Dietary supplements ~ useless or useful?

There is a general tenet in human nutrition that if one eats a healthy diet, then there is no incremental benefit from taking additional nutrients either as fortified food or as supplements. A healthy diet should provide all of one’s nutrient requirements. I would go so far as to say that, among nutritionists, this is more a doctrine than a mere tenet. In recent times, several papers have been published which challenge this concept. A good place to start is with a major survey of 12,000 US adults to ascertain and characterise usage of dietary supplements[1]. In 2011, Americans spent $30 billion on dietary supplements, which, to put it into perspective is equal to or greater than the annual GDP of Ethiopia, Jordan or Bolivia. Some 77% of the users of dietary supplements do so through their own choice with 23% doing so on professional advice. In general, users of supplements are happier with their health than non-users, which suggests that they use supplements as some sort of insurance. The vast majority of respondents stated that they took supplements to “improve” or “maintain” health. So, are they wasting their money?  A recent meta-analysis would say that indeed they are wasting their money where the end point was mortality. In this study, the authors completed a meta-analysis of dietary supplement (multi-minerals and multi-vitamins) intervention studies, which involved a final list of 21 publications, involving 91,074 adults, with a mean age of 62 and a mean duration of supplement use of 43 months. A total of 8,794 deaths was recorded. When the death rate of those assigned to intervention with the supplements was compared to that of those receiving a placebo, no statistically significant differences in death rate were seen. So, taking dietary supplements doesn’t make you live longer. But do they make you healthier?

Late in 2012, two papers were published from the “Physicians’ Health Study II Randomized Controlled Trial”. This began in 1997 with 14,641 male physicians aged 50 years or greater entering the study. There were several treatments. One involved a multi-vitamin supplement. Two others involved either vitamin E alone or vitamin C alone. A final group received a placebo. After an average follow up of 11.2 years, 1,732 cases of major cardiovascular events (non-fatal serious heart attack or stroke) were observed[2]. No statistically significant differences were observed in cardiovascular events between treatment and placebo. So supplements wont make you live longer and wont make your heart any healthier. However, a second paper from the same Physicians Health Study Randomized Controlled trial did show that the overall risk of cancer was moderately reduced in those assigned to the vitamin supplements as opposed to those assigned to the placebo[3]. The authors conclude that: “Although the main reason to take multivitamins is to prevent nutritional deficiencies, these data provide support for the potential use of multivitamin supplements in the prevention of cancer in middle-aged and older men.” What a pity these studies didn’t employ modern genomics and metabolomics technology to look at responders and non-responders. When will nutritional epidemiology enter the 21^st century?

The issue of vitamin supplementation was the subject of yet another recent paper, this time with a focus on folic acid supplementation in the pre-natal period and during pregnancy. Normally the end-point of such interventions would be neural tube defects such as spina bifida but in this case it was autism. The study was within the Norwegian Mother and Child Cohort study, which recorded the use of folic acid prior to conception and in the first 8 weeks of pregnancy[4]. Among the 85,176 children born in the cohort after exclusion of some births (12,000) for reasons such as premature delivery or lack of data on folic acid use, some 114 cases of autism were observed, equating to a rate of 0.14%. Among women who took folic acid supplements the rate was 0.10% while among women who didn’t take folic acid supplements the rate was 0.21%. This difference was statistically significant even when controlled for maternal and paternal education and age, a planned pregnancy, parity, year of birth and maternal BMI and smoking habits.

Clearly, some people benefit from dietary supplement use and the challenge to nutritional science must be to use modern technologies to ascertain those that do and don’t benefit with a view to customizing supplement use to optimise health. The doctrine that states that you should get all your nutrients from foodstuffs is codswallop.

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[1] Bailey RL et al (2013) JAMA Int Med, On line February 4th

[2] Sesso et al (2012) JAMA, 308, 1751

[3] Gaziano JM et al (2012) JAMA, 308, 2012

[4] Suren P et al (2013) JAMA, 309, 570

Diet and cancer: a damning analysis

This month’s edition of the American Journal of Clinical Nutrition carries a very important review of the epidemiological data relating food to cancer[1]. It is well written and sensitive in its conclusions but, reading between the lines, it is quite simply damning of the quality of the epidemiological research basis linking food intakes and cancer. The authors started off with The Boston Cooking-School Cook Book.  Using a random number generator to correspond to page numbers, they searched the cook-book for recipes. All of the unique ingredients in each recipe was identified and the process was repeated until 50 unique food ingredients were identified. The next stage of the process was to explore the scientific literature to examine the most recent studies, if any, linking any one of the 50 ingredients to cancer. The 10 most recent studies were selected and if there were less than 10 studies available, synonyms (e.g. mutton for lamb) were used to further explore the availability of studies. In addition to individual studies, the authors also searched for meta-analysis studies that combine data from several individual studies to increase statistical power.

 

The next stage of the process was to extract data from each individual study or meta-analysis. This involved an examination of the abstract with an emphasis on the author’s conclusions, an analysis of the statistical methodology used and an assessment of the exposure levels examined for each ingredient. From the 50 ingredients randomly chosen from the cookbook, 40 (80%) were found to be the subject of a scientific investigation into its links with cancer. The food ingredients included: veal, salt, pepper spice, flour, egg, bread, pork, butter, tomato, lemon, duck, onion, celery, carrot, parsley, mace, sherry, olive, mushroom, tripe, milk, cheese, coffee, bacon, sugar, lobster, potato, beef, lamb, mustard, nuts, wine, peas, corn, cinnamon, cayenne, orange, tea, rum and raisin. A total of 216 publications were found linking these ingredients to cancer. Of the 40 ingredients, 36 were identified in at least one study as either increasing or decreasing the risk of cancer. In their examination of the statistical analysis used, the authors of the review concluded that, of the studies that claimed an increased risk of cancer, 75% were associated with “weak or non-nominally significant” effects and for those that reported a negative effect, the corresponding figure was 76%.  In 65% of the studies, these effects were based on comparison of extremes of consumption such as >43 drinks per week versus none or “often” compared with “never”.  The authors compared the calculated risk from individual studies with the risk calculated from meta-analyses where like studies were pooled. The latter showed a narrow range of risk where as the former showed a huge range of positive and negative risk.  

The authors conclude that the vast majority of claims for increased or decreased risk were based on “weak statistical evidence”. Moreover, they show an appalling practice of relegating negative or weak results to the fine detail of the text of the paper but excluding such from the abstract. The abstract is most likely to be read and certainly to be the basis of any media interpretation of the study.

All in all, this is a damning analysis of the field of nutritional epidemiology. It would be wrong to throw the baby out with the bathwater since nutritional epidemiology has been the basis for many substantiated diet-disease links (folic acid and neural tube defects, atherosclerosis and dietary lipids, calcium intake and osteoporosis and so on).  The problem with diet and cancer is that intervention studies to experimentally prove a cause and effect relationship are simply not possible. Heart disease relates to one organ, the heart, whereas cancer can relate to almost all organs. In the study of diet and heart disease we can use biomarkers (plasma HDL and LDL cholesterol for example) while no such biomarkers exist for cancer.

In the analysis of how extremes of exposure were used, the authors found that the meta-analysis approach was almost exclusively based (92%) on extremes of consumption of the particular food ingredient. Epidemiological studies, by definition are very large and as such, the tools to measure diet must be relatively simple and this usually involves a food frequency questionnaire, which examines frequency of intake. However, nutritional epidemiology absolutely ignores the well know phenomenon of under-reporting of food intake.  Thus, when extremes of food intake are compared, they are largely based on truly flawed measures of food intake. This was not considered in the present study and more often than not, insufficient data is presented in papers to allow readers to make any conclusions as to the extent of under-reporting based on the match of reported energy intake and estimated energy requirements. The editorial boards of journals should insist that all studies involving food intake have a section in which the authors explain the extent of energy under-reporting and the specific implications for the study in question.

No doubt, this damning review of the epidemiology of diet and cancer will be swept under the carpet by the field of nutritional epidemiology. However, this blogger has always held the view that bad science will always be found out.

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[1] Schoenfeld JD & Ioannidis JPA (2013) “Is everything we eat associated with cancer? A systematic cookbook review” Am J Clin Nutr 97, 127

Treating diabetes: Diets, gyms and scalpels

In the US, 27% of those aged 65 or older have diabetes. Based on fasting blood glucose levels or glycated haemoglobin levels, the estimate of the prevalence of pre-diabetes is 79 million cases. The economic cost has been estimated at around $2,000 per person per annum. The maths aren’t complicated working out at about $22 billion per annum.  Most  cases of type 2 diabetes are treated initially by lifestyle changes and then by drugs to manage blood glucose. In 2009, the American Diabetes Association defined partial remission from diabetes when fasting blood glucose levels were lowered to below the diagnostic norm and complete remission when fasting blood glucose levels returned to normal, in both cases in the absence of drug therapy. Relatively little is really known of the extent to which such partial or complete remission can be achieved with lifestyle interventions. In 2001, a large multicenter study was established in the US known as “Look Ahead”, (Actions for Health in Diabetes)^[1]. The trial, funded by the National Institute of Health, involved 2,262 type 2 diabetics given a basic diabetes lifestyle intervention and a group of 2,241 type 2 diabetics given an intensive lifestyle intervention. The former were given 3 group sessions per year while the latter participated in weekly group and one-on-one counseling for the first 6 months followed by 3 sessions per month for the next 6 months and twice monthly sessions thereafter. For this group, a target caloric intake was set between 1,200 and 1,800 calories per day with an exercise goal of 175 minutes of moderately intensive exercise per week (25 minutes per day).  The Look Ahead trial laid out its hypothesis quite clearly: that there would be a significant reduction in heart disease and stroke in the intensively counseled group compared to the group receiving standard advice on lifestyle. The trial has produced over 80 peer reviewed papers and has shown that intensive lifestyle intervention can significantly improve body-weight, blood pressure, blood glucose control and blood lipid levels.

On October 19th this year, when the trial was well into its 11th year, the NIH announced the end of the trial on foot of recommendations from the trial’s data and safety monitoring board. This independent body of experts noted that despite the above improvements on risk factors for cardiovascular disease, there was no statistically significant difference in cardiovascular events between the two groups which was the central hypothesis. Recently, the trial study group published a paper in the Journal of the American Medical Association showing that intensive lifestyle intervention did indeed lead to a greater rate of remission of type 3 diabetes compared to the standard intervention^[2]. The big disappointment was, however, that the impact of intensive lifestyle was very small. The rate of partial or complete remission in year 1 was 11. 5% in the intensively tutored group, falling to 7.3% at year 4. In contrast, the group receiving standard counseling showed a 2% reduction at both time points. Very clearly, type 2 diabetes is not a reversible condition for the vast majority of subjects. And just as clearly, this low response rate in correcting diabetes pathologies explains why no differences in heart disease were observed between the two treatment groups.

In the same issue of this journal, an editorial looks at the overall evidence for lifestyle and surgical interventions in obesity^[3]. The latter are usually confined to subjects with very severe cases of obesity. The latter leads to type 2 diabetes remission rates, which are 12 to 24 fold greater than intensive lifestyle interventions. The Swedish Obesity Study, also published in this year’s JAMA, reported on the long-term effects of the surgical treatment of obesity. Subjects were morbidly obese at baseline (1987 was the start date) and the average duration of follow up was 14.7 years^[4]. Compared to conventional medical and lifestyle treatment, the surgical intervention reduced fatal heart attacks by 47%, all heart attacks by 52% and stroke by 34%. Surgery is expensive but so too is intensive lifestyle interventions and thus some cost comparisons between the two would be interesting.

Clearly, we are in a mess and we must now live with the mess. But how can we prevent the mess for future generations?. Whilst 79 million Americans have prediabetes and are at risk of developing diabetes, the remaining 233 million don’t. Of those aged over 65 years, 11.2 million have type 2 diabetes while the remaining 30 million over 65s do not. They all live in the same obesogenic US environment. One day, not far from now, we will be able to predict who is likely to to draw the short straw and develop obesity-related type 2 diabetes. Moreover, this genetic information will soon be able to zone in on that aspect of diet and lifestyle, which is most responsible for the development of diabetes. For some, it may be a metabolically based genetic factor. For others, it may be a food choice factor that is the driver and for others it may be a defective satiety system. Understanding personal risk and understanding personalised solutions is the future for nutrition and health. In the meantime, we have a mess.

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^[1] https://www.lookaheadtrial.org

^[2] Gregg et al (2012) JAMA 308,2489

^[3] Arterburn DE & O’Connor PJ (2012) JAMA 308, 2517

^[4] Sjostrom L et al (2012) JAMA 307, 56

Obesity and Nature v Nurture re-visited

In the obesogenic environment that we live in, not everyone becomes obese. To the high priests of nutrition, that variability is put down to variation in self-control and self-discipline and that in turn relates to level of education and social class. The idea that this variation might be genetically based is dismissed with the old reliable falsism that since our genes have not changed during the recent epidemic of obesity, it’s the environment that counts. Well, yet another twin study shows that this is nonsense and this twin study is somewhat special since it pooled data from 23 twin cohorts from four countries: Denmark, Australia, Canada and Sweden involving just over 24,000 children[1]. Moreover, this pooling study was able to provide data on twins from birth through 19 years of age. By comparing variation within and between both identical and non-identical twins, it is possible to distinguish the effect of genes from the effect of the environment and the latter can be split into common and unique environments. At birth, only 8% of variation in weight or body mass index (BMI) could be explained by genetic factors. By 5 months this had increased to 65% and rose into the 70% decile up to 9 years of age. In the early teens the genetic variation had reached into to 80% decile and by late teens it had hit 90%.  As children got older, the environmental explanation of obesity had fallen from 74% at birth, to 25% at 6 years and down to about 10% in late teens. While this study clearly shows the powerful effect of genetic factors on obesity, it does raise the question as to why this genetic dimension increased with age. Clearly, the genetic make up remained constant so most likely, changes in gene expression were the contributory factor. Growth in childhood and especially in adolescence is associated with significant biological adjustments, which could create the environment for altered gene expression.

One of the reasons which I personally think public health nutritionists are wary of the genetic influence on obesity is that the subject is strongly orientated toward basic biology, effectively, the digestion, absorption, transport, distribution and utilisation of calories from fat, carbohydrate, protein and alcohol. However, genetic influences on behaviour are to my mind far more important   than the genetics of basic biological elements. A recent twin study has looked at the heritability of taste[2].  Subjects were given a strawberry jelly with or without the hot spice capsaicin derived from chili peppers. They were also asked questions on their liking or otherwise of spicy foods and spices and of foods that have mild, strong and extremely strong pungency properties. 50% of the variation in preference for spicy foods and spices and 58% of the variation in “pleasantness of strong pungency” was explained by genetic factors. Another twin study looked at food neophobia in a group of children aged 8 to 11 years, comprising 5,390 pairs of identical and non-identical twins[3].  Parents were asked about their children’s attitude to foods with four statements: “My child is constantly sampling new and different foods”, “My child doesn’t trust new foods,” “My child is afraid to eat things/he has never had before.” and “If my child doesn’t know what’s in a food s/he won’t try it.” A food neophobia score was worked out and the highly robust finding of the study was that a staggering 78% of variation in food neophobia was genetic in origin. Only 22% was learned from the environment. These studies show that the genetic component of obesity need not be related to the biochemistry of energy metabolism, but rather to more complex behavioural traits such as food choice.

Twin studies of obesity always raise the question of assortative mating, that is fat partners mating with other fat partners and similarly for slim partners. Assortative mating has been shown to occur in personality type, education, religion, politics, age, smoking habits and anti-social behaviour. Researchers at the Rowett Institute in Aberdeen used DEXA scans to accurately measure body fat levels in 42 couples[4]. Strong evidence for assortative mating in relation to body fat was found. For example, subjects with disproportionately large arms assortatively mated with like partners. Given the high heritability of the propensity to develop obesity, assortative mating will accelerate the incidence of obesity sine the children of such parents are likely to inherit genetic patterns from both parents.  

The high priests of public health nutrition may dislike the implications of a genetic dimension to obesity but they are being increasingly isolated from the scientific truth.

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[1] Dubois et al (2012) PLoS ONE 7, e30153

[2] Tornwall et al (2012) Physiology & Behaviour, 107, 381-389

[3] Cooke et al (2007) Am J Clin Nutr 86, 428-433

[4] Speakman et al(2007) Am J Clin Nutr 86, 316-323