutes before taking NA, has also been shown to mitigate the “niacin flush.”[21] Additionally, research has shown that eating a medium- to large-sized apple before high-dose NA intake will mitigate this benign yet bothersome cutaneous flushing.[22]

The research consistently shows NA to be an effective and inexpensive option for patients with hyperlipidemia

There is further concern regarding the more serious effects of hepatotoxicity and gastrointestinal toxicity with therapeutic doses of NA.5 While these effects appear to be infrequent, they are serious and should be considered when approaching NA as a treatment for hyperlipidemia.[23] If toxicity occurs, it is generally at dosages of 1 g/day or higher of NA.5 The severity of hepatotoxicity ranges from elevated liver enzymes to acute liver failure.[24] While this is of very significant concern, occurrences in clinical studies are still rare, suggesting that utilizing NA at therapeutic doses of 2 to 4 g/day as a treatment for hyperlipidemia can be done safely under medical supervision and appropriate monitoring.[25] Another possible side effect of high-dose NA is a transient, modest, and reversible rise in fasting glucose and hemoglobin A1C (HbA1c), which occurs more typically in dysglycemic patients.[26]

Extended-Release Nicotinic Acid (ER-NA)

Extended-release nicotinic acid (ER-NA) is available as a prescription drug that has been approved by the FDA, as well as a dietary supplement.[27] It has a delivery system that allows slower absorption times than the free form of NA.[28] The uptake of NA from ER-NA can vary based on specific delivery matrix. ER-NA produces lower peak serum concentrations when compared to NA, but they are sustained for longer periods of time9 and achieve therapeutic plasma levels.[29] ER-NA has comparable lipid-lowering effects to NA and can be considered as an alternative to NA for hyperlipidemia.12 However, the extended-release form is approximately twice as hepatotoxic as free NA and carries a lower safe upper limit.16,26 As a matter of fact, many of the most severe documented cases of toxicity from niacin therapy have occurred following uninformed switching from free NA to ER-NA without any adjustments to the dosage.9,27 Flushing still occurs with ER-NA, typically two to four hours after ingestion, but may be substantially reduced.[30]

Nicotinamide/Niacinamide (NAM)

Nicotinamide, also known as niacinamide and NAM, is the amide form of niacin. It is readily bioavailable and well tolerated.7 NAM can be converted to NAD through a two-step salvage pathway to be used as a cellular coenzyme.[31] It can also prevent niacin deficiency, or pellagra. However, NAM is not sufficiently converted to NA in the bloodstream.[32] Because of this, it does not produce the undesirable flushing effect, the risk of toxicity, or an effective change on plasma lipids.[33] NM shows promise in preliminary studies for less well-known clinical uses of niacin because of its lack of flush and lower risk profile.[34] Nicotinamide riboside (NR) has been used as a precursor to NAD in studies looking to achieve the beneficial metabolic effects of increased NAD without the side effects noted with other forms of niacin.

Because of the low plasma NA values with supplementation of IHN, there is no flush reaction. This is generally much better tolerated by patients. This also offers a better safety profile to patients compared to NA or ERNA.

Inositol Hexanicotinate (IHN)

Inositol hexanicotinate (IHN), often marketed as “flush-free niacin,” is composed of six molecules of nicotinic acid attached to an inositol molecule. The intestinal absorption of IHN varies, with an average of 70% of ingested IHN entering the bloodstream and remaining intact, making it a bioavailable form.[35] IHN can be metabolized to release NA, but this process is rather inefficient. Individuals given IHN will reach peak plasma levels of NA at six to 12 hours following their dose, but these peak levels are drastically lower compared to the ingestion of NA alone.[36] One study revealed a peak plasma level of 30 mcg/mL following a dose of 1,000 mg of free NA and only a 0.2 mcg/mL peak plasma level following 1,000 mg of IHN.[37]

Because of the low plasma NA values with supplementation of IHN, there is no flush reaction. This is generally much better tolerated by patients. This also offers a better safety profile to patients compared to NA or ERNA. However, research suggests that IHN is not an effective lipid-control agent, when compared to similar dosing with NA.[5] A three-arm, double-blind, randomized clinical trial by Keenan et al. compared 1,500 mg/day in three divided doses of ER-NA, IHN, and a placebo group. The ER-NA group had significantly reduced total cholesterol and LDL-C, with an increase in HDL-C. The IHN group had no significant effects on any lipid group.[38]

A few smaller studies suggest that IHN could still prove to be an effective hyperlipidemic agent when used at higher dosages. One study by Welsh and Ede showed a decrease in total cholesterol by 12% and 17% following IHN supplementation, but only included two patients.59 Other studies have found no change in lipid levels until reaching an IHN dose of at least 2400 mg/day, suggesting that this amount is needed to produce a meaningful change in lipids.[39] The results with IHN for lipid management are controversial but if positive results could be repeated on a larger scale, it could give hope to those seeking an effective, niacin-based approach to hyperlipidemia without the undesirable side effects.

A double-blind, placebo-controlled trial with only 11 subjects revealed no changes in plasma lipids after three months of taking 1,500 mg of IHN daily.[40] However, this study did reveal significant improvements in flow-mediated dilation of blood vessels and improved endothelial function. Several studies reveal promising results for IHN improving peripheral blood flow, which is clinically significant in cases of Raynaud’s disease and intermittent claudication.[41],[42] The adult dose of IHN for peripheral blood flow improvement is 3 g/day and up to 4 g/day.[43] The mechanism of action for IHN in intermittent claudication and Raynaud’s is not fully understood, yet it would make sense that some of the NA that is metabolized from IHN could produce a vasodilating effect that is less intense than those effects experienced following ingestion of NA or ER-NA.12 It is also hypothesized that IHN may lead to a reduction in fibrinogen, improvements in blood viscosity, and improvements in overall oxygen transport.[44]

Although these derivatives can all go by the name niacin, they are not all created equal. Each niacin form discussed in this article can fulfill the nutritional requirements from niacin, with different safety and side-effect profiles, and different levels of therapeutic efficacy with regards to hyperlipidemia.



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[3] Sharma M, et al. Evaluation of efficacy and safety of fixed dose lovastatin and niacin(ER) combination in asian Indian dyslipidemic patients: a multicentric study. Vasc Health Risk Manag. 2006;2(1):87-93.

[4] Brown BG, et al. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol. 1997;80(2):111-5.

[5] MacKay D, et al. Niacin: chemical forms, bioavailability, and health effects. Nutr Rev. 2012;70(6):357-66.

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[8] Bechgaard H, Jespersen S. GI absorption of niacin in humans. J Pharm Sci. 1977;66:871-2.

[9] Sebrell WH, Butler RE. A reaction to the oral administration of nicotinic acid. JAMA. 1938;11:2286-7.

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[11] Knopp RH, et al. Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin. Metabolism. 1985;34:642-50.

[12] McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271:672-7.

[13] Shepherd J, et al. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism. J Clin Invest. 1979;63:858-67.

[14] Wahlberg G, et al. Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia. J Intern Med. 1990;228:151-7.

[15] Carlson LA, et al. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med. 1989;226:271-6.

[16] Rader JI, et al. Hepatic toxicity of unmodified and time-release preparations of niacin. Am J Med. 1992;92:77-81.

[17] Pignone M. Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease. In: Post TW, ed. UpToDate. Waltham, MA: (Accessed on May 01, 2021)

[18] Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol. 2008;101(8A):20B-26B.

[19] Jacobson TA. A “hot” topic in dyslipidemia management–“how to beat a flush”: optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. Mayo Clin Proc. 2010;85(4):365-79.

[20] Capuzzi DM, et al. Niacin dosing: relationship to benefits and adverse effects. Curr Atheroscler Rep. 2000;2:64-71.

[21] Kalogeromitros D, et al. A quercetin containing supplement reduces niacin-induced flush in humans. Int J Immunopathol Pharmacol. Jul-Sep 2008;21(3):509-14.

[22] Moriarty PM, et al. Apple pectin for the reduction of niacin-induced flushing. J Clin Lipidol. Mar-Apr 2013;7(2):140-6.

[23] Hathcock JN. Niacin, nicotinic acid and nicotinamide. In: Hathcock JN, ed. Vitamin and Mineral Safety. 2nd ed. Washington, DC: Council for Responsible Nutrition; 2004:85-91.

[24] Clementz GL, Holmes AW. Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol. 1987;9:582-4.

[25] Habibe MN, Kellar JZ. Niacin Toxicity [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jun 25 [cited 2021 Jul 13]. Available from:

[26] Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc. 2008 Apr;83(4):470-8.

[27] Abourjaily HM. A review of Niaspan®, an extended-release niacin. Nutr Clin Care. 2001;4:250-55.

[28] Pieper JA. Understanding niacin formulations. Am J Manag Care. 2002;8(12 Suppl):S308-S314.

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[30] Paolini JF, et al. Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors. Cardiol Clin. 2008;26(4):547-60.

[31] Fang EF, et al. Nad(+) In Aging: Molecular Mechanisms And Translational Implications. Trends Mol Med. 2017;23(10):899-916.

[32] Fukuwatari T, et al. Bioavailability of nicotinamide-rich powder obtained from bonito as niacin source in humans and rats [in Japanese]. J Home Econ. 2005;56:265-72.

[33] Dollerup OL, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018;108(2):343-53.

[34] Walocko FM, et al. The role of nicotinamide in acne treatment. Dermatol Ther. 2017;30(5).

[35] Harthon JG, Lindqvist JT. On the elimination of unabsorbed hexanicotinic acid esters of meso-inositol in the feces. Arzneimittelforschung. 1964;14:1170-1.

[36] Welsh AL, Ede M. Inositol hexanicotinate for improved nicotinic acid therapy. Preliminary report. Int Record Med. 1961;174:9-15.

[37] Harthon L, Brattsand R. Enzymatic hydrolysis of pentaerythritoltetranicotinate and meso-inositolhexanicotinate in blood and tissues. Arzneimittelforschung. 1979;29:1859-62.

[38] Keenan J. Extended-release nicotinic acid versus inositol hexanicotinate for the treatment of dyslipidemia. J Clin Lipidol. 2010;4:216-7.

[39] Dib JG, Dedeyan S. Purported benefits of inositol niacinate. Am J Health Syst Pharm. 2004;61(3):307-308. doi:10.1093/ajhp/61.3.307

[40] Benjó AM, et al. Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment. Atherosclerosis. 2006;187:116-22.

[41] Head A. Treatment of intermittent claudication with inositol nicotinate. Practitioner. 1986;230:49-54.

[42] Ring EF, Bacon PA. Quantitative thermographic assessment of inositol nicotinate therapy in Raynaud’s phenomena. J Int Med Res. 1977;5:217-22.

[43] O’Hara J, et al. The therapeutic efficacy of inositol nicotinate (Hexopal) in intermittent claudication: a controlled trial. Br J Clin Pract. 1988;42:377-83.

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The information provided is for educational purposes only. Consult your physician or healthcare provider if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.

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