Life Extension Magazine March 2005
The Making of Killer E
By Terri Mitchell
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.”
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.