Possible Explanations for the Disagreement between the Findings of Observational Studies and Clinical Trials

Various explanations have been given for the different findings of observational studies and intervention trials. Clearly, nonrandomized studies are unable to exclude the possibility that antioxidants are simply acting as a surrogate measure of a healthy diet or lifestyle and that the protective effect of certain dietary patterns, which has been presumed to be associated with dietary antioxidants, may in fact be due to other compounds in plant foods, substitution of these foods for others, or a reflection of other health behaviors common to people who have a high fruit and vegetable intake. However, although intervention studies provide a more rigorous source of evidence than observational studies, they are not without weaknesses from a nutritional perspective and the trials have been criticized for a number of reasons:

• The nature of the supplements used: It has been suggested that the synthetic forms used in most trials may have different biological activity or potency from natural forms of these vitamins, although trials using the natural forms have not found different clinical effects. The type of isomer used has also been questioned (e.g., ^-carotene versus other caro-tenoids such as lycopene or lutein or a-tocopherol versus 7-tocopherol). Trials have not investigated other potentially beneficial antioxidants in foods, such as flavonoids and lycopenes.

• The use of high doses of one or two antioxidants: Mechanistic and epidemiological data suggest that antioxidants act not only individually but also cooperatively and in some cases synergistically. Single supplements may interfere with the uptake, transport, distribution, and metabolism of other antioxidant nutrients. An optimal effect would therefore be expected to be seen with a combination of nutrients at levels similar to those contained in the diet (corresponding to higher levels of intake associated with reduced risk in the observational studies). The findings of clinical trials testing the effect of a cocktail of antioxidant nutrients at low doses are awaited, but the Heart Protection Study did not demonstrate a protective effect of multiple antioxidants and a small RCT of 160 patients with coronary disease, using a combination of antioxidant nutrients (800 IU a-tocopherol, 1000 mg vitamin C, 25 mg ^-carotene, and 100 mg selenium twice daily) for 3 years, showed no benefit for secondary prevention of vascular disease.

• Insufficient duration of treatment and follow-up: Most of the intervention trials published to date (except the Physicians Health Study, which found no effect despite 12 years of follow-up) had durations of treatment and follow-up lasting only approximately 4-6 years. Diseases such as cancer and CVD develop over a long period of time and trials may have been too short to demonstrate any benefit.

• The use of high-risk groups: Many of the supplementation trials have not been undertaken on normal 'healthy' individuals but on those with preexisting oxidative stress, either through smoking or through preexisting disease, among whom increasing antioxidant intake may not have been able to repair the oxidative damage process sufficiently to affect cancer or CVD risk.

• Lack of information about the impact of genetic variability: Unknown genetic factors (interacting with nutrition) may explain some of the lack of effect in intervention studies. A greater understanding of the impact of factors such as genotype, age, and ill health on the interactions between antioxidants and reactive oxygen species would be helpful in designing future trials.

The Supplementation en Vitamines et Mineraux AntioXydants Study (SU.Vi.MAX) has taken account of many of these issues in its design. This is a randomized, placebo-controlled trial testing the efficacy of supplementation among more than 12 000 healthy men and women over an 8-year period with a cocktail of antioxidant vitamins (120 mg vitamin C, 30 mg vitamin E, and 6mg ^-carotene) and minerals (100 mg selenium and 20 mg zinc) at doses achievable by diet (approximately one to three times the daily recommended dietary allowances) on premature death from CVD and cancer. Early reports suggest that this regime has not demonstrated an effect on CVD risk but has led to a 31% decrease in cancer incidence and a 37% reduction in total mortality among men but not women. This may reflect higher dietary intakes of these nutrients among the women in the trial compared to men, but publication of these results is still awaited. However, this is a good illustration of the type of nutritional approach that may be needed in the future.

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