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The Making of Killer E

March 2005

By Terri Mitchell

Behind the Headlines, Controversy Rages

The ink was barely dry on the “killer E” meta-analysis before the criticism erupted. Experts of all kinds, including doctors, dieticians, and medical researchers, have questioned the validity of the analysis: “one might well expect that they should produce conclusions that are consistent with the authors’. This, unfortunately, is not the case . . .”; “You describe the pooled risk difference . . . But when I add the numbers . . . I get a risk difference of . . .”; “ . . . this Lancet study made an entirely different conclusion from your above study . . .”.28 The controversy will rage for months, if not years. Its effect will be positive, as more attention will be paid to the design of future antioxidant clinical trials, and the inadequacies of such studies in general will become more widely recognized.

But the question remains: why did the Annals of Internal Medicine publish such nonsense? The answer was clearly stated in that same publication. The point was to make public policy. The “killer E” meta-analysis was a call for an end to all “high-dose” supplements, a dare to American institutions to reverse their policies on vitamin E, and a challenge to “regulators and policymakers” to control which vitamins Americans take. Who are these people who want to control which vitamins we take?

The study authors are not unfamiliar with the glow of headlines. In the New England Journal of Medicine, they claimed that fish oil increases heart attack risk,29 a claim that was refuted in the same issue by a different research group.30 The editor who published the “killer E” meta-analysis in the Annals of Internal Medicine has a long history of trying to dictate public policy, and has announced that he is using that journal as the mouthpiece for a committee that he formerly chaired, known as the US Preventive Services Task Force.31 Among other things, he acknowledges only meta-analyses and mega-clinical trials as bona fide scientific evidence, and has led the “task force” in assigning “ratings” to the value of such things as prostate cancer screening (no approval), vitamin use (no approval), and cost-benefit analyses (strong approval).31-33

In upcoming issues, Life Extension will be telling members more about what this editor, his “task force,” and others have in store for you. Stay tuned for more sequels to the “killer E” meta-analysis, coming to a newspaper or website near you in the new age of “shared decision making” and sensational “science.”


Because it is less expensive than natural vitamin E, synthetic vitamin E is often used in research studies. Many of the studies that make up the Hopkins vitamin E meta-analysis used synthetic vitamin E instead of natural d-alpha tocopherol.1 The researchers tried to account for this difference by converting all vitamin E dosages in the studies to international units based on the relative biological activity of synthetic vitamin E. Natural and synthetic vitamin E, however, are biochemically distinct, and thus this method of comparing them may not be highly accurate.

Alpha tocopherol is the most biologically active form of vitamin E,34 and its natural form consists of one isomer. By contrast, synthetic vitamin E is a mixture of eight isomers, of which only one occurs in nature and is thus compatible with human body chemistry. Very little research has been done on the separate pharmacology of the other seven synthetic, unnatural isomers. The pharmacology of synthetic vitamin E is quite different from that of natural vitamin E; it demonstrates an entirely different dose-response curve, proving that it is an entirely different drug by modern pharmacological standards. The two supplements are not equivalent at any dosage ratio.35 Strangely, only in the case of synthetic versus natural vitamin E do scientists ignore the rule that different isomers are different drugs, and that different dose-response curves produce entirely different effects.

The body processes vitamin E by the same enzyme pathway that metabolizes up to 40% of prescription drugs.35,36 Because it consists of eight isomers, synthetic vitamin E may have a greater potential of interacting with and modifying the effects of prescription drugs than does the single isomer that makes up natural d-alpha tocopherol.

The vitamin E meta-analysis not only failed to differentiate between natural and synthetic vitamin E, but also did not distinguish between different fractions of vitamin E. Alpha tocopherol is the most predominant form of vitamin E in the human body, and is the form most frequently sold as a supplement. There are three other tocopherol forms of vitamin E: beta, delta, and gamma. Until recently, no one thought there was much difference between alpha tocopherol and other forms of vitamin E. In light of recent research, however, such thinking is on the way out.

In recent years, gamma tocopherol has moved to the forefront of nutritional research. Gamma tocopherol is found in the muscles, veins, skin, and fat, in contrast to alpha tocopherol, which is often found in the blood and cell membranes.37 Taking supplemental alpha tocopherol changes the body’s ratio of alpha tocopherol to gamma tocopherol, lowering serum levels of gamma tocopherol.38 Gamma tocopherol has biological actions that alpha tocopherol does not, including anti-inflammatory properties.39 Thus, any ill effects from supplemental alpha tocopherol may be due to its tendency to lower serum levels of beneficial gamma tocopherol. (See also “American Medical Association Discovers Gamma Tocopherol,” Life Extension, January 2005.)


A staggering 24% of Americans take vitamin E. For most nutrition-conscious people, vitamin E is synonymous with “antioxidant,” which is synonymous with anti-aging and anti-heart attack. This sound-bite version sounds good, but is not exactly accurate. While vitamin E has numerous proven benefits, it cannot be expected to reverse advanced heart disease, to single-handedly stop aging, or to cure anything else that comes along. Vitamin E is a victim of its own success, and we may need to reassess our conceptions of it.

Not only is vitamin E not a wonder drug, but its most common form (alpha tocopherol) may not be as powerful as some of its cousins. There are eight known forms of vitamin E—four tocopherols and four tocotrienols—and all can be called “vitamin E.” Each is responsible for unique actions in the body, and the benefits of each continue to be discovered.

Vitamin E is a fat-soluble antioxidant, but not all free radicals occur in fat; some occur in watery parts of the body like blood. Different types of free radicals require different types of antioxidants, which is why supplements are sometimes advertised as providing antioxidant protection that is hundreds of times stronger than that provided by vitamin E. The advertisements are accurate: some supplements are hundreds of times more powerful than vitamin E against certain types of free radicals. Vitamin E is by no means the beginning and end of antioxidants, nor is alpha tocopherol the sum total of vitamin E; unfortunately, in many medicine cabinets, a bottle of alpha tocopherol is the beginning and end of antioxidants.


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