EBy 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;119:1417-1436.

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. 1996 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

Formula Ocuvite Preservision

Preservision Smoker’s Formula

ICaps AREDS

Paul Harvey’s Optim-3

Centrum Silver

Vit A 28,640 IU 28,640 IU 20,000 IU 3500 IU

Vit C 452 mg 452 mg 452 mg 1200 mg 50 mg

Vit E 400 IU 400 IU 400 IU 440 IU 40 IU

Zinc 69.6 mg 69.6 mg 69.6 mg 60 mg 15 mg

Copper 1.6 mg 1.6 mg 1.6 mg 8 mg 2 mg

Lutein 10 mg 383 mg 250 mcg

Other Ingredients

No No No Yes 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;119:1417-1436.

Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. “Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.” Lancet. 2004 Oct 2;364(9441):1219-28.

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 334:1150-1155.

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; 2000.

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;105:831-6.

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; 142:37-46.

NEI Website, “Review Supports Vitamin E Dosage in AREDS,” Dec 14, 2004. http://www.nei.nih.gov/news/statements/vitamine.asp

National Institutes of Health Office of Dietary Supplements fact sheet. http://ods.od.nih.gov/factsheets/vitamine.asp

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;75:634-40.

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