Every era of cardiology has a cautionary tale about treating the lab report instead of the patient. Niacin may be the clearest one we have — and it is suddenly relevant again, because millions of people are now taking niacin’s modern descendants, the “NAD boosters” NR and NMN, in doses far beyond anything found in food.
The trial results we never explained
Prescription niacin reliably raised HDL and lowered LDL. On paper it looked like a winner. But when two large outcome trials — AIM-HIGH and HPS2-THRIVE — put it to the test, high-dose niacin prevented essentially nothing. Better numbers, same heart attacks. For a decade, nobody could fully explain why.
A likely answer: the leftovers
In 2024, Stanley Hazen’s group at the Cleveland Clinic published a study in Nature Medicine that may have solved it. The body can only use so much vitamin B3; the surplus is degraded into terminal metabolites, 2PY and 4PY. Among thousands of patients studied on two continents, those in the highest quartile of blood 4PY faced roughly twice the risk of heart attack, stroke, or death within three years — and in mechanistic experiments, 4PY directly activated VCAM-1, an adhesion molecule that recruits inflammatory cells to the artery wall. A genetic variant in the same pathway tracked with VCAM-1 levels in roughly 106,000 people.
In other words: the extra niacin may have been feeding vascular inflammation at the same time it was polishing the cholesterol panel.
Why NAD boosters inherit the problem
NR and NMN are precursors in the same B3 pathway, and their excess is broken down into the same 2PY and 4PY. Taking grams of a precursor means producing grams of leftovers. No long-term cardiovascular outcome trial of NR or NMN exists — the 4PY data is the closest thing we have, and it points the wrong way.
A better way to think about nutrients
I favor nutrients in the form nature built: food first, and when supplementing, whole-food sources — freeze-dried organ supplements, shilajit resin, freeze-dried wild salmon roe — rather than isolated megadoses. We understand a handful of nutrient ratios, like copper to zinc; we do not understand copper to boron, or countless others. Whole foods let the body choose what to absorb and in what proportion. We are still students of Mother Nature, and she has not shown us all her work.
Educational content, not medical advice. Discuss any supplement or medication decision with your own clinician.
— Andrew Rudin, MD, cardiologist and board-certified cardiac electrophysiologist. More at AndrewRudinMD.com and BestHeartBeat.com.