Reference
Zhang Z, Liu M, Zhou C, et al. Evaluation of dietary niacin and new-onset hypertension among Chinese adults. JAMA Netw Open. 2021;4(1):e2031669.
Purpose and Design
In order to determine a prospective association between dietary niacin intake and new-onset hypertension, and to seek other factors that might modify this association, investigators compared dietary intake of niacin in a nationwide cohort of Chinese adults with risk of incident hypertension during an extended follow-up period.
Participants
The average age of participants was 41.2 years, and 5,728 (46.8%) were men.
This prospective cohort study utilized 7 rounds of data gathered from 1997 to 2015 by the China Health and Nutrition Survey (CHNS), which is an ongoing multipurpose, longitudinal, open-cohort study established in 1989.
Individuals were excluded who had pre-existing hypertension, or who had inadequate niacin-intake data, or for whom dietary energy data were extreme (for men, >8,000 or <800 kcal/d; women, >6,000 or <600 kcal/d). A total of 12,243 participants were included in the final analysis.
Study Medication and Dosage
Investigators calculated dietary intake of niacin from 3 consecutive 24-hour dietary recalls in combination with a weighing inventory taken over the same 3 days at the household level.
Outcome Measures
The outcome measure was new-onset hypertension, which included systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg, a hypertension diagnosis by physician, or any antihypertensive treatment during the follow-up.
Key Findings
A total of 4,306 participants developed new-onset hypertension during a median follow-up duration of 6.1 years.
The overall average intake of dietary niacin was 14.8 mg/day.
Niacin intake was divided into quartiles, and the lowest risk of new-onset hypertension was found in participants in quartile 3 (14.3 to <16.7 mg/d; adjusted hazard ratio, 0.83; 95% CI, 0.75–0.90) versus those in quartile 1 (<12.4 mg/d).
In those with dietary niacin intake less than 15.6 mg/d, there was a 2% decrease in new-onset hypertension for every 1 mg/d increase in dietary niacin (adjusted HR, 0.98; 95% CI, 0.96–1.00). In participants with dietary niacin intake more than 15.6 mg/d there was a 3% increase in new-onset hypertension for every 1 mg/d increase in dietary niacin (adjusted HR, 1.03; 95% CI, 1.02–1.04). Representing these results graphically yields a J-shaped association between dietary niacin intake and new-onset hypertension, with an inflection point at 15.6 mg/d and a minimal risk at 14.3 to 16.7 mg/d (quartile 3) of dietary niacin intake.
In the figure below, “the shaded area indicates 95% confidence intervals for adjusted hazard ratios (HR). The model was adjusted for age, sex, body mass index, smoking status, systolic blood pressure, diastolic blood pressure, region, education, and occupation, as well as energy intake and sodium-to-potassium intake ratio.”
Figure. Dietary niacin intake and the risk of new-onset hypertension. Copyright 2021 Zhang Z et al. JAMA Network Open. This is an open-access article distributed under the terms of the CC-BY License.
Practice Implications
Hypertension remains a leading cause of noncommunicable disease, mortality, and disability worldwide.1 In China, approximately one-third of the adult population, or more than 300 million people, had hypertension between 2014 and 2015.2 In the United States, according to September 2021 information published by the Centers for Disease Control and Prevention, nearly half of adults (47%, or 116 million) have hypertension, defined as a systolic blood pressure greater than 130 mmHg or a diastolic blood pressure greater than 80 mmHg or are taking medication for hypertension.3 Understanding and identifying strategies that might prevent, reduce, or reverse risk of hypertension is a clinically relevant goal. The data in this study suggest that even slight shifts in niacin consumption might impact millions of people.
Niacin (also known as nicotinic acid or vitamin B3) is a precursor of nicotinamide adenine dinucleotide (NAD) and is essential for energy metabolism and redox reactions.4 The essential amino acid tryptophan can be converted into niacin. Because niacin is water soluble, the consensus has long been that any excess niacin will be excreted in the urine. Niacin acts as a coenzyme: More than 400 enzymes have been identified that depend on niacin to catalyze their reactions. As a result, niacin participates in a wide range of reactions that include conversion of nutrients into energy, creating cholesterol and fats, building and repairing DNA, and acting as antioxidants.5
Niacin was once called the “anti-black-tongue factor” because deficiency caused this distinct symptom in dogs.6 In humans, niacin deficiency leads to another distinct condition called pellagra, which was first reported in Italy in the 1700s. The name derives from the Italian: pella means skin, and agra rough, so rough skin. Rough skin is characteristic, if not pathognomonic, of niacin deficiency.7
Pellagra was first reported in the US in 1902. Over the next 20 years, the disease spread across the southern states as if it were an infectious epidemic. Risk factors for the disease seemed to be a combination of poverty and corn consumption.8 As etiology remained unclear, a “pellagraphobia” arose among the public, and patients were shunned and ostracized. Joseph Goldberger, MD, of the United States Public Health Service eventually solved the puzzle of pellagra.9 If you are unfamiliar with his fascinating story, it is worth reading about.
Elvehjem and colleagues first isolated the vitamin now called niacin and showed that it could reverse both black tongue and pellagra in 1937.10 Niacin deficiency is now rare in developed nations.
Niacin is measured in milligrams (mg) or niacin equivalents (NE). One NE equals 1 milligram of niacin or 60 mg of tryptophan. The Recommended Dietary Allowance (RDA) for adults is 16 mg NE for men, 14 mg NE for women, 18 mg NE for pregnant women, and 17 mg NE for lactating women.11
Dietary niacin comes from cereals, meat, and vegetables.12 However, much of the niacin in flour, along with other B vitamins and nutrients, is lost when the germ and bran are removed during refining. To prevent deficiencies, white flour in the US has been “enriched” since 1938. Current Food and Drug Administration (FDA) requirements specify that 24 milligrams of niacin be added to each pound of white enriched flour.13
Niacin was once called the “anti-black-tongue factor” because deficiency caused this distinct symptom in dogs.
High-dose niacin (1–3 grams) acutely decreases plasma concentration of free fatty acids by inhibiting their mobilization from adipose tissue.14 As a result, the FDA approved high-dose niacin, both alone and in combination with a statin (eg, Niaspan, Advicor), to treat dyslipidemia. Currently, there is a hesitation to use such high-dose niacin, which began when it became apparent that excessive niacin was linked to certain pathologies including insulin resistance and elevated homocysteine.15
High-dose niacin also may create side effects that many patients find intolerable. Skin flushing is the most commonly reported, but high-dose niacin may also cause stomach upset, diarrhea, coughing, or pruritis.16
Early clinical trials suggested that high-dose niacin was associated with reduced cardiovascular disease (CVD) events and death, but 2 larger clinical trials published in 2011 and 2014 failed to confirm this.17,18 These were large, randomized, placebo-controlled trials, which followed participants for 4 years. High-dose niacin (1,500–2,000 mg daily) was given alone in 1 trial and with a statin in the other. Both trials concluded that taking niacin brought no benefit. Specifically, there was no reduction in strokes, heart attack, or CVD deaths even though high-density lipid (HDL) cholesterol and triglyceride levels improved.
The 2014 study, which used extended-release niacin with laropiprant, reported a significant increase in adverse reactions compared to the placebo group, including increased incidence of type 2 diabetes, gastrointestinal bleeding and ulcers, and diarrhea. Additionally, a 2017 Cochrane review by Stefan Schandelmaier et al analyzed 23 randomized controlled trials on high-dose niacin to prevent CVD and reported that niacin did not reduce overall deaths, CVD deaths, heart attacks, or strokes, but was associated with negative side effects.19 Such results led the FDA to change its minds about the efficacy of niacin for CVD protection, issuing a statement in 2016 that the “scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events.”20
The past research on niacin has focused on the effects of high doses of niacin in high-risk populations and not diet-derived niacin in the general population. This recent study by Zhuxian Zhang et al turns our attention to slight variations in low, dietary intake of niacin and suggests that it may impact CVD risk to a degree we had not previously suspected. While Zhang’s work examined only risk of hypertension, we can easily extrapolate and worry that increasing risk of hypertension will lead to an increase in CVD. Most notably Zhang’s data provide a target for daily intake. Their data demonstrate a classic hormetic response: Risk of subsequent hypertension is lowest in study participants who consumed 15.6 mg/d of niacin but is higher for those consuming either lower or higher amounts.
Many other examples of the J-shaped dose-response curves as reported in this paper have come to light in recent years so that most of us are now familiar with this concept of hormesis and the Goldilocks’s need for more precise, targeted dosing of nutrients. Plant-derived substances, such as curcumin, ginseng, Ginkgo biloba, resveratrol, and green tea, all induce a broad spectrum of desired effects via hormesis in which higher or lower doses are less effective than an ideal target dose.21 We might mention that in September 2021, vitamin B12 levels were also reported to have a J-shaped dose response associated with mortality.22 An August 2021 trial suggests that vitamin D’s protection against preeclampsia also varies, following a similar hormetic pattern.23
Another recent study reported that folate measured in red blood cells (RBCs) is associated with cardiovascular disease risk and that the relationship follows a J-shaped hormetic curve. Twum et al reported in September 2020 that, based on data from 2,986 NHANES participants, those with intermediate folate levels were at lower risk of death from CVD and acute myocardial infarction (MI). After adjustment for age, sex, and other factors, the data revealed that those with higher levels of RBC folate were more than twice as likely to die of acute MIs than those with intermediate folate levels. In Twum’s data, intermediate RBC folate levels for men were defined as 137 to 256 ng/mL.24 MedScape, however, still lists a normal range for RBC folate as 140 to 628 ng/mL.25
These studies are a timely reminder that more is not necessarily better when it comes to dosing nutritional supplements, be they herbs or nutrients. Our reflexive paradigm is often to fall back on history and what was true a century ago; we automatically seek to blame illness on nutrient deficiency. The modern food supply, however, is one of superabundance, and our problems may result from overconsumption and excess rather than deficiency.
I have put off examining the multivitamin on our shelf until now to see how much niacin it contains. The label reveals that my multi supplies 80 mg niacin per suggested daily dose. This makes me turn back to Zhang’s paper to double check their results. Zhang’s data suggest a daily intake of between only 14.3 to 16.7 mg/d is associated with the lowest risk of developing hypertension. This study, if the results hold true, will have serious clinical implications.
