April 9, 2019

expert reaction to nutrient intake, dietary supplement use and mortality in the US

Research published in Annals of Internal Medicine demonstrate that use of dietary supplements was not associated with mortality benefits among a study of US adults.

Sam Jennings, Director of Berry Ottaway & Associates Ltd, said:

Does the press release accurately reflect the science?

“The press release overstates some of the findings in relation to the level of evidence provided in the paper and the authors themselves state that the findings “should be considered exploratory and interpreted with caution”.

Is this good quality research?  Are the conclusions backed up by solid data?

“The paper is based on a mass of data, but a great number of assumptions and adjustments have been made during the analysis of the raw data. As such, the results have to be interpreted with caution. 

How does this work fit with the existing evidence?

“The work shows that supplementation can help people increase their intake of nutrients to rise above sub-optimal levels. It also shows that appropriate levels of all nutrients from all sources have a beneficial effect on health, whereas excessively high intake of certain isolated nutrients can carry some risks. This is in line with reports from the UK governments Expert Group on Vitamins and Minerals (EVM), the Scientific Committee on Food (SCF)/European Food Safety Authority (EFSA) and other official scientific bodies’ findings.

Why would supplements not provide the same effect as nutrients derived directly from the food? Is it about the supplement themselves? Do we know a mechanism for this? Is there a confounding factor to be aware of?

“This is only an exploratory conclusion made by the authors; it has not been demonstrated by other credible studies on bioavailability. The absorption of nutrients can be affected by both the sources used in food supplements and those obtained from foods. Indeed, as people age, their ability to absorb certain naturally occurring nutrients from food can decrease owing to changes within their gastrointestinal tract and they can benefit from the specific sources used in food supplements (e.g. vitamin B12). 

Why might we see: “Excess calcium intake from supplement use was found to be linked to an increased risk of cancer death when supplement doses exceeded 1,000 mg/day.” How large is a dose of 1,000 mg/day in real terms? Are many people likely to be taking that much and how much greater is the increased risk of cancer?

“This is not new news. Indeed, following a detailed review of the safety, both from reputable scientific bodies and published papers, the EU industry recommendation is for a maximum level of 1000mg/day for calcium supplements (see Food Supplements Europe 2014 publication on “Risk management approaches to the setting of maximum levels of vitamins and minerals in food supplements for adults and for children aged 4–10 years”).

A 1000mg (1g) calcium tablet will be quite large and is unlikely to be consumed by the majority of consumers. The nutrient reference value (NRV) in the UK/EU for calcium is 800mg and the majority of food supplements do not exceed this amount.

Should we stop taking supplements?

“Absolutely not on the basis of this one paper. The UK government and many other national governments globally recommend supplementary intake for specific situations (e.g. in the UK, vitamin D is recommended for the general population, folic acid for women of child-bearing age, supplements containing vitamins A, C and D for children aged from 6 months to 5 years etc.). In addition, a detailed review of the recent National Dietary Nutrition Survey in the UK has shown that for a number of micronutrients, there is a worryingly large percentage of the population (up to 60% in cases) that are not reaching the Lower Reference Nutrient Intake. Although the concerning detail has not been clearly tabulated within the NDNS report, the Executive Summary does state that “There was a downward trend in intakes of most vitamins and minerals over the 9-year period for many age/sex groups.”

Are there important limitations to be aware of?

“There are a large number of conclusions in the paper that are based on assumptions, of which the authors admit to some. In addition, the authors have chosen to focus on the very small percentage of prevalence of nutrient intakes above the upper safe levels (ranging from 0.1 to 7.1%) as opposed to focussing on the far greater and more concerning percentages of prevalence of nutrient intakes below the estimated average requirements (0.1 to 99.1%).

“The authors have not reported the degree of significance for all statements. For example, the authors state that supplement users had higher intake levels of nutrients from foods for 23 nutrients. However, when these intake levels are compared against those of non-supplement users, many of the differences are unlikely to be significant. Indeed, as Table 2 in the paper shows, even the consumers of supplements have intakes of certain micronutrients below those recommended by the US government. 

“The paper appears to identify two known categories of supplement takers – those intent on a healthy lifestyle, who take supplements to try and ensure they reach the recommended intake levels; and those who have been diagnosed with a medical condition and who have started to take supplements in a belated attempt to improve their dietary intake (the latter are highlighted in Table 1 as the significant numbers with comorbid conditions). What the paper should have focussed on in more detail are the groups in-between. 

What are the implications in the real world?  Is there any overspeculation?  

“For a ‘real world’ situation, the paper highlights the potential risk of intake of excessively high levels of a single nutrient, which has been known for a very long period of time. It also highlights that, even with supplementary intake, consumers may have intakes below the levels that are recommended by governments. 

“There is a great deal of speculation by the authors, particularly in the abstract.

“What must be borne in mind is that the dietary and supplementary intake pattern in the US is very different to the patterns in the UK, the rest of Europe and many other countries. The data analysed within the paper do not represent the UK and Europe dietary patterns, and great care must be taken when extrapolating study findings from one region to another.” 

Prof Martin Hewison, Professor of Molecular Endocrinology at University of Birmingham, said:

“The press release is too simplistic as there are a number of important limitations with this study, many of which are highlighted by the authors that affect how the results should be interpreted.

“It is important to recognize that this study was simply based on questions asked to some participants at one point in time.  The health outcomes were then assessed many years later. Diet and (as the authors point out) supplement habits may have changed dramatically in the time between the subject being questioned and the analysis of health outcome (e.g. whether the subject died).  For example, the vitamin D-sufficiency or deficiency of the subjects in this study was based on a single measurement of vitamin D taken many years before the health assessment. It is therefore impossible to conclude anything from these findings. Someone who was vitamin D-sufficient during the study (questionnaire) period may have been vitamin D-deficient for several years leading up to their death and vice versa.

“None of the supplements taken were measured so, for example, it is impossible to know if the subjects taking vitamin D supplements took an accurate measure of vitamin D and there is no evidence that the supplements had any effect on blood levels of vitamin D. The data are not particularly good quality.  For vitamin D, the doses reported in the current study are well below anything used in current supplementation trials and would therefore unlikely to have any significant effect on blood levels of vitamin D. For example, any of the subjects in this study could have gone outside on a sunny day and made much greater levels of vitamin D simply by exposing their skin to sunlight!

“For example, the recent high profile VITAL trial used 50 micrograms/day (2,000 IU/day) whereas the highest vitamin D supplementation dose in the published study was >10micrograms/day (400 IU/day). In 2011 the Institute of Medicine in the USA recommended 15 micrograms/day (600 IU/day).

“So, are we now to believe that taking 600 IU/day vitamin D is bad for you? The answer is of course no. It is important to recognize that for some dietary factors such as vitamin D it is difficult to get any of the daily requirement from food. We get most of our vitamin D from the action of sunlight on skin or from supplements.

“The study does not take this into consideration. In 2016, the UK Science Advisory Council on Nutrition (SACN) made a clear statement that in countries such as the UK it was impossible for everyone to make sufficient vitamin D. SACN recommended that everyone in the UK obtains 10 micrograms/day (400 IU/day) vitamin D through food or supplements to maintain blood levels of vitamin D above 25 nmol/L. This is because most people in the UK are below the 50 nmol/L mentioned in the study. There is a much greater risk of health problems due to low vitamin D levels (particularly in children and the elderly) than the apparent negative effects reported in the current study.

“The group of people who used supplements were completely different to those who did not use supplements. This includes marked economic and education differences – those with lower income were much less likely to take supplements (and presumably were also less likely to have access to good quality US healthcare). The most important difference was that the supplement user group were significantly older that the non-users, which may have influenced any eventual health differences between the groups.

“The study involves large numbers of subjects from a large national health questionnaire study in the USA. In this regard the study reflects American diet and supplement habits and it is very hard to relate this to other countries such as the UK.  It doesn’t fit in with existing data for the simple reason that it is a report on the dietary habits of US people which has then been re-examined with respect to health outcomes in these people. Other studies have been much more objective and examined the effects of for example vitamin D supplementation on a particular disease using a randomized placebo-controlled trial. In these studies, the effects of supplementation on blood levels of vitamin D would then be determined by specific assays at the start and end of the trial. The current study is not a controlled trial.

 “There are many limitations in this study. The authors list some of them and I have listed others above. The major problem with this study is that it could discourage many people, particularly in countries such as the UK, to stop taking vitamin D supplements when these supplements may be essential for the much more urgent health problems associated with vitamin D-deficiency. The UK government has recognized that vitamin D-deficiency is a severe health problem – there have been several reported cases of young children dying of severe vitamin D-deficiency. The published study only mentions adverse effects for those with vitamin D levels greater than 50 nmol/L. However, most people do not know their level of vitamin D and may be tempted to not take a supplement that may be essential for their health.”

Dr Zaki Hassan-Smith, Consultant Endocrinologist (University Hospitals Birmingham NHS Foundation Trust) and Visiting Professor (Faculty of Health and Life Sciences, Coventry University), said:

“Although this is a large-scale observational study and the data are solid, I would exercise caution with regards to the findings on vitamin D and calcium and follow NHS/ UK Guidelines. This is especially important for patients at risk of severe vitamin D deficiency, osteomalacia, rickets and with fragility fractures or osteoporosis. It is also important to exercise caution with regards to inferring causality.”

“There are a number of studies that have demonstrated the benefits of vitamin D and calcium for bone health. There are some large interventional studies that will be reporting on so-called ‘extra-skeletal outcomes’ which should shed more light on this area. In general, there are data that back up safe intakes here. For vitamin supplements in patients without specific medical conditions or confirmed deficiencies there are limited data to back up this anyway – so this paper is welcome in adding further evidence.”

“There are a number of potential confounders, which may include that those with nutrient deficient diets may also have a number of adverse risk factors. A deficient diet can be associated with lower income, socio-economic status, or other lifestyle factors such as physical activity and stress. 1000mg/day is set as a target for recommended dietary intake by a number of sources, so these findings are controversial in light of previous data. As such this is an association and this type of observational study is not evidence for causation, mechanistic work along with prospective randomised controlled studies are needed to confirm these findings.”

“I would be cautious with this data at this stage. There are some large prospective randomised studies assessing the effects of vitamin D on cancer risk and whether vitamin D supplementation may reduce cancer risk has been debated. The recent VITAL study looked at over 25,000 participants and reported that there was no evidence of reduced risk of cancer with vitamin D. A number of other studies and meta-analyses looking at serum vitamin D status have shown U-shaped correlations with mortality.”

“Vitamin D supplementation is definitely part of mainstream advice for people with vitamin D deficiency, osteomalacia, rickets and in people with evidence of low bone mineral density (fragility fractures and osteoporosis). Mainstream advice should be followed in scenarios such as pre-conception and early pregnancy where folate supplementation is advised. There are also particular medical conditions where vitamin deficiency has been proven where supplementation is important i.e. in vitamin B12 deficiency. There is information on this from the NHS, and national bodies such as Public Health England.”

Prof Hugh Montgomery, Director, UCL Institute Human Health and Performance, University College London (UCL), said:

“The data from this paper support an expanding literature in this field. The growing message is that routine vitamin supplementation offers little if any benefit to health and may cause harm. Meanwhile, it is clear that diets high in these components are healthy. Supplementing some vitamins and/or minerals can benefit those at risk (e.g. folic acid in pregnancy) or who may benefit for specific medical reasons (such as osteoporosis). However, in general terms, those otherwise healthy may do better overall to concentrate on consuming a healthy diet rich in vegetables, nuts, seeds, whole grain and fruit than to spend money on supplements. The latter are not generally an effective substitute for, or supplement to, the former.”

Prof Tom Sanders, Professor emeritus of Nutrition and Dietetics, King’s College London (KCL), said:

“This study compares associations of vitamins provided by diet with those provided by supplements on health outcomes in a USA population who are very unlikely to suffer from micronutrient deficiencies except perhaps for vitamin B12 (vegans) and iron (premenopausal women) deficiencies. Folic acid is mandatorily added to all wheat products and milk is fortified with vitamin D in the USA. Many other foods (e.g. breakfast cereals) are also fortified with synthetic forms of vitamins. Dietary deficiencies of vitamin A, zinc, magnesium and vitamin K do not occur among people self-selecting their diets.  However, carotene (provitamin A), magnesium and vitamin K are indices of vegetables high in chlorophyll such as spinach. It would be wrong to conclude from this study that vitamins in supplements do not have the same effect as those in food.

“People who self-medicate with supplements are often the “worried well” or those who have health problems. Furthermore, there are those who eat poor quality diets but take a supplement as an insurance policy. You can’t turn a bad diet into a good diet with handful of pills.

“Calcium deficiency does not occur in human beings self-selecting their diets but in women over the age of 40 years who are often prescribed calcium with vitamin D to help reduce the risk of osteoporosis. There is good evidence from clinical trials that calcium and vitamin D supplementation helps maintain bone density and in elderly people it reduces risk of bone fractures. However, some trials indicate that high calcium supplements may increase risk of cardiovascular disease. Milk products which are a major source of calcium are not associated with risk of cardiovascular disease. The reported association with calcium supplements and cancer risk is opposite to what has been found in randomised controlled trials which suggest a possible protective effect for colorectal and prostate cancer.

“Vitamin D is normally made by the action of sunlight on the skin and there are few dietary sources (eggs, oily fish and mushrooms that have been irradiated with ultraviolet light). Most studies find low vitamin D status as measured by the level of 25-OH vitamin D in blood to a higher risk of cancer. A finding in contrast to what is suggested in this report.

“Furthermore, the suggestion that vitamin D supplementation is harmful is likely to cause confusion. Low blood levels of vitamin D are common in the winter months when UV exposure is limited as in countries such as the UK. At the turn of the 20th century rickets, the manifestation of vitamin D deficiency in children, was endemic in children the UK. The UK and Nordic countries have long had a policy of fortifying food with vitamin D. Rickets is now rare but still occurs in some infants who are breastfed for prolonged periods without supplementation. Vitamin D supplementation is advised for pregnant and lactating women, infants and in the elderly and where ultraviolet exposure is limited and dietary intake is insufficient to meet requirements.”

Prof Hilary Powers, Emeritus Professor of Nutritional Biochemistry, University of Sheffield, said:

“The authors report findings from a prospective cohort study of possible associations between micronutrient intakes from food and supplements and mortality outcomes in adults in US. They conducted a thorough analysis on multiple nutrients, correcting for a number of known confounders.

“Their findings of no beneficial associations between supplement use and mortality outcomes support findings in previous large cohort studies.

“The authors also report that adequate intakes from food, of a small number of specific micronutrients, is associated with beneficial effects on mortality outcomes. This may reflect health benefits of the food sources rather than the micronutrients themselves, given the limitations of the dietary intake tool used, and the complexity of food matrices. It may be worth noting that wholegrains are a good source of several of the specific micronutrients identified, and diets rich in wholegrains have consistently been shown to have health benefits.

“Findings relating higher intakes of calcium and of vitamin D with increased risk of all cancer mortality need to be interpreted cautiously, given the divergent evidence for some nutrient exposures at different cancer sites, and the need to correct for site-specific confounders. Vitamin D supplement use of greater than 10µg per day, by people with baseline biomarker status indicative of adequate intake, was associated with greater risk of cancer death. However, the data analysis precludes a thorough understanding of the dose response; the association may have been driven by high-dose supplement use, achieving very high plasma vitamin D levels.

“Overall this seems to be a well-conducted study that makes a useful contribution to the supplement debate. The authors acknowledge the study’s limitations.”

Professor Judy Buttriss, Director General, British Nutrition Foundation, said:

“The finding that use of dietary supplements does not reduce mortality is consistent with the findings of many other studies, and with a conclusion of the British Nutrition Foundation’s recently published Task Force report on diet and cardiovascular disease, which reported that micronutrient supplements do not reduce the risk of cardiovascular disease. 

“On the other hand, adequate intakes of nutrients achieved through diet have been shown to be beneficial. Nutrient rich foods often contain a range of essential nutrients, fibre, and naturally occurring bioactive compounds. Studies have shown positive associations between foods/diets and good health but it is often not clear precisely which food component is responsible. This, in part, may explain the findings with supplements reported by Chen et al.

“Research on diet is increasingly looking at the effects on health of dietary patterns, rather than isolated nutrients, and it’s clear that it’s the diet as a whole and not single nutrients in isolation that can have the greatest beneficial impact on health. As the paper points out, antioxidant supplement trials in the 1990s reported adverse outcomes associated with antioxidant supplement use, despite promising associations between fruit/veg intake and reduced disease risk.

“However, there are some situations where experts recommend specific micronutrient supplements alongside a healthy, varied diet, examples being folic acid before and during the early weeks of pregnancy to protect the developing fetus and vitamin D in the winter months because 1 in 5 adults in Britain and almost 40% of teenage girls have low blood levels of vitamin D, which has the potential to adversely affect musculoskeletal health.  Ten micrograms of vitamin D per day – as a supplement – is recommended during the winter months.  For those who are housebound or always cover their skin, a supplement is recommended throughout the year.

“The paper describes a large, nationally representative prospective study with over 30,000 participants in the USA, followed up for about 6 years. Statistical methods were used to control for the fact that those who take dietary supplements are often also better educated, wealthier and have a healthier lifestyle than those who do not – indeed the authors found that initial associations with lower risk of mortality and supplement use disappeared when these factors were taken into account.

“This type of study does not provide evidence of a causal relationship and, as is often the case in large epidemiological studies, measures of dietary intake were taken at just one time point (one 24 hour recall assessment, followed up with another measurement 3-10 days later) in the study, which may not provide an accurate picture of habitual dietary intake in the medium to long term. Participants were asked whether they had used any dietary supplements in the last 30 days, which may not reflect habitual use or capture changes in use, and is subject to recall bias.

“The authors refer to associations between cancer risk and calcium and vitamin D from supplements, and the inconsistency of the evidence to date. Prospective studies such as this cannot be used to infer causality and in its detailed analysis of the evidence base concerning vitamin D supplementation, SACN concluded that the available evidence (largely from observational cohort studies) for non-musculoskeletal health outcomes such as cancer is inconsistent and could be due to reverse causality or confounding by other factors associated with cancer. However, there is robust evidence linking vitamin D (10 micrograms per day) and musculoskeletal health.”

‘Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults’ by Fan Chen et al. was published in Annals of Internal Medicine at 22:00 UK time on Monday 8 April.

Declared interests

Sam Jennings: I am an independent scientific consultant to the food industry. As part of my consultancy role, I am Technical Adviser to the Council for Responsible Nutrition UK, which is a trade association for food supplements and functional foods (www.crnuk.org). I have advised both governments and industry globally on issues relating to food supplements and functional foods. 

Martin Hewison: No conflicts of interest.

Dr Zaki Hassan-Smith: No conflicts of interest.

Prof Tom Sanders: Honorary Nutritional Director of HEART UK and scientific governor of the British Nutrition Foundation

Prof Hilary Powers: “I was Chair of the SACN review of Vitamin D, resulting in a Report in 2016.”

Prof Judy Buttriss: Professor Buttriss has been a member of UK government expert/advisory committees considering topics such as nutrient profiling, food based dietary guidelines and dietary surveys. As Director General of the British Nutrition Foundation (BNF – a UK charity that engages with healthcare professionals, academics, schools, government, the food industry and the media), she provides advice on a variety of nutrition and food related matters to stakeholders across the nutrition sector, including a range of food/beverage companies (all fees are paid directly to BNF).

BNF’s funding comes from a variety of sources including EU projects; contracts with national government departments and agencies; conferences, publications and training; membership subscriptions; donations and project grants from food producers and manufacturers, retailers and food service companies; and funding from grant providing bodies, trusts and other charities. BNF is not a lobbying organisation nor does it endorse any products or engage in food advertising campaigns. More details about BNF’s work, funding and governance can be found at www.nutrition.org.uk/aboutbnf. 

None others received