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Letters to the Editor Issue 148

by Letters(more info)

listed in letters to the editor, originally published in issue 148 - June 2008

Cochrane Review Of Antioxidant Supplements In Prevention Of Mortality

Nutrients with antioxidant activity include vitamin A, vitamin C, vitamin E and selenium. All are essential nutrients, not only on account of their antioxidant activity in the cells and tissues, but also for a whole host of other effects on immune function, the blood, the nervous system and the musculosketelal system. The totality of evidence from epidemiological studies, animal trials and various studies in humans for these essential nutrients suggests that they have many health benefits, and that inadequate intake can increase the risk of poor health. Moreover, a significant number of British people have diets lacking in these essential nutrients. A supplement containing the recommended daily amount of these, and all essential vitamins and minerals, will ensure that a person’s intake does not fall below recommended levels.

Pamela Mason (Nutritionist and spokesperson for Health Supplements Information Service (HSIS) comments: “Nutrients with antioxidant activity, including vitamin A, C, E and selenium are essential for human health. Vitamin A is essential for the health of the eyes and mucus membranes, such as the respiratory tract. Vitamin C is essential for the health of all connective tissue, such as the bones, joints, blood vessels and gums. Vitamin E is essential for the health of the nervous system and selenium participates in many biochemical reactions throughout the body as a result of its involvement in key enzymes.”

Pamela continues: “Each one of these nutrients has proven antioxidant activity in the tissues, which means that they reduce the adverse effects of reactive oxygen and reactive nitrogen species on biochemical functions in the body’s tissues. In this antioxidant role, these nutrients have a wide variety of protective roles in the body, all of which help to maintain health. Vitamin E protects the lipid (fat) component of cell membranes from damage. Vitamin C protects the DNA in human sperm from oxidative damage, and the eye tissue from damage caused by ultraviolet light.”

The Cochrane Systematic Review
Pamela goes on to discuss the Cochrane review published this week which concluded that there was no evidence that antioxidant supplements extend life.1 “This meta-analysis, which included 67 randomised controlled trials, combining data from 232,550 participants was large, but it is important to note that it included only trials which looked at mortality. A total of 405 trials considered by the review group were excluded from the meta-analysis because these trials did not report on mortality in their papers. When the authors of the Cochrane review contacted the authors of the trials not reporting on mortality, in one fifth of these trials, i.e. more than 80 trials, mortality was zero – i.e. no one participating in the trials had died. In short, the Cochrane review only included trials in which someone had died. Had these other trials been included, the conclusions would have been very different.

The Cochrane review also excluded studies that used supplements for replacement of nutrient deficits. In addition, this meta-analysis did not look at particular population groups whose antioxidant status and intakes of antioxidants are low and who may well have derived key benefits.

Given that nutrient supplements, including those with antioxidant activity, are intended primarily to replace shortfalls of nutrients in the diet and contribute to health maintenance, this is a serious problem with the meta-analysis, which may also have skewed the results.

Another thing to note is that this review demonstrates nothing new whatsoever. Indeed, this review was published last year in the Journal of the American Medical Association.[2] The trials it includes have been in the public domain for at least 3 years.

What is also important is that the National Diet and Nutrition Survey (NDNS) showed that substantial numbers of the adult population have inadequate intakes of vitamins and minerals. This is particularly so in younger adults aged 19-24 years, but poor intakes occur throughout the population. Vitamin and mineral supplements including antioxidants, taken in recommended amounts, can make good these dietary gaps and ensure that everyone achieves adequate intakes.

Pamela concludes: “Antioxidant vitamins, including these included in this Cochrane review, are essential for health, and UK national dietary surveys have shown that some people have poor intakes. Antioxidant vitamins, like any other vitamins, were never intended for the prevention of chronic disease and mortality. They are not magic bullets. They are intended for health maintenance on the basis of their various physiological roles in the body and in the case of the antioxidant vitamins, this does, in appropriate amounts, include a protective antioxidant effect in the body’s tissues.

What we need now, I’m afraid, is yet further research, looking at the role of antioxidant vitamins in different groups of people at different stages of life and throughout life, and possibly also in different mixtures and amounts. Further consideration is also required around the methods used to conduct meta-analyses, which trials to include and so on.

What we do know is that these vitamins are essential for health and that many people in the UK do not have an adequate intake according to recommended daily amounts. A vitamin supplement taken in recommended amounts can be beneficial for health, especially for those people whose intakes are poor.


1.    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant Supplements for Prevention of Mortality in Healthy Participants and Patients with Various Diseases. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD007176. DOI: 10.1002/14651858.CD007176. 2008.
2.    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 28;297(8):842-57. 2007.

Further Information

Eva Levin, Consultant Senior Account Executive, Nexus Healthcare. Tel: 020-7052 8853;;

Antioxidant Supplements and Mortality – Research Critique

by Patrick Holford BSc Dip ION FBANT
This is the fourth time Bjekalovic and his group have reviewed the effects on selected studies on antioxidants. Anyone following the science of antioxidants over the past 20 years will be aware of a vast number of studies reporting positive results. So, how do you end up with a headline that implies antioxidants increase mortality?

In this review, which is a rehash of their paper published last year in the Journal of American Medical Association (JAMA), they first excluded over 400 trials, many of which had positive outcomes, but had no deaths. They then decided which trials they liked (low risk bias) and did not like (high risk bias), a factor that has received criticism in mainstream medical journals.

What the Experts Say

One of the world’s leading experts in this field, Dr Balz Frei said “This is a flawed analysis of flawed data, and it does little to help us understand the real health effects of antioxidants, whether beneficial or otherwise.”[1]

Dr Bernadine Healey, former director of the National Institute of Health said, “Blenderizing these diverse trials into one giant 232,606-patient-strong study to come up with a seductively simple proclamation is just silly. When the researchers tallied up the mortality from the 68 trials, there was no difference based on vitamin intake. The headlines that these supplements significantly increase the risk of death by 5 percent overall came only when the researchers pulled out the 47 trials they deemed to have been the best executed. Actually, in the 21 randomized trials they peeled off, mortality was decreased by 9 percent among those taking the vitamins.”[2]

How did they Come Up with the Reported Results?

Not surprisingly, the selection process in today’s review excluded many of the most positive studies. For example, quoting the review itself, ‘In secondary prevention trials (meaning people with disease) with high-bias risk, mortality was significantly reduced by supplements.’ In those they called ‘low-bias risk’ there was no significant change in mortality.

To report an even more negative result, which is what newspapers often home in on, they also excluded all trials on selenium, which actually reduced mortality the most of all the antioxidants considered.


As an example, let’s look at beta-carotene, which is given the worst rating. The review states “Beta-carotene used singly or in combination with other antioxidants had no significant effect on mortality when including all 24 trials” BUT “After exclusion of high-bias risk and selenium trials, however, beta-carotene singly or combined significantly increased mortality in 12 trials.”

Antioxidants and Cancer

Even if we were to accept the exclusion of the so-called high-bias risk trials, let’s look more closely at the apparently negative studies. A graph of all these trials shows five that skew the results towards a negative. I thought I’d look closer at these trials. The first was by Dr Correa from the pathology department at the Louisiana State University Health Sciences Centre, and showed a clear protective effective of antioxidant supplements against gastrointestinal cancer.[3]

I decided to contact Dr Correa and he was “amazed”, he said, because his research, “far from being negative, had shown clear benefit from taking vitamins.” Correa told us there was no way the study could show anything about mortality. “Our study was designed for evaluation of the progress of pre-cancerous lesions”, he said. “It did not intend, and did not have the power, to study mortality and has no value to examine mortality of cancer.”

Vitamin E and Statins

The next, called the DATOR trial, gave people with high cholesterol, high dose vitamin E (750iu) and statins.[4] As nutritionists we caution against this because statins stop you making CoQ10 which results in vitamin E becoming a potentially harmful oxidant. That’s exactly what this trial reported, “These results indicate that the antioxidant effect of Vitamin E is attenuated (reduced) when given in conjunction with this statin.” So these negative effects of vitamin E might actually be because it’s taken with a drug that makes it harmful! Given that the majority of the trials included in this review were on sick people, presumably taking medication, this kind of confounding variable really should be taken into account. It is not.

Selenium’s Protective Effects

The next trial, published in the Mayo Clinic’s journal, that skewed the results to a negative reported a positive outcome.[5] It investigated the effect of selenium of oesophageal cancer. It found that “among subjects with mild esophageal squamous dysplasia (early stage) at baseline, selenomethionine did have a protective effect.” For those with more advanced cancer, it did not.

In January this year the authors published a paper Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis.[6] Their conclusion was that “beta carotene supplementation appeared to increase cancer incidence and cancer mortality among smokers, whereas vitamin E supplementation had no effect. Selenium supplementation might have anticarcinogenic effects in men and thus requires further research.”

What does all this Mean?

If you look at all the studies reviewed, strictly for reducing mortality, not for other benefits, Bjekalovic concludes “Beta-carotene, vitamin A and vitamin C, used singly or in combination with other antioxidants had no significant effect” although a number of vitamin C studies did report reduced mortality. “Selenium used singly or in combination with other antioxidants significantly decreased mortality.’[7] Beta-carotene, as we know, is best not taken singly by smokers. Vitamin E in high dose, as we know, should not be taken by those on statins without additional CoQ10. Selenium and vitamin C are most likely to be beneficial.

Should we Throw Away our Antioxidants?

Certainly not. I haven’t recommended isolated antioxidant supplementation for 20 years and doubt they would produce much effect in sick people with advanced disease states, except for vitamin C at high doses – a subject not examined in this review. Antioxidants are team players.


3.    P Correa et al. Chemoprevention of Gastric Dysplasia: Randomized Trial of Antioxidant Supplements and Anti-Helicobacter Pylori Therapy. Journal of the National Cancer Institute. (2000), vol 92, pp1881-8.
4.    Manuel-Y-Keenoy B et al. Impact of Vitamin E Supplementation on Lipoprotein Peroxidation and Composition in Type 1 Diabetic Patients Treated with Atorvastatin. Atherosclerosis. 175(2): 369-76]. 2004.
5.    Bardia et al. Randomized, Placebo-Controlled, Esophageal Squamous Cell Cancer Chemoprevention Trial of Selenomethionine and Celecoxib. Gastroenterology. 129(3): 863-73. Sep 2005.
6.    Bardia A et al. Efficacy of Antioxidant Supplementation in Reducing Primary Cancer Incidence and Mortality: Systematic Review and Meta-Analysis. Mayo Clin Proc. 83(1): 23-34. 2008.
7.    Bjelakovic et al. Antioxidant Supplements for Prevention of Mortality in Healthy Participants and Patients with Various Diseases (Review), Cochrane Library. Issue 2. 2008.

Further Information and Credit Acknowledgement

Patrick Holford


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