Niacin has been used for primary and secondary coronary heart disease prevention for nearly 50 years by both the natural medicine and pharmaceutical industries. Though some studies in recent years didn’t always find it helpful in the treatment of cardiovascular disease, this new research actually presumes it is harmful.
Coronary Heart Disease (CHD), which is the most common type of heart disease in the United States, (1) is also known as 'Coronary Artery Disease' (CAD), 'Ischemic Heart Disease', or 'Coronary Atherosclerosis'. When people talk about 'heart disease' they often mean CHD. As the leading cause of death for men and women in the United States, about 697,000 died from it in 2020 - which is 1 in every 5 deaths. (2) With CHD being such a significant health risk, it is prudent to consider risk factors from any angle possible. Could this even include your vitamins?
Niacin – the Biochemistry Backstory
Niacin is one of the water-soluble B vitamins, 'Vitamin B3' to be exact. The name ‘niacin’ is actually a generic term for a cluster of related compounds, notably nicotinic acid (pyridine-3-carboxylic acid), nicotinamide ('niacinamide' or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside. Though naturally present in many foods, niacin is added to some food products, and available as a dietary supplement.
All tissues in the body convert absorbed niacin into its main metabolically active form, the coenzyme nicotinamide adenine dinucleotide (NAD). More than 400 enzymes require NAD to catalyze reactions in the body, which is more than for any other vitamin-derived coenzyme (3). NAD is also converted into another active form, the coenzyme called 'nicotinamide adenine dinucleotide phosphate' (NADP), in all tissues except skeletal muscle.
Niacin Used to Treat Cardiovascular Disease
Very high doses of nicotinic acid—more than 100 times the RDA—taken for months or years can be effective treatments for both high undesirable LDL cholesterol and low protective HDL, (Low-Density Lipoprotein and High-Density Lipoprotein respectively). Nicotinamide does not have this effect because, unlike nicotinic acid, it does not bind to the receptors that mediate nicotinic acid’s effects on lipid profiles (3). Studies conducted since the late 1950s show that these doses can increase high-density lipoprotein (HDL; good) cholesterol levels by 10%–30% and reduce low-density lipoprotein (LDL; bad) cholesterol levels by 10%–25%, triglyceride levels by 20%–50%, and lipoprotein(a) levels by 10%–30% (3). Some trials have shown incorporating niacin as part of an intervention strategy consistently demonstrated reduction in clinical events and lesion improvement, including ≥6% absolute mortality reduction (4). You might expect that these accomplishments would always result in a reduced risk of first-time or subsequent cardiac events, such as heart attacks and strokes, among adults with CHD. They haven't.
There is more than one reason for discrepancies in the data. This is because CHD management, in part, should be more than just chasing cholesterol levels; consideration needs to be given to inflammation, lifestyle and more. Another part to this topic is that there are significant differences between the earlier clinical trials that revealed cardiovascular benefits of niacin and some of the more recent trials that failed to demonstrate a benefit. "These differences include dyslipidemia types, niacin formulation, dosing, and timing. In general, the patient population that benefits the most from incorporating niacin in their treatment regimen can be defined by elevations in low-density lipoprotein cholesterol and triglycerides, and reduced high-density lipoprotein cholesterol" (4). So ultimately, despite dozens of published clinical trials, experts still do not agree on the value of nicotinic acid to treat CHD, especially given its poor patient compliance.
Niacin's 'Royal Flush'
Poor patient compliance is why I rarely lead with niacin as a therapy for patients with lipid profile problems. Thirty to 50 mg or more of nicotinic acid typically causes flushing; the skin on a person’s face, arms, and chest turns a reddish color because of vasodilation of small blood vessels near the surface of the skin. This flushing may be accompanied by burning, tingling, and itching sensations. Such signs and symptoms are typically transient and can occur within 30 minutes of intake or over days or weeks with repeated dosing; they are considered an unpleasant, rather than a toxic, side effect (3). Rarely, the flushing can be accompanied by more serious signs and symptoms, such as headache, rash, dizziness, and/or a decrease in blood pressure. Supplement users can reduce the flushing effects by taking nicotinic acid supplements with food, slowly increasing the dose over time, or simply waiting for the body to develop a natural tolerance.
Niacin Paradox of Lowering Cholesterol But Not Lowering Heart Disease Risk
Now let's get back to inflammation, as one of the other considerations and drivers of CHD mentioned above.
It was the search for new pathways contributing toward residual cardiovascular disease risk which prompted a team of researchers out of Cleveland Clinic to begin tracking metabolites of niacin. Recent scientific papers have explored how dysregulation of the metabolism for niacin-based coenzyme NAD contributes to the initiation and progression of age-associated diseases, including chronic kidney disease (CKD) (5).
As it turns out, niacin as a single entity wasn’t the driver of risk, in any specific one of its forms, but rather two terminal metabolites of niacin -- N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) -- were associated with an up to twofold increased risk of cardiovascular disease (CVD) independent of traditional risk factors, reported Stanley Hazen, MD, PhD, and colleagues (6). These associations between 2PY and 4PY were supported by validation studies with over 3,000 participants. So it's not the niacin going into the body that is the culprit, it is the downstream metabolites that come from it which contribute to inflammation, and then to increased CHD event risk .
But the researchers took it a step further, following the footprints of genetic variants being expressed among people with the higher levels of 2PY and 4PY. Such reviews examine the association between single-nucleotide polymorphisms, or other types of DNA variants, tested across a large number of different phenotypes, and included analysis of the genetic variant rs10496731,(6) where they found evidence of an association between these metabolite levels and increased levels of a form of vascular cellular adhesion molecule-1 (VCAM-1), a known contributor to vascular inflammation and atherogenesis, (7). Discovering the associations between these niacin metabolites and increased risk of CHD, while exposing a common genetic variant among the same group goes far to explain the potential biological mechanism for association of 2PY and 4PY levels with increased risk of CHD.
The Future of Niacin Supplements, Prescriptions and Food Fortifications
This has called into question the use of niacin in supplements and fortification in foods. Adults need to consume at least 15 mg per day of niacin to avoid niacin deficiency syndromes such as pellagra. The mandated addition of niacin to wheat flour and other cereals has been effective for decades, accompanied by a near elimination of pellagra-induced deaths in the U.S. since the Great Depression.
But without having an upper limit to how much niacin can be consumed before levels of 2PY and 4PY become problematic, is itself, problematic. “There is no upper amount of niacin that I can give to say that ‘Above this amount a person is going to make 4PY,’” one of the study authors was recently quoted as saying during an interview. He also that it would be useful, though, to have a clinically available in vitro diagnostic test to measure 4PY. “People need to have niacin in their diet, and you can’t help but [consume] it, because there’s so much of it in everything that’s in the base of our food pyramid now, because of all the mandated fortifications that are there”(8).
What's more, at this time there are no commercially available laboratory testing for these niacin metabolite products. So while more research is surely needed into this topic, readers would do well to consult with licensed professionals who specialize in nutritional supplements and natural medicine and explore alternatives. After all, the first principle to which newly graduated naturopathic physicians swear by during their ceremony is: 'First Do No Harm'.
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References:
4. Superko, Harold Robert et al. “Niacin and heart disease prevention: Engraving its tombstone is a mistake.” Journal of clinical lipidology vol. 11,6 (2017): 1309-1317. doi:10.1016/j.jacl.2017.08.005.
7. Troncoso, Mayarling Francisca et al. “VCAM-1 as a predictor biomarker in cardiovascular disease.”
The content and any recommendations in this article are for informational purposes only. They are not intended to replace the advice of the reader's own licensed healthcare professional or physician and are not intended to be taken as direct diagnostic or treatment directives. Any treatments described in this article may have known and unknown side effects and/or health hazards. Each reader is solely responsible for his or her own healthcare choices and decisions. The author advises the reader to discuss these ideas with a licensed naturopathic physician.