In a recent meta-analysis of randomized clinical trials, Miller

Brief Communication: The Prevalence of High Intake of Vitamin E from the Use of Supplements among U.S. Adults Earl S. Ford, MD, MPH; Umed A. Ajani, MBBS, MPH; and Ali H. Mokdad, PhD Article Background: People who consume at least 400 IU of vitamin E per day from supplements may be at slightly increased risk for premature mortality. Objective: To estimate the percentage of U.S. adults age 20 years or older who consume at least 400 IU of vitamin E per day through the use of vitamins, minerals, or other dietary supplements. Design: Cross-sectional analysis. Setting: The 1999 2000 National Health and Nutrition Examination Survey. Patients: Representative sample of the civilian, noninstitutionalized U.S. population. Results: Among 4609 adults, 11.3% (95% CI, 9.7% to 13.1%) consumed at least 400 IU of vitamin E per day from supplements. Such intake increased with age, was about equal for men and women, and was more common among white persons (14.1%; CI, 11.9% to 16.7%) than African-American (3.7% [CI, 2.6% to 5.2%]) or Mexican-American persons (3.9% [CI, 2.8% to 5.4%]). The median dietary intake of vitamin E was 8.8 IU per day. Limitations: Information about vitamin E intake was selfreported. Conclusions: The use of vitamin E supplements in dosages of at least 400 IU per day is common among U.S. adults. Measurements: Participants answered questions about the use of vitamins, minerals, or other dietary supplements. Ann Intern Med. 2005;143:116-120. For author affiliations, see end of text. www.annals.org In a recent meta-analysis of randomized clinical trials, Miller and colleagues reported that the intake of vitamin E of at least 400 IU per day from supplements was associated with a small increase in mortality from all causes (1). The recent findings of the Women s Health Study, in which participants consumed 600 IU of vitamin E every other day, were consistent with the results from this meta-analysis (2, 3). Furthermore, the Heart Outcomes Prevention Evaluation researchers linked the use of 400 IU of vitamin E per day to an increased risk for congestive heart failure (4). Vitamin E intake of 400 IU per day or greater can practicably be achieved only through supplementation. Among adults older than 20 years of age who participated in the U.S. Department of Agriculture s 1994 1996 Continuing Surveys of Food Intake by Individuals, the median intake of vitamin E was 5.6 mg of -tocopherol equivalents per day (6.7 IU) for men and 4.0 (4.8 IU) for women (5). Supplemental use of vitamins and minerals has increased in the United States, and supplemental use of vitamin E increased rapidly between 1987 and 2000 (6, 7). The extent to which supplements containing high doses of vitamin E are used in the United States remains incompletely documented, however. Therefore, our objectives were to estimate the percentage of U.S. adults who use supplements leading to intake of vitamin E of 400 IU or greater per day and to examine the social and demographic variations in these estimates. METHODS We used data from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2000 (8). This survey included a representative sample of the civilian, noninstitutionalized U.S. population selected through stratified, multistage sampling. Trained interviewers, using a computer-assisted personal interview system, interviewed participants at home. Subsequently, participants completed additional questionnaires (including a single 24-hour dietary recall); underwent basic neurosensory, anthropometric, fitness, and oral health evaluations; and provided a blood sample at the mobile examination center. The response rate was 81.9% for those interviewed and 76.3% for those examined. An Institutional Review Board at the Centers for Disease Control and Prevention approved the survey. Participants provided informed consent. Participants who responded affirmatively to the question Have you used or taken any vitamins, minerals, or other dietary supplements in the past month? were asked to provide additional details about the dose, frequency, and duration of use. The interviewer also asked to see the containers of the supplements to record information about the name and manufacturer of the supplements. If participants could not produce the containers, interviewers asked them See also: Print Editors Notes... 117 Summary for Patients....I-39 Editorial comment....143 Related letters....150 Web-Only Conversion of figures and table into slides 116 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 www.annals.org

High Vitamin E Intake among U.S. Adults Article Context Vitamin E supplements (400 IU or more daily) have no clear clinical benefits and may be harmful. Contribution Self-reported data from 4609 adults who participated in the 1999 2000 National Health and Nutrition Examination Survey showed that about 11% consumed at least 400 IU of vitamin E daily. Use was highest among older white adults who also consumed other antioxidant supplements. Cautions We do not know the form of vitamin E that adults consumed, but -tocopherol is the form most commonly found in supplements. Implications Many adults may be taking vitamin E supplements that have no proven clinical benefits and might be harmful. The Editors RESULTS Figure 1 shows the numbers of participants who were included in the analyses. The participants who did not have a serum determination of -tocopherol were an average of 2.2 years older (P 0.017) than the other participants, but the percentages who were male, were white, and who had at least a high school education did not significantly differ. Overall, 11.3% (CI, 9.7% to 13.1%) of adults used supplements that led to a daily intake of 400 IU or greater, and 25.7% (CI, 24.0% to 27.5%) consumed less than 400 IU per day from such supplements. As illustrated in the Table, such intake increased with increasing age (P 0.001 for linear trend), was about equal for men and women (P 0.2), and was more common among white persons than African-American (P 0.001) or Mexican- American persons (P 0.001). Participants who had a history of coronary heart disease, angina pectoris, stroke, or diabetes were more likely to use high doses of vitamin E than participants without these conditions (P 0.001 for all age-adjusted differences). to recall this information. We estimated the dietary intake of vitamin E from a single 24-hour recall. Laboratory personnel measured serum concentrations of - and -tocopherol using a Waters Alliance high-performance liquid chromatography system (Waters Corp., Milford, Massachusetts). A detailed description of laboratory quality control procedures used in the survey can be accessed at the Centers for Disease Control and Prevention Web site (9). Among participants age 20 years or older, we estimated the percentage (95% CI) who 1) did not use supplements or used supplements that did not contain vitamin E, 2) consumed less than 400 IU per day from the use of supplements, and 3) used supplements providing at least 400 IU per day. We examined the variation in the intake of vitamin E, 400 IU or greater per day, by the following characteristics of participants: age; sex; race or ethnicity; educational status; presence of chronic conditions (coronary heart disease, angina pectoris, stroke, and diabetes); smoking behavior; strata of blood pressure; serum total cholesterol concentration; and body mass index. We present results only for the 3 major racial or ethnic groups (white, African-American, and Mexican-American) because the sample sizes for the other groups were small. Other results are based on all available data. For 2-sample tests of proportions, we used a t-test. For characteristics with 3 levels, we tested the differences in the intake of vitamin E from supplements with a test for linear trend. We used SUDAAN statistical analysis software (Research Triangle Institute, Research Triangle Park, North Carolina) to account for the complex sampling design of the survey and to produce proper estimates of the standard errors (10). Figure 1. Sample-size flow for 1999 2000 National Health and Nutrition Examination Survey. www.annals.org 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 117

Article High Vitamin E Intake among U.S. Adults Table. Unadjusted Percentages of Adults Aged 20 Years or Older Who Consume 400 IU of Vitamin E per Day from the Use of Vitamin, Mineral, or Dietary Supplements (1999 2000 National Health and Nutrition Examination Survey)* Variable Participants Who Provided Information about Supplement Use Participants Who Provided Information To Allow Estimation of Vitamin E Intake Overall, n Participants Taking Any Supplements, % Participants Taking Supplements Containing Vitamin E, % Overall, n Total 4863 52.0 1.4 40.6 1.3 4609 11.3 0.9 Participants Taking >400 IU of Vitamin E per Day from Supplements, % Age 20 39 y 1693 43.3 1.8 32.7 1.6 1571 4.0 0.7 40 59 y 1345 56.1 1.9 44.5 1.9 1275 12.9 1.5 60 y 1825 63.3 1.7 50.6 2.0 1763 23.2 1.6 Sex Men 2261 46.9 1.5 37.1 1.5 2166 11.2 1.1 Women 2602 56.7 1.7 43.7 1.6 2443 11.4 0.9 Race or ethnicity White 2229 58.2 1.9 46.1 1.8 2093 14.1 1.2 African-American 922 36.0 2.2 26.7 1.8 880 3.7 0.6 Mexican-American 1276 33.3 2.3 24.0 1.8 1224 3.9 0.6 Education Less than high school 1889 34.7 2.1 25.4 1.8 1835 6.7 0.8 High school graduate 1095 48.4 2.2 36.0 2.1 1030 10.0 1.4 More than high school 1863 62.2 1.5 50.4 1.7 1730 14.3 1.4 History of heart attack or coronary heart disease Yes 310 60.9 2.8 47.3 3.6 301 26.2 3.3 No 4523 51.5 1.5 40.3 1.4 4280 10.6 0.9 History of angina pectoris Yes 179 64.3 4.2 45.3 4.5 174 24.9 3.7 No 4659 51.7 1.4 40.5 1.3 4410 10.9 0.9 History of stroke Yes 189 60.9 4.8 48.5 4.6 185 14.5 3.8 No 4670 51.8 1.4 40.4 1.4 4420 11.2 0.9 History of diabetes Yes 479 52.9 3.7 38.9 3.6 461 14.8 2.3 No 4381 51.9 1.5 40.7 1.4 4145 11.0 0.9 Smoking status Current 996 43.0 1.8 30.0 1.6 956 6.1 1.1 Former 1297 61.2 2.1 48.9 1.9 1229 15.0 1.2 Never 2561 52.2 1.9 42.0 1.9 2415 12.1 1.2 Blood pressure status Normal 1520 51.2 2.1 39.6 2.1 1415 9.2 1.1 Prehypertension 1215 48.3 1.8 39.3 1.8 1158 10.1 1.4 Hypertension 1689 57.9 1.7 44.0 1.9 1624 16.8 1.5 Cholesterol status 5.18 mmol/l ( 200 mg/dl) 1958 48.8 1.8 36.9 1.7 1862 9.8 1.0 5.18 6.22 mmol/l (200 240 mg/dl) 1388 56.9 1.8 46.2 1.9 1312 13.7 1.6 6.22 mmol/l ( 240 mg/dl) 767 55.4 2.9 46.2 2.9 718 14.6 1.7 Body mass index 25 kg/m 2 1412 56.3 2.4 45.7 2.2 1321 11.6 1.3 25 30 kg/m 2 1535 51.3 2.0 39.9 2.0 1460 12.7 1.2 30 kg/m 2 1421 48.1 2.0 36.2 2.1 1357 10.6 1.5 *Values reported with a plus/minus sign are means SE. The distribution of concentrations of serum -tocopherol for 3875 participants reflected the intake of vitamin E (Figure 2). For participants who did not use supplements or did not use supplements containing vitamin E, the median serum concentration of -tocopherol was 22.85 mol/l (n 2506); in comparison, participants using supplements had median concentrations of 30.22 mol/l (intake of 400 IU per day; n 953) and 49.03 mol/l 118 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 www.annals.org

High Vitamin E Intake among U.S. Adults Article Figure 2. Concentrations of serum -tocopherol (top) and -tocopherol (bottom) among U.S. adults age 20 years or older by intake of vitamin E from the use of vitamin, mineral, or dietary supplements (1999 2000 National Health and Nutrition Examination Survey). 400 IU per day from such supplements, and 0.30 for participants who did not use supplements or did not consume vitamin E from supplements. Participants who used supplements containing vitamin E commonly used other antioxidants, such as vitamin C or -carotene. The percentages of participants who used supplements containing vitamin C were 84.9% (CI, 80.8% to 89.1%) among participants who consumed 400 IU per day of vitamin E from supplements, 97.9% (CI, 96.7% to 99.2%) among participants who consumed less than 400 IU per day from such supplements, and 6.4% (CI, 5.1% to 7.8%) among participants who did not use supplements or did not consume vitamin E from supplements. For -carotene, these percentages were 50.4% (CI, 42.8% to 58.1%), 66.0% (CI, 61.8% to 70.2%), and less than 1.0%, respectively. For the self-reported use of cholesterollowering medications, these percentages were 19.7% (CI, 14.8% to 24.6%), 7.1% (CI, 5.2% to 9.0%), and 6.3% (CI, 4.9% to 7.8%). Among 4239 participants who attended the mobile examination center and completed the 24-hour dietary recall, the median intake of vitamin E from diet was 7.40 mg of -tocopherol equivalents per day (8.8 IU) and ranged from 0.03 to 153.26 mg of -tocopherol equivalents per day (0.04 to 182.7 IU). Among participants who consumed at least 400 IU per day from supplements, 1 participant s total intake of vitamin E from diet and supplements exceeded 400 IU per day. (intake of 400 IU per day; n 409). The ratios of concentrations of -tocopherol to total cholesterol for the 3 groups were, respectively, 4.47 mol/mmol (n 2494), 5.85 mol/mmol (n 947), and 9.04 mol/mmol (n 408). Serum -tocopherol concentrations were 6.01 mol/l (no supplementation; n 2172), 4.40 mol/l ( 400 IU per day; n 827), and 2.08 mol/l ( 400 IU per day; n 377); the respective ratios of concentrations of - to -tocopherol were 3.61 mol/ mol (n 2161), 6.81 mol/ mol (n 824), and 24.22 mol/ mol (n 358). To examine the Pearson correlation coefficients between log-transformed concentrations of the 2 tocopherols, we used a smaller set of participants (n 1474) who attended the mobile examination center in the morning, had fasted at least 8 hours, and had concentrations of triglycerides measured using a reference method that was performed only among morning attendees. After adjustment for age and concentrations of total cholesterol and triglycerides, the Pearson correlation coefficient was 0.62. The adjusted correlations were 0.48 for participants who consumed at least 400 IU of vitamin E per day from supplements, 0.56 for participants who consumed less than DISCUSSION In this representative sample of U.S. adults, about 11.3% used supplements leading to an intake of vitamin E 400 IU per day or greater. Such intakes were especially high among white participants and those age 60 years or older. Although we could not distinguish among the different forms of tocopherol, -tocopherol is the most common form found in supplements; its predominance is supported by the serum profiles of concentrations of -tocopherol in our analyses. The median dietary intake of vitamin E of about 8.8 IU per day reported by adults in the 1999 2000 NHANES emphasizes the difficulty in achieving intakes of 400 IU per day or greater through diet alone. Vitamin C recycles oxidized -tocopherol to its unoxidized form. Our results indicate that participants who consumed supplements with vitamin E were very likely to be consuming vitamin C. Furthermore, the use of -carotene was also common among people using supplements with vitamin E. This may be of some concern because supplementation with -carotene may increase all-cause mortality (11). Consistent with previous studies, serum concentrations of - and -tocopherol were inversely associated in the 1999 2000 NHANES (12 14). The correlation coefficients were especially strong among users of supplements containing vitamin E. By decreasing circulating concentra- www.annals.org 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 119

Article High Vitamin E Intake among U.S. Adults tions of -tocopherol, supplementation with high doses of -tocopherol may adversely affect health. Our results were based on self-reported data and, therefore, are subject to all of the limitations inherent in such data. About 14% of participants reported using supplements containing vitamin E but could not provide sufficient data to allow an estimation of the amount of intake of vitamin E from this source. We could not separate the use of natural from synthetic forms of vitamin E, tocopherol from other forms of vitamin E, or tocopherols from tocotrienols. If people who consume 400 IU or greater of vitamin E per day are indeed at increased risk for premature death, a sizeable percentage of U.S. adults fall into this risk group. Health care professionals are well situated to ask their patients about the use of various vitamin supplements and offer advice about their judicious use. Furthermore, a report showing that 64% of health care professionals had a daily vitamin E intake of 400 IU or greater (15) suggests that many medical professionals themselves may need to reconsider the use of high doses of vitamin E. From the Centers for Disease Control and Prevention, Atlanta, Georgia. Potential Financial Conflicts of Interest: None disclosed. Requests for Single Reprints: Earl Ford, MD, MPH, Centers for Disease Control and Prevention, 4770 Buford Highway, MS K66, Atlanta, GA 30341. Current author addresses and author contributions are available at www.annals.org. References 1. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase allcause mortality. Ann Intern Med. 2005;142:37-46. [PMID: 15537682] 2. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-304. [PMID: 15753114] 3. Miller ER 3rd, Appel LJ, Guallar E, Pastor-Barriuso R. High-dosage vitamin E supplementation and all-cause mortality [Letter]. Ann Intern Med. 2005;143: 156-8. 4. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293:1338-47. [PMID: 15769967] 5. Maras JE, Bermudez OI, Qiao N, Bakun PJ, Boody-Alter EL, Tucker KL. Intake of alpha-tocopherol is limited among US adults. J Am Diet Assoc. 2004; 104:567-75. [PMID: 15054342] 6. Briefel RR, Johnson CL. Secular trends in dietary intake in the United States. Annu Rev Nutr. 2004;24:401-31. [PMID: 15189126] 7. Millen AE, Dodd KW, Subar AF. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc. 2004;104:942-50. [PMID: 15175592] 8. Centers for Disease Control and Prevention. NHANES 1999-2000 public data release file documentation. Accessed at www.cdc.gov/nchs/about/major /nhanes/currentnhanes.htm on 7 February 2005. 9. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey: laboratory procedures manual. Accessed at www.cdc.gov /nchs/data/nhanes/lab7-11.pdf on 7 February 2005. 10. Research Triangle Institute. SUDAAN User s Manual, Release 8.0. Research Triangle Park, NC: Research Triangle Institute, 2002. 11. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361:2017-23. [PMID: 12814711] 12. Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. Oral alphatocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr. 1985;115:807-13. [PMID: 3998871] 13. Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003;133:3137-40. [PMID: 14519797]] 14. Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L, et al. New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic Biol Med. 2004;36:1-15. [PMID: 14732286] 15. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002;162:1472-6. [PMID: 12090883] 120 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 www.annals.org

Current Author Addresses: Drs. Ford, Ajani, and Mokdad: Centers for Disease Control and Prevention, 4770 Buford Highway, MS K66, Atlanta, GA 30341. Author Contributions: Conception and design: E.S. Ford, A.H. Mokdad. Analysis and interpretation of the data: E.S. Ford, U.A. Ajani, A.H. Mokdad. Drafting of the article: E.S. Ford, A.H. Mokdad. Critical revision of the article for important intellectual content: E.S. Ford, U.A. Ajani, A.H. Mokdad. Final approval of the article: E.S. Ford, U.A. Ajani. Statistical expertise: E.S. Ford. W-30 19 July 2005 Annals of Internal Medicine Volume 143 Number 2 www.annals.org