Cautious interpretation is essential

The meta-analysis to be published next January in the Annals of Internal Medicine (Volume 142, Issue 1) , suggests that mortality in people taking over 400 IU of Vitamin E a day is increased. The study, published electronicallyon the journal's website,re-analyses data from 19 clinical trials involving Vitamin E published between 1993 and 2004 and was undertaken by researchers at Johns Hopkins Medical Institutions.

In the view of the Alliance for Natural Health, which represents doctors, practitioners, consumers and leading-edge companies with interests in sustainable healthcare and natural therapies, it is of paramount importance that the study results are interpreted with caution.

Scaremongering headlines, based largely on misinterpretations of the study, which have begun to appear today, do nothing to help the development of responsible self-care patterns in consumers which are urgently required in the face of escalating heart disease and cancer rates.

Limitations of the study

In a widely circulated press release publicising the study, Dr Edgar Miller, lead author of the meta-analysis at Johns Hopkins University School of Medicine, claims that “If people are taking a multivitamin, they should make sure it contains no more than a low dose of vitamin E … our study shows that use of high-dose vitamin E supplements certainly did not prolong life, but was associated with a higher risk of death."

However, the study has a number of very important limitations which mean that sweeping generalisations such as those made by Dr Miller should not be made. Such statements could be regarded as irresponsible particularly as they are likely to cloud consumer views over the importance of food supplementation as a means of compensating for the now well demonstrated inadequacies of the typical, western diet.

Some of the most important limitations of the study are:

·All trials in the study were performed using only one of the seven forms of Vitamin E, namely a-tocopherol, which is often used in its synthetic form. There is now strong scientific evidence which demonstrates that other forms of Vitamin E, as found in natural food sources, are much more effective as antioxidants, these being for example y-tocopherol and the four tocotrienol forms. While a-tocopherol has long been the yardstick by which vitamin E activity is measured, y-tocopherol, the most abundant form found in foods, has in recent years been demonstrated to have unique roles in the prevention of both cardiovascular disease and cancer (Stone WL and Papas AM, J Nat Cancer Inst, 1997; 89 (14): 1006-14).

·The studies were undertaken in the main on elderly persons suffering chronic diseases, so it is not possible to conclude that higher supplemental doses of Vitamin E promote disease or increase death among healthy people. This limitation is acknowledged in the Johns Hopkins study, the authors indicating, “we could not evaluate the generalizability of our findings to healthy adult populations.”

·Although the study includes 19 trials and is referred to as a meta-analysis, there is huge variation between the scale of the various trials and in the case of the 11 high dose trials, the bulk of the data come from just two large studies, namely the Cambridge Heart Antioxidant Study [CHAOS] and the Medical Research Council/British Heart Foundation Heart Protection Study [MRC/BHF HPS]. This latter study shows nearly double the number of deaths compared with all the other high dosage studies combined, and four times as many as in the other high dose studies with increased mortality. The study used a combination of synthetic beta-carotene and synthetic Vitamin E.

·The follow-up periods for the 19 studies were often short, averaging from 1.4 to 8.2 years. In many cases the chronic diseases suffered by study participants would not be able to be significantly impacted over shorter time periods.

A number of additional limitations have been cited by the authors of the study.

Misinterpretations of the study

The principles of study selection and analysis used by the Johns Hopkins team are on the whole reasonable and can be justified scientifically, albeit with an acceptance of the study's limitations.
The biggest issues affecting consumer choice and governmental regulation are related to study interpretation, both by the authors and others subsequently.

Dr Robert Verkerk, executive director of the Alliance for Natural Health, commented, “The Johns Hopkins study provides another interpretation of information that has been known for some time. However, it tells us nothing about the supplemental use of natural forms of Vitamin E and how people can use Vitamin E and other ingredients in food supplements to reduce their risk from chronic diseases like heart disease and cancer.”

The authors of the study make no mention of the good body of evidence that shows that synthetic forms of Vitamin E, or purified natural forms that are limited to a-tocopherol, have the ability to reduce the body's absorption of other forms of Vitamin E (e.g. Handelman GJ et al, J Nutr 115; 807-13,1985; Burton GH et al, Am J Clin Nutr 67; 669-84, 1998; Huang HY, Appel LJ J Nutr 133; 3137-40, 2003) which are much more powerful antioxidants.

This, coupled with the possible pro-oxidant behaviour of a-tocopherol at high doses, considered by the Johns Hopkins authors as a possible mechanism explaining the apparent increased incidence of death shown in the meta-analysis, might at least partially explain the observed results.

In addition, there is recent evidence that many of the beneficial properties of Vitamin E may be related to non-antioxidant mechanisms involving specific molecular reactions with enzymes and proteins (see Munteanu A, et al J Cell Mol Med, 2004; 8(1): 59-76), so antioxidant-focused intervention trials may be limited in their ability to assess the full range of benefits of Vitamin E-containing supplements.

Dr Verkerk added, “The clinical trials used in the meta-analysis all use a classic, orthodox medicine intervention approach, where vitamins are used much in the same way as drugs, and are often delivered on their own in their synthetic form or in very limited combinations. There are as yet no studies which attempt to explore benefits of balanced combinations of nutrients, comparable to those that may be found in a theoretical, ultra-healthy diet. Most committed users of food supplements are aware that food-form supplements are desirable over synthetic forms, and that complex combinations of nutrients are required rather than single vitamins. The continuing development of nutritional therapy as a complementary healthcare approach would suggest that many thousands of people have experienced benefits from such ‘high dose' nutrient therapies, often used in combination with healthy diets, exercise and other lifestyle changes.”

Negative implications of the study

Negative publicity about Vitamin E, spawned by misinterpretations of the science behind the Johns Hopkins study, could scare people unnecessarily and stop them using important food supplements. Food supplements are invaluable as a means of guaranteeing levels of key nutrients, such as natural Vitamin E, known to be depleted or deficient in today's typical diets. Recommended Daily Allowances, although largely discredited by the scientific community and bearing no relationship to the levels required for optimum health, are still used by many governments as the yardstick by which to determine acceptable intakes of vitamins and minerals,

It is a very rich irony that the European Commission has seen fit to allow only the a-tocopherol form of Vitamin E in its new Food Supplement Directive, set to come in to force across Europe in August 2005 unless challenged successfully. The Directive bans the natural, food-forms of Vitamin E and some 300 forms of vitamin and mineral presently on the European market. In many cases these food forms have been shown to be considerably more beneficial to health. The Alliance for Natural Health is presently challenging the Directive in the European Court of Justice. The case is expected to be heard in early 2005.

Last week in Bonn, Germany, United Nations' Codex Committee on Nutrition and Foods for Special Dietary Uses finalised the text of an international guideline for vitamins and minerals. The next stage will be the development of guidelines for maximum dosages, which will use a so-called evidence-based risk assessment approach. In September, the Food & Agricultural Organisation and the World Health Organisation released a consultation document* for which comments must be received by 10 December. The timing of the release of the Johns Hopkins meta-analysis seems set to give the regulators justification to be excessively restrictive, particularly if the media can be relied on to exaggerate and distort the findings of the study.

Whatever levels are developed for the international Codex guidelines are then likely to filter back into national or regional legislative systems, including the Food Supplements Directive in Europe. There is no doubt that even the United States' Dietary Supplement Health & Education Act (DSHEA), which has been viewed as the bastion of liberal natural healthcare legislation for some 10 years, is now deeply under threat.

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Dr Robert Verkerk
executive director, Alliance for Natural Health
Tel: +44 (0)1252 371 275
Email: [email protected]