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 Zinc 80 mg
Vit E 400 IU Copper 2 mg
Lutein and Zeaxanthin were not commercially
available
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.
Fundus photographs from participants in the Age-
Related Eye Disease Study (AREDS) illustrating eyes in
age-related macular degeneration Categories 2 and 3
Age-Related Eye Disease Study Research Group, Arch Ophthalmol 2001;119:1417-1436.
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
Vitamin E Study
Miller, E. R. et. al. Ann Intern Med 2005;142:37-46
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
Common AMD & General Nutritional
Supplements
Formula Ocuvite Preservision ICaps Paul Centrum
Preservision Smoker’s AREDS Harvey’s Silver
Formula Optim-3
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 No No No Yes Yes
Ingredients
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.
Clinical Trials of Vitamin E Supplementation
and Risk for All-Cause Mortality, Ordered by
Dosage of Vitamin E
Miller, E. R. et. al. Ann Intern Med 2005;142:37-46