Niacin — vitamin B3 — has a long history in cardiology. For decades we prescribed it to raise HDL and lower LDL. The numbers moved. Then the outcome trials came back: no fewer heart attacks, no fewer deaths. Niacin quietly fell out of favor, and most of us moved on without asking the obvious question — why would a vitamin that improves cholesterol fail to protect the heart?
A study from the Hazen lab at the Cleveland Clinic, published in Nature Medicine in 2024, offers a troubling answer. And it matters far beyond prescription niacin, because the wellness world is now megadosing niacin’s cousins — nicotinamide riboside (NR) and NMN — as “NAD boosters.”
What the study found
Ferrell and colleagues measured metabolites in the blood of patients undergoing cardiac evaluation. One stood out: 4PY, a terminal breakdown product of excess niacin. Patients in the top quartile of 4PY had roughly double the risk of heart attack, stroke, or death over the next three years — an adjusted hazard ratio of 1.89 in the US cohort of 2,331 patients, and 1.99 in a separate European validation cohort of 832. Two independent populations, same signal.
How excess niacin becomes 4PY
Your body can only use so much niacin. Once the useful pathways are saturated, the excess is broken down into terminal metabolites — 2PY and 4PY — and excreted. For years we assumed those leftovers were inert. They are not.
4PY and vascular inflammation
In the same paper, 4PY — and specifically 4PY, not its sibling 2PY — induced VCAM-1 in mice. VCAM-1 is the adhesion molecule that makes the artery wall “sticky” for inflammatory cells; it is one of the early steps in atherosclerosis. The genetic data pointed the same way: a variant in the niacin-metabolism pathway tracked with soluble VCAM-1 levels in roughly 106,000 people. This fits everything we know about inflammation as a root cause of heart disease.
Why this reframes the failed niacin trials
AIM-HIGH and HPS2-THRIVE gave high-dose niacin to tens of thousands of patients. Cholesterol numbers improved. Outcomes did not. If the excess niacin was simultaneously generating an inflammatory metabolite, the arithmetic starts to make sense: whatever benefit came from the lipid changes may have been cancelled by the 4PY. A better lab report is not the same thing as a better artery.
NAD boosters: the same pathway
Here is the part the longevity world has not absorbed. NR and NMN — the NAD-boosting supplements — feed into the same niacin pathway, and their excess is catabolized into the same 2PY and 4PY. Megadosing a precursor is megadosing niacin’s leftovers. The long-term cardiovascular effects of that have never been tested; the 4PY data is the first hard look, and it is not reassuring.
The whole-food alternative
This is what happens with isolated, megadosed nutrients, and it is why I favor whole-food forms — freeze-dried organs, shilajit resin, freeze-dried wild salmon roe. We know the copper-to-zinc ratio matters. But what about copper to boron? Nobody knows. In whole-food form your body decides what to absorb, and in what ratios. We are always studying and copying Mother Nature, and we will never fully learn all of her secrets.
The bottom line
Ordinary dietary B3 is not the issue — you need niacin to live. The issue is the megadose: prescription-strength niacin, and gram-level NAD boosters taken indefinitely on the promise of longevity. If your goal is a healthier heart, the levers that actually move outcomes remain the unglamorous ones: sleep, food, movement, stress, insulin resistance, inflammation. Test, don’t guess — and be skeptical of any pill that promises to shortcut biology.
Educational content, not medical advice. Talk with your own clinician before starting or stopping any supplement or medication.
— Andrew Rudin, MD, cardiologist and board-certified cardiac electrophysiologist. More at andrewrudinmd.com.