Cleveland Clinic-led study finds link between high levels of niacin – a common B vitamin – and heart disease

• Excess niacin fuels inflammation and cardiovascular disease through a newly identified pathway.

Cleveland 2024: Cleveland Clinic researchers have identified a new pathway that contributes to cardiovascular disease associated with high levels of niacin, a common B vitamin previously recommended for lowering cholesterol.

The team, led by Stanley Hazen, M.D., Ph.D., discovered a link between 4PY, a breakdown product of excess niacin, and heart disease. Higher circulating levels of 4PY were strongly associated with the development of heart attacks, strokes and other adverse cardiac events in large-scale clinical studies. The researchers also showed in preclinical studies that 4PY directly triggers vascular inflammation, damaging blood vessels, which can lead to atherosclerosis over time.

The study, published in Nature Medicine, also details genetic links between 4PY and vascular inflammation. The findings provide a basis for potential new interventions and therapies to reduce or prevent that inflammation.

“What’s exciting about these results is that this pathway appears to be a significant but previously unrecognised contributor to the development of cardiovascular disease,” said Dr. Hazen, chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute and co-section head of Preventive Cardiology at the Heart, Vascular & Thoracic Institute. “What’s more, we can measure it, which means there is potential for diagnostic tests. These insights set the stage for developing new approaches to counter the effects of this pathway.”

Niacin (vitamin B-3) is very common in the Western diet. “For decades, the United States and more than 50 other countries have mandated niacin fortification of staple foods such as flour, cereals and oats to prevent diseases related to nutritional deficiency,” said Dr. Hazen. However, in the researchers’ patient cohorts, one in four subjects appears to be getting too much and has high levels of 4PY, which appears to contribute to the development of cardiovascular disease.

Dr. Hazen compares our niacin intake to several taps pouring water into a bucket. Once the bucket is full, it starts to overflow. The human body then needs to process that overflow and produces other metabolites, including 4PY.

“The main takeaway is not that we should cut out niacin entirely – that’s not a realistic approach,” said Dr. Hazen. “Given these findings, a discussion could be considered on whether continued niacin fortification of flour and cereals is warranted in the United States.”

Dr. Hazen notes that the more widespread use of over-the-counter supplements made with different forms of niacin has also become popular because of their supposed anti-ageing benefits. He adds that patients should talk to their doctors before taking over-the-counter supplements and focus on a diet rich in fruit and vegetables, avoiding excess carbohydrates.

The new findings could also help explain why niacin is no longer considered a preferred treatment for lowering cholesterol. Niacin was one of the first treatments prescribed to lower LDL, or “bad” cholesterol. Eventually, however, niacin was shown to be less effective than other drugs for lowering cholesterol and was associated with other negative effects and higher mortality rates in previous research.

“Niacin’s effects have always been somewhat paradoxical,” said Dr. Hazen. “Despite lowering cholesterol, the clinical benefits have always been less than expected given the degree of LDL reduction. This led to the idea that excess niacin causes unclear adverse effects that partially offset the benefits of lowering LDL. We believe our findings help explain this paradox. This shows why investigating residual cardiovascular risk is so critical; we learn so much more than what we set out to find.”

The study authors note that long-term research is needed to assess the effect of chronically raised 4PY levels on atherosclerosis and other phenotypes.

This research is part of Dr. Hazen’s ongoing work to identify contributors to residual cardiovascular risk. His team follows patients over the long term, collecting blood samples to identify chemical signatures that can predict the development of heart disease. Throughout his career, he has made pioneering discoveries in atherosclerosis and inflammatory disease research, including the seminal discovery linking gut microbial pathways with cardiovascular and metabolic diseases.

Dr. Hazen also directs Cleveland Clinic’s Center for Microbiome and Human Health and holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.

Marc Ferrell, a former M.D., Ph.D. student in Dr. Hazen’s lab and a student in Case Western Reserve University’s Medical Scientist Training Program, is the first author of the manuscript. The research reported in this publication was supported in part by the National Institutes of Health under grant numbers R01HL103866, P01HL147823, R01HL133169, R01HL148110, R01HL168493 and U54HL170326.

About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical centre that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based on the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. Among Cleveland Clinic’s 77,000 employees worldwide are more than 5,658 salaried physicians and researchers, and 19,000 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,699-bed health system that includes a 173-acre main campus near downtown Cleveland, 23 hospitals, more than 275 outpatient facilities, including locations in northeast Ohio; southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2022, there were 12.8 million outpatient encounters, 303,000 hospital admissions and observations, and 270,000 surgeries and procedures throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries.