Study Claims Antioxidant Danger—A Repeat of Flawed Conclusions
By Alan R. Gaby, MD
Healthnotes Newswire (April 17, 2008)—A new
study published by the Cochrane Database of Systematic Reviews reports that
taking antioxidant supplements does not prolong life, and that using certain
specific antioxidants may slightly increase the risk of death.
But vitamin users shouldn’t take this report as seriously as its widespread
publicity would suggest. The new study is essentially
a rewritten version of a study published a year
ago in the Journal of the American Medical Association that received
heavy media coverage. The new study presents the
same data that has already been reported and subsequently discredited.
Exclusion of certain trials skewed results
As before, the researchers looked at 67 clinical trials involving antioxidants
and categorized them as either a high or low risk for error. The
20 clinical trials considered “high-bias risk”
were excluded from the study—but just why the researchers felt the need
to exclude these trials isn’t clear and, unfortunately, excluding them
significantly changed the results.
After excluding these trials, when the data from the remaining 47 trials
(involving a total of 180,939 people) were pooled, taking any antioxidant
increased the risk of death by 5%. For individual supplements, the risk was
increased by 4% with vitamin E, 7% with synthetic beta-carotene, and 16% with
vitamin A. All of these increases were statistically significant. Vitamin C and
selenium had no significant effect on mortality.
Also as before, the reasons for the exclusion don’t make scientific sense.
Criteria the researchers used to decide whether a clinical trial should be
considered reliable included the way in which participants were assigned to
receive antioxidants or placebo, and whether the trial was double-blind. While
these methods are usually the standard to which we agree most studies should be
held, a study of this type doesn’t require that kind of strict research design
because a subtle imperfection in randomization method or a researcher’s
awareness of treatment assignments is unlikely to influence a result as
objective as death. In other words, a researcher assigning a participant to a
particular treatment or knowing which treatment someone is getting probably
won’t affect whether that person dies.
In the case of the current study, the so-called “high-bias risk” studies
probably did not endanger the reliability of study results and there was,
therefore, no compelling reason to exclude them.
Had the researchers included those trials, there would have been no significant
effect of antioxidant use in general, or of any specific antioxidant, on
mortality.
Combining divergent studies not appropriate
Another weakness in this study was the pooling of the results of trials that had
crucial differences, which led to inappropriate conclusions about the overall
effects of antioxidants. Even though this study was published in a reputable and
well-known medical journal, the Cochrane Database is not a publication that
specializes in nutrition, and neither the
authors nor the reviewers who read the material prior to publication appear to
have been aware of how failing to adjust for the differences between these
trials may have affected the study conclusions. (For specific examples of
how these oversights might impact interpretation, see “Study details” at the end
of this article.)
Previous research can’t be ignored
Antioxidant supplements are used by tens of millions of people, with many uses
supported by a wide body of research developed over many years and published in
reputable medical journals that are dedicated more specifically to managing
health through nutrition. Studies have shown, for example, that
vitamin C may prevent or help treat heart
disease, diabetes, high blood pressure, asthma, and more. Vitamin E is
beneficial for intermittent claudication (difficulty walking caused by hardened
arteries) and rheumatoid arthritis. Selenium may help prevent heart disease and
certain types of cancer. Only rarely could a single study negate an
entire body of research; rather, each new study adds to the medical
“conversation” and helps determine the direction of future investigation.
Even within this study, despite its negative overall conclusions, some of the
“low-bias risk” trials that were included showed a clear benefit from
antioxidant supplementation. For example, in a study that lasted 7.5 years and
included more than 13,000 people, modest doses of a combination of vitamin C,
vitamin E, beta-carotene, selenium, and zinc
reduced the death rate in men by 37%, although no effect was seen in
women. Results like these should encourage further research to determine what
doses and combinations of nutrients are safest and most effective for people of
different ages and different genders and with different health concerns and
lifestyles.
Even the most enthusiastic nutritional supplement supporters recognize the
importance of a broad-spectrum approach to managing wellness and preventing
disease that includes eating well, exercising, limiting exposure to toxins, and
supplementing with nutrients that may not be obtained from the typical diet.
Despite the concern that is likely to result from the republishing of this old
research, it’s important to put its findings into context and remember that
there is well-demonstrated evidence that
antioxidants may improve or prevent certain medical conditions and improve
overall quality of life.
(Cochrane Database of Systematic Reviews 2008: CD007176.
DOI:10.1002/14651858.CD007176.)
Study details:
As described in the above article, the pooling of the results of trials that had
crucial differences, which led to inappropriate conclusions about the overall
effects of antioxidants. For example:
• Beta-carotene—It is well established
that synthetic beta-carotene increases the risk of lung cancer and death in
smokers, possibly because of a toxic interaction with cigarette smoke. In
nonsmokers, however, synthetic beta-carotene has no effect on mortality (natural
beta-carotene, which has a different chemical structure, has not been well
studied). Pooling all of the beta-carotene trials was therefore inappropriate,
and led to the erroneous conclusion that synthetic beta-carotene supplements are
bad for everyone, not just for smokers.
• Vitamin A—Researchers concluded that
vitamin A increases risk of death by pooling five vitamin A trials, the largest
of which studied smokers given a combination of vitamin A and synthetic
beta-carotene. The increased mortality seen in the supplement group compared
with the placebo group may have been due
entirely to the beta-carotene and unrelated to the vitamin A.
In another of the vitamin A trials, patients with a previous skin cancer
received 25,000 IU of vitamin A per day or a placebo for up to five years.
During the entire trial, which included a follow-up period after vitamin A was
discontinued, the death rate was slightly higher
in the vitamin A group than in the placebo group (5.4% versus 4.6%). However,
during the time that people were actually taking vitamin A, the death rate was
slightly lower in the vitamin A group
than in the placebo group (2.07% versus 2.11%). The bottom line: there is no way
of knowing whether vitamin A was responsible for the small increase in mortality
that occurred after supplementation was stopped.
In a third vitamin A trial, elderly nursing home residents were given a single
dose of 200,000 IU of vitamin A or a placebo, and were then observed for signs
of infection. During the follow-up period, the death rate was higher in the
vitamin A group than in the placebo group (11.3% versus 7.1%); however,
people receiving vitamin A were on average 4.8
years older than those receiving placebo. The higher death rate may have
been entirely due to that age difference.
• Vitamin E—The issues surrounding
vitamin E are complicated and some of the
concern about adverse effects may be justified. In one large trial, the
combination of vitamin E and beta-carotene was given to cigarette smokers. The
increased mortality observed in that trial may have been entirely due to the
beta-carotene and unrelated to vitamin E. In other trials, however, the adverse
effect of vitamin E is difficult to dismiss.
It is important to note, however, that while vitamin E occurs in food in four
different forms—alpha-, beta-, gamma-, and delta-tocopherol—virtually all of the
research on vitamin E has used pure alpha-tocopherol.
Alpha-tocopherol has a number of positive effects on cardiovascular function.
But taking large amounts of it can deplete gamma-tocopherol, a component of the
“vitamin E complex” that may be even more important for the heart than alpha-tocopherol
is. Therefore, “mixed tocopherols,” which
contains all four naturally occurring forms of vitamin E, may be preferable to
pure alpha-tocopherol, both in terms of safety and effectiveness.
• Selenium—It is curious that the study’s
authors paid such little attention to evidence of a beneficial effect. When all
of the trials were pooled, selenium
supplementation reduced mortality by 9%. When the “high-bias risk” trials
were excluded, selenium’s beneficial effect was even more pronounced (10%
reduction) but, because of the smaller number of participants, that improvement
was no longer statistically significant.
An expert in nutritional therapies, Chief
Medical Editor Alan R. Gaby, MD, is a former professor at Bastyr University of
Natural Health Sciences, where he served as the Endowed Professor of Nutrition.
He is past-president of the American Holistic Medical Association and gave
expert testimony to the White House Commission on Complementary and Alternative
Medicine on the cost-effectiveness of nutritional supplements. Dr. Gaby has
conducted nutritional seminars for physicians and has collected over 30,000
scientific papers related to the field of nutritional and natural medicine. In
addition to editing and contributing to The Natural Pharmacy (Three Rivers
Press, 1999), and the A–Z Guide to Drug-Herb-Vitamin Interactions (Three Rivers
Press, 1999), Dr. Gaby has authored Preventing and Reversing Osteoporosis (Prima
Lifestyles, 1995) and B6: The Natural Healer (Keats, 1987) and coauthored The
Patient's Book of Natural Healing (Prima, 1999).