E By Caleb Sawyer, MD Faculty Advisor: Kelly Mitchell, MD

Alpha-Tocopherol a.k.a. Vitamin E

E-Facts Plays a role in immune function, DNA repair, other metabolic processes, and in protecting other antioxidants U.S. RDA : 15 mg (22.5 IU) per day Typical Western diet provides 14 mg (21 IU) of Vit E 400 IU = 20 bowls of Total = 2667 bowls of Corn Flakes Upper allowable intake (prior to Meta-Analysis): 1000mg (1500 IU)

Health Hopes of Vitamin E Heart Disease: Mixed results Cancer: Promising but not conclusive Breast cancer: two opposing studies Colon and G.I. cancer: probably no benefit Prostate and bladder cancer: possible benefit Alzheimer’s: theoretical but not well studied

Vitamin E & Cataracts 1998: “Antioxidant vitamins and nuclear opacities: the longitudinal study of cataract” Cataract risk reduced by ½ in Vit E supplement users 764 participant observational study (low significance) However, 1997: “Long-term supplementation with alpha- tocopherol and beta-carotene and age-related cataract” No benefit to Middle-aged male smokers taking vitamin E supplements on the incidence of cataract formation

Age-Related Eye Disease Study (AREDS) Evaluated risk of AMD & Cataract advancement Dosing Vit A 28,640 IU Vit C 500 mg Vit E 400 IU Lutein and Zeaxanthin were not commercially available Zinc 80 mg Copper 2 mg

Early AMD. People with early AMD have, in one or both eyes, either several small drusen or a few medium- sized drusen; these people do not have vision loss from AMD. Intermediate AMD. People with intermediate AMD have, in one or both eyes, either many medium-sized drusen or one or more large drusen; in these people, there is usually little or no vision loss. Advanced AMD. In addition to drusen, people with advanced AMD have geographic atrophy or CNV in at least one eye.

Age-Related Eye Disease Study Research Group, Arch Ophthalmol 2001;119: Fundus photographs from participants in the Age- Related Eye Disease Study (AREDS) illustrating eyes in age-related macular degeneration Categories 2 and 3

AREDS Conclusions Patients with intermediate AMD or uniocular advanced AMD (category 3 & 4) should consider high-dose antioxidants and zinc Categories 1 & 2 had too little statistical power to draw conclusions Reduce risk of AMD advancement by 25% Reduce risk of visual acuity loss by 19% No effect on the risk of cataract development

Problems with Beta-Carotene in Smokers Alpha-tocopherol, beta-carotene (ATBC) cancer prevention study Controlled, randomized study of 29,000 middle-aged smokers High-dose Beta-carotene resulted in increased incidence of lung, prostate, and stomach cancer Vit E resulted in lower incidence of prostate and colorectal cancer, but higher incidence of stomach cancer “Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease,” NEJM Randomized, controlled study of 18,314 smokers, former smokers, and workers exposed to asbestos High-dose beta-carotene group had a relative risk of lung cancer of 1.28 No significant risk of other forms of cancer

2005 Annals of Int Med: “Meta-Analysis: High- Dosage Vitamin E Supplementation May Increase All-Cause Mortality” Three previous meta-analyses that did not consider the dose-dependent effect of vitamin E concluded that vitamin E was neither beneficial nor harmful. New Conclusion based on 19 randomized controlled trials: High-dosage (>=400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

Miller, E. R. et. al. Ann Intern Med 2005;142:37-46

AREDS

Miller, E. R. et. al. Ann Intern Med 2005;142:37-46 Vitamin E Study

Criticisms “Trials that tested high dosages involved adults with chronic diseases, and these findings may not be generalizable to healthy adults.” “Some trials evaluated multivitamin combinations.” “The findings don't clearly establish the lowest dosage of supplementation that is associated with increased mortality risk.” Excluded studies in which fewer than 10 people died.

NEI Response “After careful study and interpretation of the data from the paper in Annals of Internal Medicine, the NEI researchers have concluded that taking a recommended 400 international units (IU) of vitamin E each day, as part of the AREDS formulation, does not increase the risk of death of persons at risk for advanced AMD.” “In the new study, the data seem to show that people taking particularly high doses of vitamin E (500 IU to 2000 IU) may have a slightly increased risk of death. However, taking 400 IU vitamin E per day did not increase the risk of death in a total of 15,000 patients studied in several different clinical trials.” -NEI Website, “Review Supports Vitamin E Dosage in AREDS,” Dec 14, 2004

Conclusions 400 IU daily cannot be said to change the risk of all-cause mortality Greater than 400 IU daily may increase the risk of all-cause mortality Therefore, regarding AMD and nutritional supplimentation: Only those with Intermediate or unilateral advanced AMD should take the AREDS formula Patients taking the AREDS formula should be cautioned against taking additional vitamin E containing supplements

FormulaOcuvite Preservision Preservision Smoker’s Formula ICaps AREDS Paul Harvey’s Optim-3 Centrum Silver Vit A28,640 IU 20,000 IU3500 IU Vit C452 mg 1200 mg50 mg Vit E400 IU 440 IU40 IU Zinc69.6 mg 60 mg15 mg Copper1.6 mg 8 mg2 mg Lutein10 mg383 mg250 mcg Other Ingredients No Yes Common AMD & General Nutritional Supplements

References Age-Related Eye Disease Study Research Group. “A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss,” AREDS Report No. 8, Arch Ophthalmol. October 2001;119: Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. “Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.” Lancet Oct 2;364(9441): Gilbert S. Omenn, M.D., Ph.D., Gary E. Goodman, M.D., M.S., Mark D. Thornquist, Ph.D., John Balmes, M.D., Mark R. Cullen, M.D., Andrew Glass, M.D., James P. Keogh, M.D., Frank L. Meyskens, M.D., Barbara Valanis, Dr.P.H., James H. Williams, M.D., Scott Barnhart, M.D., M.P.H., and Samuel Hammar, M.D. “Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease,” NEJM. May 2, 1996; Volume 334: Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. A report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes Food Nutrition Board. Washington, DC: National Academies Pr; Leske MC, Chylack LT Jr., He Q, Wu SY, Schoenfeld E, Friend J, Wolfe J. Antioxidant vitamins and nuclear opacities: The longitudinal study of cataract. Ophthalmology 1998;105: Miller, Edgar R. III, MD, PhD; Roberto Pastor-Barriuso, PhD; Darshan Dalal, MD, MPH; Rudolph A. Riemersma, PhD, FRCPE; Lawrence J. Appel, MD, MPH; and Eliseo Guallar, MD, DrPH. “Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality,” Annals of Internal Medicine, January 4, 2005; 142: NEI Website, “Review Supports Vitamin E Dosage in AREDS,” Dec 14, National Institutes of Health Office of Dietary Supplements fact sheet. Teikari JM, Virtamo J, Rautalahti M, Palmgren J, Liesto K, Heinonen OP. Long-term supplementation with alpha-tocopherol and beta-carotene and age-related cataract. Acta Ophthalmol Scand 1997;75:

Miller, E. R. et. al. Ann Intern Med 2005;142:37-46 Clinical Trials of Vitamin E Supplementation and Risk for All-Cause Mortality, Ordered by Dosage of Vitamin E