Niacin has long been a public health darling. But an excess could be bad for the heart, study suggests

Niacin, or vitamin B3, has long been a U.S. public health darling to the point that it is added, by law, to cereal products. But a new study published Monday in Nature Medicine points to a potentially concerning effect of an excess of the vitamin: It may increase the risk of cardiovascular disease.

The study looked into two cohorts of patients without active heart disease, 60% of whom were treated with statins, and found a strong association between a metabolic product of excess niacin and an increased risk of major adverse cardiovascular events such as a heart attack or stroke. One in four of the people in the study had excess niacin, which doubled their risk of major cardiovascular events to levels comparable with diabetes or a previous heart attack.

“It’s a fairly sizable risk. It’s on par with what we consider other large risks,” said Stanley Hazen, the section head of preventive cardiology and cardiac rehabilitation at the Cleveland Clinic and senior author of the study. “This opens up the door; it lays the foundation for new studies and new interventions from both a diagnostic and therapeutic perspective to try to reduce inflammation and cardiovascular disease.”

Niacin’s ability to increase high-density lipoprotein cholesterol (HDL) — often referred to as “good” cholesterol — and lower low-density lipoprotein cholesterol (LDL) — the “bad” type — made it a first line of intervention to prevent cardiovascular disease prior to the introduction of statins. But the new findings suggest that excess niacin, which is also thought to support nervous and digestive system health, may have mixed effects on the body, though outside experts caution that it’s too early to say for certain whether niacin truly increases cardiovascular risk.

“To draw an inference that niacin increased cardiovascular risk in those trials is not necessarily accurate,” said Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center who did not participate in the study. “Coronary heart disease and related mortality were not significantly increased. … So I have difficulty in connecting the dots.”

Researchers identified the cause of increased cardiovascular risk in N1-methyl-4-pyridone-3-carboxamide (4PY), a niacin metabolite. They argue that 4PY increases cardiovascular risk through an inflammatory reaction and say they’ve identified a previously unknown pathway that can cause adverse cardiovascular events. In fact, said Hazen, the researchers didn’t set off to study niacin in the first place. They were originally trying to understand why, when traditional risk factors such as high cholesterol, smoking, and diabetes are treated, half of patients still go on to have cardiovascular events.

“We began by looking to see if there was something in fasting blood samples from subjects who were followed over time to see who went on and developed a heart attack or stroke or died — and it ended up being a compound which was unknown,” said Hazen, referring to 4PY. “And when we finally figured out what it was and where it came from, it can only be made by excess niacin ingestion.”

Excess niacin also resulted in the production of N1-methyl-2-pyridone-5-carboxamide (2PY), which, however, was not linked to inflammation and higher risk of cardiovascular disease.

The results were consistent with findings in two large niacin studies (HPS2-THRIVE and AIM-HIGH), which found that when people already had low levels of bad cholesterol, putting them on niacin led to worse cardiovascular outcomes, even though the compound is known to increase levels of good cholesterol. “Our study, through the back door, now helps explain what the dark side of niacin has been: It helps foster vascular inflammation through the formation of 4PY, but only in people who have too much.”

Cereals such as wheat and rice are a dietary staple for billions of people. The authors argue that their findings suggest that it may be time to reconsider the mandatory fortification of foods with niacin.

“There is no doubt that mandated fortification has been one of the best public health programs and was an amazing success,” said Hazen, who notes that there have been no recent U.S. cases of pellagra, a potentially deadly condition caused by niacin deficiency that can lead to diarrhea, dementia, and excruciating mouth sores. Still, he said, it may be time to allow for non-fortified cereal products to be sold in the U.S. — as they are in most parts of the world — to offer an alternative to people who may have increased risk of cardiovascular disease and could benefit from reduced intake of niacin.

William Boden, a professor of medicine at Boston University School of Medicine who did not participate in the study, was hesitant to conclude niacin excess equals cardiovascular risk.

“While it is true that in the current statin era, we do not have compelling evidence that niacin treatment reduces cardiovascular death, [heart attack], or stroke, I am wary to conclude that there is definitive evidence of harm associated with niacin based on this study,” he wrote in an email to STAT.

The study does not address the situation of patients taking prescription niacin, which is delivered in concentrations 20 times higher than in supplements, said Daniel Rader, a professor of medicine and genetics at the University of Pennsylvania who was also not involved in the study. “What are the levels of 2PY and 4PY in people who are taking pharmacologic doses of niacin? The expectation would be that they would be astronomically higher because the amount of intake of niacin is orders of magnitude higher,” said Rader. (Hazen responded by noting that while none of the participants in this study took prescription niacin, other studies have reported increased levels of 2PY and 4PY.)

“If 4PY really is pro-inflammatory and increases risk, as they suggest, I guess I just would expect that pharmacologic doses of niacin would be very clearly bad for you,” he said. However, numerous previous clinical studies of pharmacologic niacin have only failed to confirm its benefits, not found significant risk associated with it, though a 2012 study of a niacin drug candidate for cardiovascular disease was halted after a “serious adverse event” among patients treated with the medication.

“This is very interesting, 4PY and its effects on inflammation, so I’m not really questioning those observations,” Rader said.