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Niacin, aka vitamin B3 – what you need to know about potential side effects

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In previous articles I have talked about the multiple beneficial effects of niacin supplementation – on both lipids (blood fats and cholesterol) and non-lipid outcomes.
 
While flushing is often reported to be the main side-effect of niacin supplementation, the flush is a natural reaction to high-dose niacin, and is not dangerous. Thus, while some people may find it uncomfortable, it is not a harmful side-effect. For more on that, see “Niacin - How to Beat the Flush
 
Other, potentially harmful side effects, are liver strain/damage, insulin resistance and blood glucose elevations, and uric acid elevations.[1] Here I will summarize what research shows on the severity of these side effects, and whether it is something you should worry about… 
 

Liver strain / damage

 
Compared to immediate-release niacin, time-release niacin is more liver toxic.[2-8] In doses that achieve equivalent improvements in blood lipid profiles, liver toxicity occurs more frequently with some time-release niacin preparations than with immediate-release niacin.[9] Half of people who take time-release niacin develop some degree of elevations in liver transaminases.[3, 10] In contrast, immediate-release niacin in usual therapeutic doses (up to 3000 to 4000 g per day) almost never causes liver injury.[10, 11] This may seem counterintuitive as immediate-release niacin causes the most intense flush.
 
One study published 1994 “A Comparison of the Efficacy and Toxic Effects of Sustained- vs Immediate-Release Niacin in Hypercholesterolemic Patients” is commonly cited by critics of niacin supplementation.[8] This study by McKenny et al. concluded that “the sustained-release (i.e. time-release) form of niacin is hepatotoxic and should be restricted from use”.[8] However, it has been criticized because it was clearly designed to maximize the potential for niacin intolerance and toxicity.[12] The study provided subjects with a high dose twice per day (bid) dosing, and intentionally escalated both the immediate-release niacin and time-release niacin to a high total daily dose of 3000 mg (1500 mg twice daily), whether or not subjects had an adequate lipid response at a lower dose.[12] As was pointed out in the critique, if the intent of the study was to show efficacy and minimize intolerance and side effects, a three times per day (tid) or four times per day (qid) dosing scheme would have been used.[12]  For example, The Coronary Drug Project (CDP) – which I covered in a previous article “Niacin – a.k.a vitamin B3 – the neglected broad spectrum cholesterol drug!” was such a study, with 1119 subjects on a daily immediate-release niacin dose of 3000 mg, taken is doses of 1000 mg three times per day for up to 6 years. The CDP study had only a 5% dropout rate due to niacin intolerance and toxicity after 1 year of treatment. In contrast, the study by McKenny et al. had a dropout rate of 39% among subjects in the immediate-release niacin group. 
 
The high dose in the study by McKenny et al. is especially troublesome for the time-release niacin group, as it is well known that time-release niacin in high doses may cause liver strain. In their comment on previous studies, McKenny et al. they state "most cases of hepatotoxicity have occurred in patient taking 2000 mg per day or more. Yes, they intentionally administered a dose that exceeds that toxicity threshold by 50%. Two other studies published in the early 1990s independently reported excellent tolerance (dropout rate of only 3-4%) and good lipid (cholesterol and blood fat) responses, using a wax-matrix time-release niacin product (Enduracin).[12, 13] Both of these studies indicated that 1500 mg per day appears to be the average optimal dose of time-release niacin, in this case Enduracin. This data was available at the time the McKenny study was conducted. Despite knowing this they giving subjects twice this dose, 3000 mg per day. It is not surprising that 78% of subjects in the time-release niacin group reported intolerance, with 52% dropping out due to hepatotoxicity.[8]
 
Another commentary on the McKenny et al. study pointed out that clinical evaluation of relative toxicity requires a comparison of toxic manifestations at doses that provide the same therapeutic benefit, rather than equal doses.[14] Data indicate that the lipid improving potency of the time-release niacin is at least twice that of immediate-release niacin; thus, the side effects of time-release niacin in doses of 1000 to 1500 mg daily should be compared to 2000 to 3000 mg of immediate-release niacin.[14]
 
The study by McKenny et al. used a time-release niacin product (Goldline Laboratories, Ft Lauderdale, FL) which has been discontinued). Whether their reported dropout rates are due to the high dose or that specific time-release niacin product, or a combination of both, is unknown. However, the study makes the misleading conclusion alluding to that all time-release niacin supplements have harmful effects on the liver, which is wrong. Multiple studies have confirmed the tolerability and liver safety – as well as efficacy in improving cholesterol profiles - of wax-matrix time-release niacin (Enduracin).[12, 13, 15-18]
 
Before you start niacin supplementation, I recommend that you get your liver enzyme levels checked. Elevated liver enzymes below 3 times the upper limit of normal may initially occur with niacin supplementation but usually resolve with continued supplementation.[19] With elevations greater than that it is advised that the dose is reduced.[20] It is also recommended to take a “liver supplement” like SAMe [21], LIV-52 [22] or milk thistle (a.k.a. silybin) [23], which may protect the liver and help prevent elevations in liver enzymes. SAMe in particular has several human studies supporting its efficacy - at a dose of 800-1200 mg per day - to improve liver function and protect the liver in people who take medications.[21]
 

Insulin resistance

 
Niacin supplementation (all forms) may cause a modest, transient, and reversible elevation of fasting blood glucose levels, and in some people also an increase in glycosylated hemoglobin (HbA1c) levels (an indicator of average long-term blood glucose levels).[24] This increase in fasting blood glucose levels and HbA1c is greater in diabetics than non-diabetics.[25, 26]
 
In the Arterial Disease Multiple Intervention Trial (ADMIT), 468 patients with peripheral arterial disease, including 125 with type 2 diabetes, were randomized to immediate-release niacin (up to 3000 mg/day or maximum tolerated dose) or placebo for 60 weeks.[25] A transient increase of fasting blood glucose levels was found as the niacin dose was up-titrated to 3000 mg, but the elevations returned to baseline levels six weeks after the niacin dosage was stabilized.[25]
 
In the assessment of diabetes control and evaluation of the efficacy of niaspan trial (ADVENT), 148 patients were randomized to receive extended-release niacin (Niaspan) 1500 mg/day or placebo for 16 weeks.[26] Fasting glucose levels of one third of diabetic patients receiving either 1000 or 1500 mg of Niaspan daily increased between weeks 4 and 8, but returned to baseline by week 16. The 1000 mg/day dose resulted in no significant alteration in glycemic control compared to placebo. The 1500 mg/day dose resulted in modest deterioration of glycemic profile, as indicated by an elevation in HbA1c from 7.21% to7.50%.[26] However, it was stated that any increased risk of microvascular diabetic complications due to this 0.29%-age point increase in HbA1c would likely be offset by the decreased risk of cardiovascular disease thanks to the significant improvements in blood cholesterol and lipoprotein profile.[26] A comprehensive review of the safety aspects of niacin supplementation also concluded that the benefits of niacin far exceed the small deterioration in glucose control.[27]
 
It was concluded in both ADMIT and ADVENT that lipid-improving dosages of niacin can be safely used in patients with diabetes.[25, 26] In people with diabetes and metabolic syndrome, who are characterized by low HDL levels, the use of a low, more tolerable dose (about 1000 mg/day) can be expected to boost HDL levels by 25%.[11, 28] This is important to underscore as the lipid abnormalities encountered in these patients (low HDL levels and dysfunctional HDL, together with elevated triglycerides and small atherogenic LDL particles) are ideally suited to niacin treatment. 
 
This position is supported by the impressive results from the coronary drug project, where supplementation with immediate-release niacin for 4 years increased fasting blood glucose levels by 7 mg/dL [29] but reduced the risk of 6-year recurrent heart attacks, as well as heart disease death and 15-year total mortality, compared with placebo.[30] These effects were independent of the small elevation in fasting blood glucose.[30] Niacin supplementation in patients with metabolic syndrome conferred the same health benefits (despite a 5.5% increase in fasting blood glucose levels).[31]
 
Thus, there is good evidence showing that the small increase in fasting blood glucose levels does not negate the overall clinical benefits of niacin supplementation, which is seen even in patients with the metabolic syndrome or diabetes.
 

Uric acid 

 
Another possible adverse effect of niacin supplementation is a small elevation in blood uric acid levels, which can lead to development of gout.[32] Extended-release niacin in doses up to 2,000 mg/day has been shown to increase uric acid levels by around 11%, but levels still remained within normal limits.[33, 34] In a head-to-head comparison study, the mean increase in uric acid levels was smaller with extended-release niacin than with immediate-release niacin dosed at 500 mg thrice daily (5.8% vs 16.2%, respectively).[35] The increase in uric acid levels after supplementation of 3000 mg/day with immediate-release niacin is of the same magnitude in non-diabetic and diabetic people.[25]
 
Although the increase in serum uric acid is moderate in patients with normal pre-treatment levels, it can be clinically relevant in patients with high levels of uric acid (over 1.5 times the upper limit of normal) before treatment or in those with pre-existing gout.[36] In these patients, niacin therapy has to be done carefully with low doses (50-100 mg immediate-release niacin per day) and close medical monitoring of uric acid levels.[27] With any increase in serum uric acid of clinical significance, treatment with allopurinol at doses of 100-300 mg per day is recommended.[27] The argument can be made that the tremendous benefits of niacin on blood lipids and cardiovascular disease protection far outweighs the potential risk due to elevation in uric acid in most people.
 

Summary

 
As with most things in life, there is a risk-to-benefit ratio. When it comes to niacin, for the large majority of people, the benefits far outweigh any potential side effects.
 
Despite concerns of liver strain/damage, insulin resistance and uric acid elevations, data shows that therapeutic doses of niacin are safe, even in people with the metabolic syndrome or diabetes.
 
When considering potential side effects of niacin it should be underscored that according to the US Food and Drug Administration's (FDA) Adverse Event Reporting System, which evaluates the safety of niacin as it is used in daily life, the safety profile of niacin compares favorably with other commonly used cholesterol drugs, including statins and fibrates.[37] The adverse liver effects with prescription extended-release niacin (Niaspan) up to 3000 mg per day are minor, and occur at rates similar to those reported for statin treatment.[38] 
 
If you are looking for an over-the-counter time-release niacin product, get the wax-matrix formulation (Enduracin). The wax-matrix form of time-release niacin has the most research backing up its safety and efficacy in doses around 1500 mg per day. With immediate-release niacin, higher doses of 3000 to 4000 mg per day are safe in most people. 
 
The important thing to remember with niacin is to “start low and go slow” – i.e. to gradually build up the dose - and let your body develop tolerance to the flush. For practical recommendations, see my previous article
 
 
References:

1.            Kei, A., E.N. Liberopoulos, and M.S. Elisaf, What restricts the clinical use of nicotinic acid? Curr Vasc Pharmacol, 2011. 9(4): p. 521-30.

2.            Henkin, Y., K.C. Johnson, and J.P. Segrest, Rechallenge with crystalline niacin after drug-induced hepatitis from sustained-release niacin. JAMA, 1990. 264(2): p. 241-3.

3.            Etchason, J.A., et al., Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin. Mayo Clin Proc, 1991. 66(1): p. 23-8.

4.            Lawrence, S.P., Transient focal hepatic defects related to sustained-release niacin. J Clin Gastroenterol, 1993. 16(3): p. 234-6.

5.            Scheer, M.S., et al., Ultrasonographic findings in niacin-induced hepatitis. J Ultrasound Med, 1999. 18(4): p. 321-3.

6.            Henkin, Y., et al., Niacin revisited: clinical observations on an important but underutilized drug. Am J Med, 1991. 91(3): p. 239-46.

7.            McKenney, J., New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med, 2004. 164(7): p. 697-705.

8.            McKenney, J.M., et al., A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA, 1994. 271(9): p. 672-7.

9.            Rader, J.I., R.J. Calvert, and J.N. Hathcock, Hepatic toxicity of unmodified and time-release preparations of niacin. Am J Med, 1992. 92(1): p. 77-81.

10.          Pieper, J.A., Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm, 2003. 60(13 Suppl 2): p. S9-14; quiz S25.

11.          McKenney, J., Niacin for dyslipidemia: considerations in product selection. Am J Health Syst Pharm, 2003. 60(10): p. 995-1005.

12.          Keenan, J.M., et al., Safety and side effects of sustained-release niacin. JAMA, 1994. 272(7): p. 513; author reply 514-5.

13.          Alderman, J.D., et al., Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio. Am J Cardiol, 1989. 64(12): p. 725-9.

14.          Weiner, M., Safety and side effects of sustained-release niacin. JAMA, 1994. 272(7): p. 514; author reply 514-5.

15.          Keenan, J.M., et al., A clinical trial of oat bran and niacin in the treatment of hyperlipidemia. J Fam Pract, 1992. 34(3): p. 313-9.

16.          Aronov, D.M., et al., Clinical trial of wax-matrix sustained-release niacin in a Russian population with hypercholesterolemia. Arch Fam Med, 1996. 5(10): p. 567-75.

17.          Dunatchik, A.P., M.K. Ito, and C.A. Dujovne, A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation. J Clin Lipidol, 2012. 6(2): p. 121-31.

18.          Keenan, J.M., Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate "no-flush" niacin in persons with mild to moderate dyslipidemia. J Clin Lipidol, 2013. 7(1): p. 14-23.

19.          Rizakallah, G.S., et al., Clinical inquiries. Should liver enzymes be checked in a patient taking niacin? J Fam Pract, 2005. 54(3): p. 265-8.

20.          ASHP Therapeutic Position Statement on the safe use of niacin in the management of dyslipidemias. American Society of Health-System Pharmacists. Am J Health Syst Pharm, 1997. 54(24): p. 2815-9.

21.          Guo, T., et al., S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PLoS One, 2015. 10(3): p. e0122124.

22.          Huseini, H.F., et al., The efficacy of Liv-52 on liver cirrhotic patients: a randomized, double-blind, placebo-controlled first approach. Phytomedicine, 2005. 12(9): p. 619-24.

23.          Loguercio, C. and D. Festi, Silybin and the liver: from basic research to clinical practice. World J Gastroenterol, 2011. 17(18): p. 2288-301.

24.          Goldberg, R.B. and T.A. Jacobson, Effects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc, 2008. 83(4): p. 470-8.

25.          Elam, M.B., et al., Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA, 2000. 284(10): p. 1263-70.

26.          Grundy, S.M., et al., Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med, 2002. 162(14): p. 1568-76.

27.          Guyton, J.R. and H.E. Bays, Safety considerations with niacin therapy. Am J Cardiol, 2007. 99(6A): p. 22C-31C.

28.          Thoenes, M., et al., The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract, 2007. 61(11): p. 1942-8.

29.          Stamler, J., The coronary drug project--findings with regard to estrogen, dextrothyroxine, clofibrate and niacin. Adv Exp Med Biol, 1977. 82: p. 52-75.

30.          Canner, P.L., et al., Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol, 2005. 95(2): p. 254-7.

31.          Canner, P.L., C.D. Furberg, and M.E. McGovern, Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol, 2006. 97(4): p. 477-9.

32.          Abbott Laboratories NIASPAN™ (niacin extended-release tablets) US prescribing information. Available at: http://www.niaspan.com2005.

33.          Guyton, J.R., et al., Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med, 2000. 160(8): p. 1177-84.

34.          Morgan, J.M., et al., Treatment Effect of Niaspan, a Controlled-release Niacin, in Patients With Hypercholesterolemia: A Placebo-controlled Trial. J Cardiovasc Pharmacol Ther, 1996. 1(3): p. 195-202.

35.          Knopp, R.H., et al., Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia. Metabolism, 1998. 47(9): p. 1097-104.

36.          Carlson, L.A., Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med, 2005. 258(2): p. 94-114.

37.          Alsheikh-Ali, A.A. and R.H. Karas, The safety of niacin in the US Food and Drug Administration adverse event reporting database. Am J Cardiol, 2008. 101(8A): p. 9B-13B.

38.          Guyton, J.R., et al., Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol, 1998. 82(6): p. 737-43.

Last modified on Wednesday, 24 August 2016 23:35
Monica

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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