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Mortality in Antioxidant Trials

recent analysis was published1 on the effects of dietary supplements used in large, randomized, disease-prevention trials, either primary (before a deleterious event, such as a heart attack or the development of a particular cancer, occurs) or secondary (prevention of the reoccurrence of a deleterious event). The authors reported that, in the studies they examined, there was significantly increased all-cause mortality with beta-carotene, vitamin A, and vitamin E, either singly or combined. Vitamin C and selenium had no significant effect on mortality. These results received widespread reporting in the press (see, e.g., “High Doses of Antioxidants May Hurt More than Help” in the 2-28-07 Wall Street Journal).

The authors used database searches to identify potentially qualifying studies and then divided them into low-bias risk and high-bias risk, with the low-bias risk being those trials with high methodological quality. All the low-bias-risk vitamin A trials were pooled; the same was done with the other nutrients. The resulting all-cause mortality was based upon the pooled results of the low-bias-risk (high methodological quality) studies.

There are several serious limitations to such a meta-analysis. Some of these were identified by the authors, who noted: “The examined populations varied. The effects of supplements were assessed in the general population or in patients with gastrointestinal, cardiovascular, neurological, skin, ocular, renal, endocrinological, and rheumatoid diseases.” There is no way to assess (from the data given in this meta-analysis) to what extent the differences among these populations would have resulted in different effects from increasing the supplies of particular nutrients. For example, while beta-carotene has been found to increase lung cancer risk in smokers, it does not do so in nonsmokers. A pooling of the effects of beta-carotene in different populations, therefore, would not reflect the effects in all the populations.

Moreover, in the cardiovascular studies, a major confounding factor that has not, to our knowledge, ever been corrected for in a dietary supplement study is that most patients with cardiovascular disease these days are taking a statin. Statins reduce the synthesis of coenzyme Q10. Since coenzyme Q10 is important in the regeneration of tocopheryl radical to tocopherol, this could have had a major impact on the results of a vitamin E study in cardiovascular patients. The patients on statins would likely have had increased amounts of tocopheryl radicals as compared to patients not on statins, a result that could arguably have had an effect on their mortality.

The authors claim: “These populations mostly came from countries without overt deficiencies of specific supplements.” On the contrary, there are large segments of even highly advanced countries, such as the United States and Britain, that have dietary levels of certain nutrients that do not meet even the generally meager RDA levels. This is particularly true for the elderly. For example, a new study2 reported that, in the winter and spring, when hypovitaminosis D is highest, 7437 white, 45-year-old British individuals were measured for vitamin D levels. 25(OH)D concentrations below 25, below 40, and below 75 nmol/L were found in 15.5%, 46.6%, and 87.1% of participants, respectively. The concentration of vitamin D identified as optimum for bone health is greater than or equal to 75 nmol/L.2 During the summer and fall, the respective numbers were 3.2%, 15.4%, and 60.9%. Vitamin D concentrations below 40 were twice as likely in the obese as in the nonobese.

The problem, as we see it, is that the design of these dietary supplement studies are modeled after drug studies, in which (usually) one or perhaps two entities are tested against a placebo. As many scientists have pointed out, antioxidants work in systems to do what they do, which is not only frequently to quench free radicals but also to alter the expression of many genes by nonantioxidant mechanisms. (Then, of course, there is the considerable “problem” of getting people to stick with a placebo for long periods of time, when they can experiment on their own with easily accessible dietary supplements.)

— Durk Pearson & Sandy Shaw


  1. Bjelakovic et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297(8):842-57 (2007).
  2. Hypponen and Power. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85:860-8 (2007).

From The Durk Pearson & Sandy Shaw® Life Extension News™,
Vol. 10, No. 1, March 2007.
(Excerpt—more will be published in the June 2007 issue of Life Enhancement.)

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