Linus Pauling Institute - Research Newsletter Spring 2008
"FATALLY FLAWED" CLINICAL TRIALS OF VITAMIN E
Over 60 years ago, E. V. Shute of Canada wrote a letter about the effectiveness of vitamin E in treating coronary heart disease that was published in the scientific journal Nature. Anecdotal evidence and clinical reports continued to emerge for decades, and Linus Pauling periodically wrote about the health benefits of vitamin E supplements. It wasn't until 1993 that the conventional medical community became excited, when two reports were published in The New England Journal of Medicine by Harvard researchers, who reported that their epidemiological studies found associations between supplemental vitamin E intake and decreased risk for coronary heart disease in men and women. Those observational studies stimulated randomized clinical trials of vitamin E and heart disease, some of which have not substantiated a reduced risk for clinical events, such as strokes, heart attack, or death, in patients with heart disease. All of the clinical trials published thus far have looked at vitamin E supplements in treating heart disease, and none has examined the long-term use of vitamin E supplements in healthy people to prevent heart disease. The only evidence we have on that score comes from observational studies like the two mentioned above by the Harvard group. The use of vitamin E to prevent or treat heart disease remains controversial.
In the Spring/Summer 2002 LPI Research Newsletter, Jeffrey Blumberg of Tufts University contributed an invited article, "Unraveling the Conflicting Studies on Vitamin E and Heart Disease," in which he suggested that results of vitamin E studies have been problematically influenced by a variety of issues, including inadequate dose, duration, suboptimum form, and polypharmacy (the use of multiple drugs) of patients. He also noted that none of the clinical studies had measured oxidative stress in the subjectsâ€â€an important shortcoming since the putative benefit of vitamin E is ascribed to its role as an antioxidant. If no measurements of oxidative stress were recorded, it was impossible to determine if supplemental vitamin E had the desired effect of attenuating oxidative stress. Most studies have also failed to measure plasma vitamin E to determine if it was increased after supplementation.
In a recent commentary published in Free Radical Biology & Medicine, Blumberg and LPI's Balz Frei discussed the results of a research paper by L. Jackson Roberts et al. in that same issue of the journal. Roberts et al. found that very high daily doses of vitamin E (1,600 IU or 3,200 IU d-alpha-tocopherol) taken for at least 16 weeks were required to ameliorate oxidative stress, which was assessed by the formation of F2-isoprostanes, in hypercholesterolemic men and women. F2-isoprostanes are formed in the body by the oxidation of arachidonic acid, an omega-6 polyunsaturated fatty acid that is essential in human nutrition. F2-isoprostanes, then, are considered biomarkers of oxidative stress. Roberts et al. found a decrease in plasma F2-isoprostanes at vitamin E doses of 400 IU/day and above, but statistically significant decreases were evident only at the highest doses, 1,600 and 3,200 IU/day. These doses decreased plasma F2-isoprostanes by about 35% and 50%, respectively. Blumberg and Frei noted that most trials of vitamin E and heart disease may be "fatally flawed" because of insufficient dosage and that "the paradox of vitamin E in CVD might be resolved by studies initiated at earlier stages, of longer durations, and using higher doses and more bioavailable forms of alpha-tocopherol [vitamin E]." Interestingly, Linus Pauling advocated taking daily doses of up to 1,600 IU of vitamin E in his book, How to Live Longer and Feel Better, published over 20 years ago. Even earlier, in an article for Executive Health in 1973, Pauling discussed the potential value of high-dose vitamin E taken for at least several months. Currently, the tolerable upper intake level for vitamin E is 1,500 IU/day of RRR-alpha-tocopherol (d-alpha-tocopherol or natural vitamin E), based on the possible risk for hemorrhage at higher doses because of impaired blood clotting.
In future clinical trials, Blumberg and Frei call for assessing the level of oxidative stress in subjects, as measured by appropriate biomarkers, in order to determine the effect of supplemental vitamin E and other antioxidants on oxidative stress. They also emphasize that investigators must pay careful attention to dose, duration, and possible drug-nutrient interactions. When such properly designed clinical trials have been conducted, we will have a much better understanding of the role of antioxidants, especially vitamin E, in heart disease.
Last updated June 2008
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