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LE Magazine March 2005

The Making of Killer E

The truth behind the recent vitamin E controversyBy 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.”

SYNTHETIC VS. NATURAL VITAMIN E

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.)

MISCONCEPTIONS ABOUT VITAMIN E

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.

References

1. Miller ER, III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2004 Jan 4;142(1):37-46.

2. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2432-40.

3. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996 Aug;64(2):190-6.

4. Anon. The effect of vitamin E and beta- carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35.

5. Anon. Mortality in DATATOP: a multicenter trial in early Parkinson’s disease. Parkinson Study Group. Ann Neurol. 1998 Mar;43(3):318-25.

6. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-toco- pherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22.

7. McNeil JJ, Robman L, Tikellis G, et al. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology. 2004 Jan;111(1):75-84.

8. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):154-60.

9. de Gaetano G. Low-dose aspirin and vita- min E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet. 2001 Jan 13;357(9250):89-95.

10. No authors. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55.

11. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet. 2000 Oct 7;356(9237):1213-8.

12. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996 Mar 23;347(9004):781-6.

13. No authors. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):23-33.

14. Riemersma RA. Coronary heart disease and vitamin E. Lancet. 1996 Mar 23;347(9004):776-7.

15. Harrison R, Burr M, Elton P. GISSI-Prevenzione trial. Lancet. 1999 Oct 30;354(9189):1554-5.

16. Verlangieri AJ, Bush MJ. Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr. 1992 Apr;11(2):131-8.

17. Davey GK, Spencer EA, Appleby PN, et al. EPIC-Oxford: lifestyle characteristics and nutrient intakes in a cohort of 33,883 meat- eaters and 31,546 non meat-eaters in the UK. Public Health Nutr. 2003 May;6(3):259-69.

18. Rauma AL, Mykkanen H. Antioxidant status in vegetarians versus omnivores.

Nutrition. 2000 Feb;16(2):111-9.

19. Helman AD, Darnton-Hill I. Vitamin and iron status in new vegetarians. Am J Clin Nutr. 1987 Apr;45(4):785-9.

20. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003 Feb 25;107(7):947-53.

21. van Aalst JA, Burmeister W, Fox PL,

Graham LM. Alpha-tocopherol preserves endothelial cell migration in the presence of cell-oxidized low-density lipoprotein by inhibiting changes in cell membrane fluidity. J Vasc Surg. 2004 Jan;39(1):229-37.

22. Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross sectional study of men aged 50. BMJ. 1997 Mar 1;314(7081):629-33.

23. Fleischauer AT, Simonsen N, Arab L. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer. 2003;46(1):15-22.

24. Solichova D, Melichar B, Blaha V, et al. Biochemical profile and survival in nonagenarians. Clin Biochem. 2001 Oct;34(7):563- 9.

25. Fletcher AE, Breeze E, Shetty PS. Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Am J Clin Nutr. 2003 Nov;78(5):999-1010.

26. Jacobs EJ, Henion AK, Briggs PJ, et al. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J

Epidemiol. 2002 Dec 1;156(11):1002-10.

27. Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW, Jr. Multivitamin use and mortality in a large prospective study. Am J Epidemiol. 2000 Jul 15;152(2):149-62.

28. Available at: www.annals.org/cgi/letters/0000605-200501040-00110v1. Accessed December 17, 2004.

29. Guallar E, Sanz-Gallardo MI, van’t Veer P, et al. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med. 2002 Nov 28;347(22):1747-54.

30. Yoshizawa K, Rimm EB, Morris JS, et al. Mercury and the risk of coronary heart disease in men. N Engl J Med. 2002 Nov 28;347(22):1755-60.

31. Sox HC. Disease prevention guidelines from the US Preventive Services Task Force. Ann Intern Med. 2002 Jan 15;136(2):155-6.

32. Sox HC. Current controversies in screening: cholesterol, breast cancer, and prostate cancer. Mount Sinai J Med. 1999 Mar;66(2):91-101.

33. US Preventive Services Task Force. Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommenda- tions and rationale. Ann Intern Med. 2003 Jul 1. 139(1):51-5.

34. Stone WL, LeClair I, Ponder T, et al. Infants discriminate between natural and synthetic vitamin E. Am J Clin Nutr. 2003 Apr;77(4):899-06.

35. Blatt DH, Pryor WA, Mata JE, Rodriguez- Proteau R. Re-evaluation of the relative potency of synthetic and natural alpha-tocopherol: experimental and clinical observa- tions. J Nutr Biochem. 2004 Jul;15(7):380-95.

36. Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem. 2002 Jul 12;277(28):25290-6.

37. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr. 1998 Apr;67(4):669-84.

38. Handelman GJ, Epstei WL, Peerson J, et al. Human adipose alpha-tocopherol and gamma-tocopherol kinetics during and after 1 year of alpha-tocopherol supplementation. Am J Clin Nutr. 1994 May;59(5):1025-32.

39. Jiang Q, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74(6):714- 22.

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