For decades, niacin (vitamin B3) seemed like a straightforward intervention—lower LDL cholesterol, raise HDL cholesterol, reduce triglycerides, prevent heart disease. This logic drove niacin fortification mandates across 50+ nations, including the United States. But clinical trials revealed something troubling: niacin reduced cholesterol effectively yet failed to prevent cardiovascular disease. Worse, some trials suggested it increased overall mortality. This became known as the “niacin paradox.” Why would a drug that dramatically improves lipid profiles provide zero cardiovascular benefit and potentially cause harm? For 60 years, the answer remained unclear. In February 2024, however, researchers led by Stanley Hazen, PhD, MD at the Cleveland Clinic published findings in Nature Medicine that finally explain this paradox and reveal an alarming new pathway to cardiovascular disease—one potentially triggered by excess niacin consumption and, by extension, NAD-boosting supplements marketed for anti-aging. The answer involves two toxic metabolites: 4-PY and 2-PY, terminal breakdown products of niacin that accumulate in the bloodstream and directly drive vascular inflammation independent of cholesterol levels.
The Nature Medicine study (Ferrell et al., Nature Medicine. 2024;30(2):424–434) combined untargeted metabolomics screening, genetic association studies, and mechanistic investigation across three independent cohorts totaling 3,163 patients. The research team first analyzed fasting blood plasma from 1,162 patients with stable coronary artery disease using mass spectrometry to identify circulating molecules predictive of major adverse cardiovascular events (MACE) independent of traditional risk factors. This screen identified a signal linked to niacin metabolism. The investigators subsequently measured levels of the two terminal niacin metabolites—N1-methyl-2-pyridone-5-carboxamide (2-PY) and N1-methyl-4-pyridone-5-carboxamide (4-PY)—and found that higher plasma levels were significantly associated with three-year MACE risk. They then validated these findings in U.S. (n=2,331) and European (n=832) validation cohorts. The results were striking: patients in the highest quartile of 4-PY levels had approximately twofold increased risk of major adverse cardiovascular events compared to those in the lowest quartile. More concerning, one in four people in the study cohorts had elevated 4-PY levels and therefore significantly elevated cardiovascular risk—a finding with major public health implications given that niacin fortification in flour and cereals is nearly universal in developed nations.
The mechanistic studies revealed why 4-PY is dangerous. Using genome-wide association studies, the team identified genetic variants associated with 4-PY and 2-PY levels, then conducted phenome-wide association analysis to determine what disease phenotypes these variants influenced. A strong association emerged with soluble vascular adhesion molecule-1 (sVCAM-1), a biomarker of endothelial dysfunction and vascular inflammation. This association held firm in a meta-analysis of 106,000 subjects across multiple independent cohorts. Functional studies in cell culture and mouse models then demonstrated the direct mechanism: treatment with physiological levels of 4-PY (but notably, not 2-PY) directly promoted expression of VCAM-1 on endothelial cells in vitro and in vivo, leading to leukocyte adhesion to the vascular wall and initiation of atherosclerosis. In mice examined by intravital microscopy, 4-PY directly increased leukocyte adherence to vessel endothelium. This is the fundamental pathway of atherosclerotic plaque formation—4-PY acts as a direct catalyst for vascular inflammation. The mechanism is completely independent of cholesterol levels, explaining why niacin drugs can lower LDL cholesterol dramatically yet increase MACE risk: they worsen the far more important inflammatory pathway.
The implications extend far beyond niacin therapeutics to the booming multi-billion-dollar NAD-boosting supplement industry. NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside)—heavily marketed for anti-aging and longevity—are both forms of vitamin B3. Mouse studies showing isotope labeling (cited by multiple researchers) indicate that both NMN and NR are converted to niacin in the human gut microbiome before absorption. If this conversion also occurs in humans (still unproven in published literature, as supplement companies have refused to fund human isotope studies that would demonstrate this), then NMN and NR supplementation would produce the same 4-PY and 2-PY metabolite accumulation as niacin itself. The Nature Medicine authors explicitly note that “all forms of vitamin B3” including NMN and NR increase circulating 4-PY and 2-PY levels. This raises a critical concern: people consuming 500 mg to 1000 mg of NMN daily for alleged anti-aging benefits may be chronically elevating 4-PY levels, potentially increasing cardiovascular disease risk by twofold while believing they are optimizing their health. Notably, niacin fortification in foods combined with NMN supplementation represents a dual pathway to 4-PY accumulation in the blood—fortified foods provide baseline niacin, while supplements dramatically amplify it.
The broader public health implications are staggering. Americans consume an average of 48 mg of niacin daily (more than triple the recommended 14-18 mg), driven by fortification of flour, cereals, and other staples, plus supplement use. The Cleveland Clinic team notes that approximately 36% of U.S. residents supplemented with niacin between 1999 and 2010 alone. With the rise of NAD-boosting supplement marketing over the past five years, and claims that high-dose niacin (1-3 g/day) increases lifespan despite no human evidence, the population-level 4-PY exposure has likely increased substantially. Historical data on niacin trials support this concern: high-dose niacin (1-3 g/day) was associated with 10% increased mortality in meta-analyses, and this increase persisted even when combined with high-potency statins. The Nature Medicine findings provide a mechanistic explanation for this mortality signal—chronic 4-PY elevation directly driving atherosclerosis and cardiovascular death. Moreover, the authors highlight an unintended consequence of 1940s nutritional policy: niacin fortification, while successfully eliminating pellagra, may have inadvertently contributed to rising cardiovascular disease mortality over the past 75 years by chronically elevating population-level 4-PY. Today, with niacin fortification well-established and diverse niacin-rich whole foods widely available, maintaining universal fortification mandates may be counterproductive to cardiovascular health. The authors suggest that reconsidering fortification policies—perhaps allowing nonfortified flour and cereal options—warrants serious discussion, particularly for vulnerable populations at high cardiovascular risk.
The practical takeaway is clear: excess niacin supplementation and NAD-boosting supplements marketed for anti-aging represent a clear-cut cardiovascular risk. Individuals interested in optimizing NAD+ and healthspan should prioritize evidence-based lifestyle interventions: resistance training, which activates AMPK and SIRT pathways naturally; periodic fasting or caloric restriction, which upregulates NAD+-dependent stress resistance pathways; adequate sleep; and stress management. These approaches maintain NAD+ without accumulating toxic metabolites. For niacin intake, targeting dietary sources (adequate whole grains, legumes, nuts) to meet the 14-18 mg recommended daily allowance is sufficient. High-dose supplementation (>50 mg daily) should be reserved for clinically confirmed niacin deficiency, diagnosed through blood testing and medical evaluation. The lesson from the niacin paradox is sobering: a substance powerful enough to alter lipid metabolism, vascular function, and lifespan cannot be assumed safe at arbitrary doses. The Nature Medicine findings demonstrate precisely this principle—niacin powerfully shifts multiple metabolic pathways, but this power comes at the cost of a toxic byproduct (4-PY) that directly drives the very disease it was supposed to prevent. As the field of longevity science matures, distinguishing between compelling mechanistic hypotheses and actual human health outcomes remains critical. The gap between mouse studies suggesting NAD+ boosters extend lifespan and human data revealing toxic metabolite accumulation is a cautionary tale about the perils of optimizing surrogate markers rather than clinical outcomes.