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Niacin metabolism was associated with incident major adverse cardiovascular events (MACE) and may be linked to the pathogenesis of heart disease via inflammatory pathways, researchers said.

In a metabolomics study of stable cardiovascular patients, 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, of Cleveland Clinic, and colleagues.

Moreover, both metabolites have genetic links to vascular inflammation, they noted in .

"Niacin, which is fortified in food staples, contributes to NAD [nicotinamide adenine dinucleotide] synthesis and has been shown to provoke increased circulating 2PY and 4PY when present in excess, such as when provided as an over-the-counter supplement or as a pharmacological agent for cholesterol lowering," Hazen's group noted.

Ultimately, the findings "raise the question of whether a continued mandate of flour and cereal fortification with niacin is warranted," they wrote.

Adults need to consume at least 15 mg per day of niacin, also known as vitamin B3 or nicotinic acid, to avoid niacin deficiency syndromes such as pellagra, Hazen and team said. Niacin fortification of wheat flour and other cereals has been mandated for decades, accompanied by a near elimination of pellagra-induced deaths in the U.S. since the Great Depression.

"However, over the past half century, with consumption of increasing amounts of processed and 'fast' food (much of which includes refined fortified flour and cereals), intake of dietary niacin has continued to increase to levels encroaching on excessive," the authors noted.

Niacin has also been used as an over-the-counter supplement, with some believing that it reduces cholesterol levels. However, its actual health benefits are questioned in the current statin era, while evidence that niacin reduces CVD events eludes researchers. Current clinical guidelines no longer recommend niacin to prevent CVD.

"In summary, the present studies, combined with recent randomized clinical trials with niacin in the modern era of high-potency statins, suggest a possible explanation for the 'niacin paradox' -- the observation that the LDL [low-density lipoprotein] lowering induced by niacin fails to achieve the expected reduction in CVD risks," Hazen and colleagues wrote.

The researchers conducted an untargeted metabolomics analysis of fasting plasma from a prospective discovery cohort of stable participants undergoing elective diagnostic cardiac evaluations, with a total of 1,162 patients. Participants were recruited at quaternary referral centers and had a high prevalence of CVD and cardiometabolic disease risk factors.

The associations between 2PY and 4PY and 3-year MACE were supported by U.S. (n=2,331) and European validation cohorts (n=832).

Based on phenome-wide association analysis of the genetic variant rs10496731, there was evidence for increased VCAM-1, a known contributor to vascular inflammation and atherogenesis, as a potential biological mechanism for association of 2PY and 4PY levels with increased risk of MACE.

Hazen's group acknowledged that their studies left room for residual confounding, and that measurement of 2PY and 4PY in the validation cohorts was performed only once.

"The translatability of our findings to both community-based cohorts with lower overall CVD and metabolic disease risk and alternative ethnicities requires further study," the group wrote.

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