While most B vitamins are water-soluble and benign in large amounts, niacin is not one of them. Recently, a study published in Nature Medicine indicates that a byproduct of niacin has been linked with a higher risk of cardiovascular events. This is concerning since niacin is often added to many foods or used in supplemental form.

These results may also show why despite niacin reducing LDL (low-density lipoprotein) and increasing HDL (high-density lipoprotein), a reduction in cardiovascular events was not observed in previous major clinical trials.

Stanley Hazen, MD and senior author of the new study advises being prudent about niacin should be considered.

He notes, "I'm not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful".

Claims about supplemental niacin include antiaging, arthritis relief, and improving brain function. However, these claims haven’t been proven. In addition, the related compound, nicotinamide, which is suggested to prevent skin cancer in high-risk patients is questionable, according to new research.

"I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further."

Based on just one study, other experts are not in agreement about this action.

Cardiovascular Risk

As chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, Hazen notes that they didn’t initially set out to study niacin.

"It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes."

Scientists started searching for compounds in plasma that suggested negative cardiovascular events in people having elective diagnostic cardiac studies. Two compounds found were related to niacin- 2PY and 4PY. These are only made when excess niacin is present.

Assays to measure 2PY and 4PY were created and more studies were done in two cohorts-2331 US individuals and 832 people in a European cohort. In both groups, high plasma levels of 2PY and 4PY predicted future cardiovascular events. A doubled risk was observed in individuals with the highest versus lowest quartile.

Hazen’s team further studied genetic variants that could lead to a potential causal relationship. Higher levels of 4PY were also associated to an inflammatory marker called vascular cell adhesion molecule 1 (VCAM-1)

They discovered that in cell culture and animal studies, 4PY influenced inflammation by stimulating VCAM-1.

"So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk," Hazen commented.

Serious Health Implications?

Hazen thought these findings could have significant health implications.

According to Hazen, Western populations have been ingesting large amounts of niacin since World War 2 when foods began to be fortified with the B vitamin niacin to prevent deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by dermatitis, diarrhea, and dementia, which is potentially fatal.

"While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?" Hazen asked.

This may be why niacin doesn’t reduce cardiovascular risk factors as you expect despite its role in cholesterol reduction.

"This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox," he said.

Understanding niacin is tricky. Niacin is a major part of nicotinamide adenine dinucleotide (NAD), an important molecule that stimulates cells to create energy.

Hazen notes, "Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, these 4PY and 2PY derivatives are generated.” However, you must consume several foods high in niacin for this to occur.

Hazen isn’t claiming that cardiovascular disease is due to niacin. "It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation.”

“There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources," Hazen commented.

Do High-Protein Diets Contribute Risk?

NAD sources include tryptophan, found in protein. One of the genetic variants connected to alterations in 4PY levels is linked to how protein in food is shuttled into the pool of niacin. This suggests that high-protein diets may raise cardiovascular risk in some people, according to Hazen.

He notes that roughly 3% of the niacin pool in a regular diet is from protein intake, but this could be much higher in a very high-protein diet.

"Our data support the concept that if we lower our 4PY level long-term, it would result in a reduction in cardiovascular disease. This is still just a hypothesis. If we lower niacin intake, we will lower 4PY," Hazen stated.

Research is at an early stage and is unclear what advice should be suggested to consumers.

"Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That's all we can really say at the moment."

In addition, niacin is often present in energy drinks. He advises to limit intake of these as well.

Below are sources of niacin to limit:

1.  Nutritional yeast

2.  Niacin-fortified energy drinks

3.  Vitamin water

4.  Niacin supplements

5.  B complex supplements

6.  Liver

7.  Anchovies

8.  Kidney

9.  Tuna

10. Swordfish

This is part one of a two-part series. Stay tuned!

Lisa Andrews, MEd, RD, LD

References:

https://www.nature.com/articles/s41591-023-02793-8

https://www.nejm.org/doi/full/10.1056/NEJMoa1300955

https://www.nejm.org/doi/full/10.1056/nejmoa2203086