April 23, 2024

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Cautionary Insights on Niacin: Potential Risks in Cardiovascular Health and Anti-Aging Claims

Cautionary Insights on Niacin: Potential Risks in Cardiovascular Health and Anti-Aging Claims

Cautionary Insights on Niacin: Potential Risks in Cardiovascular Health and Anti-Aging Claims

Miracle drug for whitening and anti-aging? Caution needed in niacin supplementation. New study in Nature Medicine finds that excess niacin metabolism products can induce cardiovascular disease.

Niacin, also known as vitamin B3 or niacin, is an essential micronutrient for synthesizing nicotinamide adenine dinucleotide (NAD). Adults need at least an additional 15 mg per day to avoid niacin deficiency syndrome.

Since the early to mid-20th century, niacin has been added to flour as a dietary supplement to alleviate conditions such as pellagra and deaths from tonsillitis, and is still included in the food pyramids of countries like the United States, stipulating that flour, cereals, and rice must be fortified with niacin.

By the late 20th century, therapeutic niacin (1,500-2,500 mg per day) was recommended as a lipid-lowering drug. In the 21st century, niacin as a precursor to NAD+ has become popular as an “anti-aging miracle drug,” with many people taking it. Recently, a study by Ferrell has helped us understand the role of niacin in cardiovascular disease (CVD) and explore the immune mechanisms of niacin in the body.

Cautionary Insights on Niacin: Potential Risks in Cardiovascular Health and Anti-Aging Claims

Cardiovascular disease has become a leading cause of disability and death globally, with a long course, wide prevalence, high cost, and high disability and mortality rates, and is recognized as a serious public health problem. Despite substantial progress in the treatment of cardiovascular disease, the residual risk of cardiovascular disease remains high, indicating that there are still many unrecognized factors involved in the development of cardiovascular disease.

In this study, based on a non-targeted metabolomics platform, researchers identified an unknown structural analyte with a high-resolution m/z = 153.0656 Da, with a composition of C7H9O2N2, which is the highest unknown metabolite associated with an increased risk of major adverse cardiovascular events (MACE).

Researchers further confirmed the unknown structural analyte’s association with two end metabolites of niacin and NAD metabolism, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), based on pathway analysis and chemical synthesis of network modules.

Researchers quantified 2PY and 4PY using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tested the circulating levels of each structural isomer in two different validation cohorts (United States, n = 2,331; Europe, n = 832) to determine their association with MACE risk. Cox proportional hazards regression models found that the end metabolites of niacin metabolism, 2PY and 4PY, are both clinically associated with cardiovascular disease, independent of traditional risk factors, and are also genetically associated with vascular inflammation.

Niacin added to staple foods contributes to NAD synthesis. It has been shown that excess niacin (e.g., as a non-prescription supplement or cholesterol-lowering agent) leads to an increase in 2PY and 4PY in circulation.

NAD can also be synthesized from scratch through a pathway regulated by the ACMSD enzyme. Authors demonstrated through GWAS and other functional studies that a variant in this gene is significantly associated with circulating levels of 2PY and 4PY, as well as sVCAM-1 levels. VCAM-1 is a gene known to mediate vascular inflammation and atherosclerosis, further validating the feasibility of functional tracking studies of this candidate gene.

It is worth noting that directly providing 4PY to endothelial cells and mice, rather than the structural isomer 2PY, directly promotes endothelial cell activation and expression of VCAM-1 (RNA and protein), enhancing the prototypic function of VCAM-1—adhesion of leukocytes to vascular endothelium. These results suggest that both end metabolites of excess niacin metabolism, 2PY and 4PY, are associated with residual cardiovascular disease risk.

Thus, this study suggests that end metabolites of excess niacin, particularly 4PY, are associated with MACE risk and may be mechanistically related to residual cardiovascular disease risk through inflammatory pathways, including direct enhancement of VCAM-1 expression.

Niacin, a common non-prescription supplement for cardiovascular disease, has unclear mechanisms of action in the disease. Furthermore, niacin, as a supplement, has been increasing in use year by year and is one of the earliest lipid-lowering drugs. The Coronary Drug Project (1966-1975) first demonstrated the efficacy of niacin in reducing total cholesterol and moderately reducing cardiovascular disease events in high-risk populations.

However, in the era of modern statin drugs, the effectiveness of niacin in reducing the risk of cardiovascular disease has been questioned. Niacin is ubiquitous in Western diets, with recommended dietary intakes varying by age and sex (recommended daily intake is 14-18 milligrams), but the United States and more than 50 other countries still require niacin to be added to staple foods to prevent pellagra. NHANES surveys from 2017 to March 2020 estimated that the average daily niacin consumption among U.S. residents was 48 milligrams, three times the recommended daily allowance. The long-term safety of adding niacin to staple foods in countries like the United States remains to be discussed.

In addition to niacin, it is worth noting that raising NAD with the molecules nicotinamide riboside and nicotinamide mononucleotide also increases the levels of 2PY and 4PY, both of which are common health supplements claimed to have anti-aging effects, but most clinical trials are still incomplete.

Furthermore, many people take niacin as a vitamin, self-administering it for purposes such as lowering blood pressure and anti-aging, which can cause systemic flushing and other allergic reactions when used in excess. It is important to note that excessive niacin consumption, both in deficiency and excess, can have harmful effects.

Cautionary Insights on Niacin: Potential Risks in Cardiovascular Health and Anti-Aging Claims

[1] Ferrell, M., Wang, Z., Anderson, JT et al. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat Med 30, 424–434 (2024).

[2] Stamler, J. The Coronary Drug Project—findings with regard to estrogen, dextrothyroxine, clofibrate and niacin. Adv. Exp. Med. Biol. 82, 52–75 (1977).

[3] Stierman, B. et al. National Health and Nutrition Examination Survey 2017–March 2020 Prepandemic Data Files—Development of Files and Prevalence Estimates for Selected Health Outcomes. National Health Statistics Reports 158(2021)

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