Niacin, heart disease, liver toxicity, and diabetes
I recently finished recording a massive niacin podcast with Chris Masterjohn, which I’ll link to when published.
Update: Here is part 1 (LINK). Here is part 2 (LINK).
I wanted to summarize some of the points I discussed on the practical use of niacin, in the form of nicotinic acid, to manage blood lipids and heart disease risk, while minimizing the chances of developing diabetes or damaging the liver.
On the whole, niacin therapy does appear to be beneficial for people who have a history of heart disease or are at risk of it.
It seems to reduce the risk of having adverse cardiovascular events,1,2 including major coronary events and heart attacks, as well as the risk of undergoing revascularization surgery (e.g., stents and bypass), even when used as a monotherapy.3
It may even reduce the risk of dying from cardiovascular disease, although it doesn’t affect the risk of dying from any cause.2
Niacin most likely benefits heart health by reducing LDL particle concentrations and triglycerides.4–6
Basically, niacin binds the niacin receptor (GPR109A) to reduce the outflow of free fatty acids from our fat cells. This deprives the liver of an essential substrate for triglyceride synthesis and secretion as VLDL,7,8 which is a precursor for LDL.
Niacin has a pronounced ability to increase HDL-C by an average of 20%,2 and also increases HDL particle counts and size,4–6 but the changes aren’t associated with the risk of having any adverse cardiovascular event.1
Niacin increases HDL by simply inhibiting HDL uptake in the liver9 — it does not seem to enhance the HDL functionality in terms of reverse cholesterol transport (efflux capacity) and anti-inflammatory effects.10,11
HDL has a strong biological rationale for reducing risk of heart disease and promoting plaque regression,12 but it relates entirely to HDL functionality, not particle number or size. Accordingly, HDL functionality is a powerful predictor of heart disease,13 but actual HDL levels are not.14,15
Niacin reduces the risk of heart disease by lowering LDL particle counts and triglycerides, not by raising HDL particle counts.
The ability of niacin (as nicotinic acid) to reduce heart disease risk comes with a price — a 34% increased risk of developing diabetes.16
The author’s state that the mechanisms of niacin-induced diabetes remain unclear, but I think there is a rather simple and straight-forward explanation: The Randle cycle.17
Remember, niacin binds the niacin receptor (GPR109A) to reduce the outflow of free fatty acids (FFAs) from our fat cells. This results in a marked suppression of FFAs for about two hours, followed by a 4-fold increase thereafter.18
Per the Randle cycle, the suppression of FFAs leads to a marked increase in glucose oxidation, and the FFA rebound impairs glucose use as an energy source. It’s the rebound that’s the issue, since long-term suppression of FAAs via the drug acipimox improves glycemic control.19
The risk of diabetes comes into play when people eat a bunch of carbohydrates during the FFA rebound period, since elevated FFAs cause a state of insulin resistance and glucose intolerance.
Accordingly, the risk of diabetes can be mitigated by simply being more aware of what and when you eat relative to taking niacin. At least one study in rats supports this hypothesis.20
The researchers observed metabolic improvements when food was eaten during the FFA suppression window, but not when food was eaten during the rebound period.
If you are going to eat, do so in the 2-hour window after taking niacin. If you are going to eat 3–6 hours after taking niacin, either take another dose of niacin first, or avoid eating a large amount of digestible carbohydrate.
Minimize the risk of developing diabetes by eating within 2 hours after taking niacin. If eating 3–6 hours after, either take another dose of niacin or minimize digestible carbohydrates.
Niacin (again, as nicotinic acid) is metabolized by two primary pathways. First, niacin goes through a methylation pathway in the liver at a rate of about 40 mg per hour.21 When that saturates, any extra niacin is conjugated to glycine for excretion by the kidneys.21
Liver toxicity occurs from niacin depleting methyl donors.22–24
This is why slow-release forms of niacin, such as inositol hexanicotinate, are more likely to be liver-toxic than the rapidly absorbed nicotinic acid.25–27
- Nicotinic acid is rapidly metabolized (500 mg/hr) and quickly maxes-out the methylation pathway, meaning that most is excreted alongside glycine and few methyl donors are used.
- Slow-release niacin like inositol hexanicotinate, a niacin formulation with six nicotinic acid molecules bound together, is metabolized at a slow rate (50 mg/hr) and therefore feeds mostly into the methylation pathway.
Extended release niacin like the drug Niaspan or generic wax-matrix nicotinic acid are formulated to be metabolized at an intermediate rate (100 mg/hr).21 So, liver damage is more of a concern than pure nicotinic acid, but less than slow-release niacin.28
Nicotinamide may also be sold as slow-release niacin, but this is misleading because it is rapidly absorbed like nicotinic acid.29,30 However, it is the first molecule that nicotinic acid converts to in the methylation pathway. The risk of liver toxicity is greatest with nicotinamide because methylation is the only way it can be metabolized.31,32
Liver toxicity can be avoided by simply eating a diet rich in methyl donors, such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline.
Side note: NAM is not associated with the flush from niacin, since niacin causes the flush by acting on the niacin receptor and niacinamide does not have affinity towards this receptor.
Niacin therapy is effective at reduce heart disease risk due to lowering LDL particle numbers and triglyceride levels, not due to increasing HDL.
The risk of diabetes can be minimized by eating within 2 hours of taking niacin and avoiding digestible carbohydrates 3–6 hours after, unless another dose of niacin is taken.
Liver toxicity can be minimized by eating a diet rich in methyl donors like folate, vitamin B12, methionine, betaine (trimethylglycine), and choline.
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- 2.Garg A, Sharma A, Krishnamoorthy P, et al. Role of Niacin in Current Clinical Practice: A Systematic Review. Am J Med. 2017;130(2):173-187. https://www.ncbi.nlm.nih.gov/pubmed/27793642.
- 3.Blankfield R, Iftikhar I. Concerning Niacin in Current Clinical Practice. Am J Med. 2017;130(8):e347. https://www.ncbi.nlm.nih.gov/pubmed/28734373.
- 4.Le N, Jin R, Tomassini J, Tershakovec A, Neff D, Wilson P. Changes in lipoprotein particle number with ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidemic patients. J Am Heart Assoc. 2013;2(4):e000037. https://www.ncbi.nlm.nih.gov/pubmed/23926117.
- 5.Jafri H, Alsheikh-Ali A, Mooney P, Kimmelstiel C, Karas R, Kuvin J. Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD. J Clin Lipidol. 2009;3(1):45-50. https://www.ncbi.nlm.nih.gov/pubmed/21291788.
- 6.Bays H, Giezek H, McKenney J, O’Neill E, Tershakovec A. Extended-release niacin/laropiprant effects on lipoprotein subfractions in patients with type 2 diabetes mellitus. Metab Syndr Relat Disord. 2012;10(4):260-266. https://www.ncbi.nlm.nih.gov/pubmed/22400810.
- 7.Wang W, Basinger A, Neese R, et al. Effect of nicotinic acid administration on hepatic very low density lipoprotein-triglyceride production. Am J Physiol Endocrinol Metab. 2001;280(3):E540-7. https://www.ncbi.nlm.nih.gov/pubmed/11171611.
- 8.Lewis G. Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol. 1997;8(3):146-153. https://www.ncbi.nlm.nih.gov/pubmed/9211062.
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- 10.Yvan-Charvet L, Kling J, Pagler T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30(7):1430-1438. https://www.ncbi.nlm.nih.gov/pubmed/20448206.
- 11.Khera A, Patel P, Reilly M, Rader D. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62(20):1909-1910. https://www.ncbi.nlm.nih.gov/pubmed/23933538.
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- 15.Voight B, Peloso G, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380(9841):572-580. https://www.ncbi.nlm.nih.gov/pubmed/22607825.
- 16.Goldie C, Taylor A, Nguyen P, McCoy C, Zhao X, Preiss D. Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials. Heart. 2016;102(3):198-203. https://www.ncbi.nlm.nih.gov/pubmed/26370223.
- 17.Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009;297(3):E578-91. https://www.ncbi.nlm.nih.gov/pubmed/19531645.
- 18.Wang W, Basinger A, Neese R, Christiansen M, Hellerstein M. Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women. Am J Physiol Endocrinol Metab. 2000;279(1):E50-9. https://www.ncbi.nlm.nih.gov/pubmed/10893322.
- 19.Makimura H, Stanley T, Suresh C, et al. Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial. J Clin Endocrinol Metab. 2016;101(3):1123-1133. https://www.ncbi.nlm.nih.gov/pubmed/26691888.
- 20.Kroon T, Baccega T, Olsén A, Gabrielsson J, Oakes N. Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]. J Lipid Res. 2017;58(1):31-41. https://www.ncbi.nlm.nih.gov/pubmed/27875257.
- 21.Pieper J. Understanding niacin formulations. Am J Manag Care. 2002;8(12 Suppl):S308-14. https://www.ncbi.nlm.nih.gov/pubmed/12240702.
- 22.McCarty M. Co-administration of equimolar doses of betaine may alleviate the hepatotoxic risk associated with niacin therapy. Med Hypotheses. 2000;55(3):189-194. https://www.ncbi.nlm.nih.gov/pubmed/10985907.
- 23.Walker A. 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver. Trends Endocrinol Metab. 2017;28(1):63-72. https://www.ncbi.nlm.nih.gov/pubmed/27789099.
- 24.Basu T, Makhani N, Sedgwick G. Niacin (nicotinic acid) in non-physiological doses causes hyperhomocysteineaemia in Sprague-Dawley rats. Br J Nutr. 2002;87(2):115-119. https://www.ncbi.nlm.nih.gov/pubmed/11895163.
- 25.McKenney J, Proctor J, Harris S, Chinchili V. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271(9):672-677. https://www.ncbi.nlm.nih.gov/pubmed/8309029.
- 26.Piepho R. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol. 2000;86(12A):35L-40L. https://www.ncbi.nlm.nih.gov/pubmed/11374854.
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- 28.Morgan J, Capuzzi D, Guyton J. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82(12A):29U-34U; discussion 39U-41U. https://www.ncbi.nlm.nih.gov/pubmed/9915660.
- 29.Stratford M, Dennis M, Hoskin P, Phillips H, Hodgkiss R, Rojas A. Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. Br J Cancer. 1996;74(1):16-21. https://www.ncbi.nlm.nih.gov/pubmed/8679452.
- 30.Dragovic J, Kim S, Brown S, Kim J. Nicotinamide pharmacokinetics in patients. Radiother Oncol. 1995;36(3):225-228. https://www.ncbi.nlm.nih.gov/pubmed/8532910.
- 31.Sun W, Zhai M, Li D, et al. Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr. 2017;36(4):1136-1142. https://www.ncbi.nlm.nih.gov/pubmed/27567458.
- 32.Jenks B, McKee R, Swendseid M, Faraji B, Figueroa W, Clemens R. Methylated niacin derivatives in plasma and urine after an oral dose of nicotinamide given to subjects fed a low-methionine diet. Am J Clin Nutr. 1987;46(3):496-502. https://www.ncbi.nlm.nih.gov/pubmed/2957911.