Niacin & NAD+ — cardiovascular safety (4PY)

A metabolite of niacin called 4-pyridone-3-carboxamide-1-β-D-ribonucleoside, mercifully shortened to 4PY, has put a serious question mark over the assumption that boosting NAD+ is straightforwardly good for your heart.

What the primary evidence shows

4PY is a terminal breakdown product of niacin and excess NAD metabolism. In a 2024 study by Ferrell and colleagues, 4PY causally drove vascular inflammation in mice by activating VCAM-1 on endothelial cells, promoting leukocyte adhesion, a key early step in atherosclerosis. In humans, higher circulating 4PY tracked with three-year risk of major adverse cardiovascular events (MACE), independent of standard risk factors such as LDL cholesterol or blood pressure [1]. That is a mechanistic finding paired with a prospective human association, which is a meaningful combination.

Two large randomized controlled trials reinforce the concern from a different angle. HPS2-THRIVE (25,673 participants) and AIM-HIGH (3,414 participants) both tested niacin added on top of statin therapy. Neither trial found cardiovascular benefit. Both found net harm: increased rates of stroke, infection, and bleeding [2, 3]. These are not small or methodologically weak studies.

The pre-statin-era nuance

Verhoeven's analysis synthesizes four meta-analyses comparing niacin against non-statin alternatives, weaker lipid-lowering controls used before statins became standard, and finds reductions in acute coronary syndrome, stroke, revascularization, and MACE, all reaching statistical significance [4]. Verhoeven's analysis suggests this means niacin probably did have real lipid-lowering benefit in an earlier treatment context.

The conflict is resolved by looking at the comparator. HPS2-THRIVE and AIM-HIGH stacked niacin on top of effective statin therapy; the meta-analyses examined niacin as the primary agent against weaker controls. Adding niacin to a statin adds no benefit and adds harm. The older meta-analysis signal does not argue for niacin in modern practice [4].

Nicotinamide is a separate issue entirely

Charles Brenner raises a distinct concern about nicotinamide (also called niacinamide, the form of vitamin B3 found in most multivitamins and B-complex supplements) [5]. At supplemental doses, nicotinamide inhibits sirtuins and PARP through feedback inhibition of the salvage pathway. Sirtuin inhibition matters because sirtuins regulate stress response and metabolic homeostasis; PARP inhibition matters because PARP enzymes are central to DNA repair. This mechanism is entirely separate from the 4PY cardiovascular pathway. Brenner's view is that people taking standard B-complex products may be suppressing both without realizing it [5]. This is expert opinion, not yet confirmed in large human trials, but it comes from a researcher with deep expertise in NAD biochemistry and warrants attention.

Do not conflate nicotinamide with niacin. They are different chemical forms of vitamin B3 with different metabolic fates and different risk profiles.

What this means for NMN and NR

NMN and NR enter NAD metabolism at a different point than niacin does. Whether high-dose NMN or NR also raises 4PY to meaningful levels, particularly in people with normal ACMSD enzyme activity, is currently unresolved. Until that question is answered, the 4PY harm signal cannot be straightforwardly imported to NMN or NR supplementation.

What it does retire is the blanket framing that "boosting NAD+ equals better health." Earlier evidence on NAD+ precursors treated that premise as broadly benign [6, 7]. The Ferrell 2024 data and the niacin RCT results together make that optimism harder to defend, at least for niacin specifically.

Where the evidence is contested

The harm case rests on solid ground: a mechanistic animal study with a plausible human correlate [1], corroborated by two large RCTs showing no benefit and net harm from niacin [2, 3].

Verhoeven's rebuttal raises two fair mechanistic points: the 4PY cohort likely had pre-existing cardiovascular disease, and improved 4PY may reflect an individual's ACMSD genetic variants rather than niacin or NAD intake per se [8]. He also argues that niacin's direct pharmacological effects are not clearly the harmful element [9]. Verhoeven's analysis of the older meta-analyses suggests a genuine historical lipid benefit [4].

The disagreement is not trivial. If 4PY elevation is primarily a marker of genetic metabolic variation rather than a consequence of niacin intake, the public health implications shift considerably. But Verhoeven's own reassurance leans on the niacin RCTs, which show no benefit and real harm, so "not worried" is difficult to square with that data. The defensible position, and LampHill's current reading, is that raising NAD+ via niacin is not a proven health strategy and carries a credible harm signal. Uncertainty about NMN and NR remains open.

References

1. Ferrell et al. 2024, Nature Medicine — niacin 4PY & CVD · PubMed 38374343
2. HPS2-THRIVE 2014, NEJM — ER niacin, no CV benefit + harm · PubMed 25014686
3. AIM-HIGH 2011, NEJM (Boden) — niacin futility · PubMed 22085343
4. Physionic — Niacin (B3) reduces heart disease (studies 198–201; 4 meta-analyses)
5. FMF — Rhonda Patrick + Charles Brenner: Boosting NAD levels
6. Physionic — "Does NMN Actually Work? What the Studies Show" (Verhoeven)
7. Klein & Yoshino 2021 — Response to Comment · PubMed 34326209
8. Physionic — "Niacin & NAD+ cause Heart Disease? [Study 282]" (video 03)
9. raw/physionic/nad-nmn/08-niacin-b3-reduce-heart-disease-study198-201.txt