High Niacin Levels Linked to Major CV Events

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.