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High dose vitamin E supplementation and all-cause mortality.
Submit responseDear Editors:
When a scholarly journal prints an article, it is common for the matter to end with the authors' rejoinder. However, since we were not able to review the response by Miller et al. prior to publication and because they misstate our position, we are writing this followup for clarification. We did not suggest that the authors *should* have fitted a linear-linear spline. Rather, we pointed out that they *could* have fitted a linear-linear spline, among other models. Many of the authors' conclusions follow not from the data but from the form of the particular model they chose. Had they chosen the linear-linear spline, they would have written a different paper. Other models could be fitted to the data, and they, too, lead to their own sets of conclusions.
We agree that the focus should not be on statistical significance. Vitamin E has been the largest consumed supplement.1 If there is a suggestion--statistically significant or not--that it may be harmful, then there is an important public health issue that needs to be addressed. However, while the data allow for the possibility that megadoses of vitamin E may prove harmful in compromised populations, we find no evidence from these data that doses of *400 IU/d or less* are harmful to healthy populations. This includes the 10 year Women's Health Study in which a dose of 600 IU every other day gives a risk ratio of 1.04 with a 95% confidence interval of (0.93- 1.16; p=0.53) for all cause mortality2. In addition, the authors reported a significant 24% reduction in death due to cardiovascular diseases in vitamin E supplemented group2 (RR, 0.76; 95% CI, 0.59-0.98; p=0.03).
Gerard E. Dallal, PhD* Joseph Lau, MD+ Mohsen Meydani, DVM, PhD* Simin Nikbin Meydani, DVM, PhD*§
*Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, §Department of Pathology, Sackler Graduate School of Biochemical Sciences, Tufts University, Boston, Massachusetts, +Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, Massachusetts,
References 1Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004; 160:339-349.
2Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005; 294: 56-65.
Conflict of Interest:
None declared
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New Evidence on Vitamin E Safety
Submit responseNew Evidence on Vitamin E Safety
An important review published in the American Journal of Clinical Nutrition in April, 2005 sheds new light on the safety of Vitamin E.
Statistical experts have already largely discredited the extremely poor meta-analysis announced last Fall by the medical journal Annals of Internal Medicine that re-analyzed only 19 studies on Vitamin E. The experts’ overwhelmingly negative responses are posted on that journal’s web site. Combining studies that did not use consistent forms or doses unfairly added variables while ignoring positive effects of the vitamin. The authors acknowledged that their findings do not apply to healthier populations and are not definitive.
The new review of Vitamin E published in the American Journal of Nutrition on April 1, 2005 states that after adjusting for variables in supplementation, the actual dose of Vitamin E that may have been slightly harmful to these seriously ill patients was statistically significant only at levels where patients took over 2,000 IU per day, well above the 400 IU suggested by the original Annals analysis.
A recent JAMA article on Vitamin E also used very sick patients but subjected positive data on Vitamin E’s benefits to different, more stringent statistical methods than the equally skimpy negative data to produce a negative result and thereby tainting the study, which had been already been rejected by the journal Lancet a year earlier.
The national Institute of Medicine’s safe upper limit of 1,500 I.U. per day of natural Vitamin E is based on their own expert review of hundreds of well-designed studies.
The National Institutes of Health (NIH) supports the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT), a multi-center, long-term, double-blind, randomized trial that includes 35,534 men age 55 and older taking 400 IU of vitamin E daily to verify earlier evidence of it preventing prostate cancer. NIH researchers carefully examined the data from these few negative reports and decided not to change their protocol, still believing that Vitamin E at this dose is unlikely to cause any harm to their patients.
This confirms the new American Journal of Nutrition review stating that there is no good evidence that levels of Vitamin E under 1,600 IU have been shown to increase health risks.
Two large observational studies (the Nurses' Health Study and the Health Professionals Follow-up Study) show that people taking Vitamin E supplements of 400 IU or more for at least two years had between 20-40% reduction in coronary heart disease. In the GISSI Prevention Trial of 11,000 heart attack survivors, Vitamin E reduced the number both of sudden deaths and deaths due to cardiovascular disease.
The scientific method of giving only one isolated nutrient has generated some brutal publicity for individual members of the antioxidant “family” because antioxidants function inter-dependently. For example, Beta-carotene has been cited in one study as putting smokers at greater risk of lung cancer, but a more thorough follow up analysis - looking at their diet plus other dietary supplements taken - revealed that the smokers’ actual danger was due to low total antioxidant levels.
One caution is that people should not try to take a high dose of any one supplement without considering that it may increase our need for other nutrients. And elderly, sick people especially need a more holistic approach, rather than using a single nutrient in high doses as if it were a drug. Nutrients just don’t work well in isolation from each other. Vitamins are essential to health and life, but the average American gets only 1/3 of the recommended daily intake of Vitamin E, the amount that the Institute of Medicine determined to be needed by the typical adult to prevent serious illnesses. Most people would benefit from taking a multiple vitamin and a Vitamin E supplement, and it would be even safer than just the Vitamin E alone.
There are also differences between natural and synthetic Vitamin E, with most studies using only the synthetic forms, which are composed of different-shaped molecules only half as effective as natural Vitamin E. Natural Vitamin E is called d-alpha tocopherol and synthetic Vitamin E is called dl-alpha tocopherol. It is known that alpha tocopherol can block absorption of gamma tocopherol, an important antioxidant. Vitamin E complexes with several forms of natural tocopherols, along with the related tocotrienols, are far better than just one kind of Vitamin E. The alpha forms have preferential absorption versus the other forms, for both tocopherols & tocotrienols, making it important to have the right balance so all can work together, as they do in healthy foods.
People with serious heart diseases are more likely to take a Vitamin E supplement than the general population, but a single supplement may not work very quickly or effectively on these seriously ill people and should not be blamed for their illnesses without some more convincing science to back it up.
There is no published evidence that the average person taking a mixture of antioxidants is at greater risk of any disease, but plenty of studies show that people eating a variety of antioxidant nutrients receive some protection from various diseases. In the case of antioxidants, there is safety in numbers.
Neil E. Levin, CCN, DANLA Saint Charles, Illinois
Neil E. Levin is a professional member of the International & American Associations of Clinical Nutritionists. He works as a nutrition educator and product formulator for the natural products industry.
Neil is a member of the Scientific Council of the national Clinical Nutrition Certification Board and has a Diplomate in Advanced Nutritional Laboratory Assessment.
Neil is also the president of Nutrition for Optimal Health Association, Inc. (NOHA: www.nutrition4health.org), a not-for-profit nutrition education corporation based in Winnetka, Illinois.
MAIN REFERENCES:
1. Margaret E. Wright , Susan T. Mayne, Rachael Z. Stolzenberg- Solomon, Zhaohai Li, Pirjo Pietinen, Philip R. Taylor, Jarmo Virtamo and Demetrius Albanes. American Journal of Epidemiology. July 2004. Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers. http://aje.oupjournals.org/cgi/content/abstract/160/1/68?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=beta+carotene&andorexactfulltext=and&searchid=1100534768534_1530&stored_search=&FIRSTINDEX=0&sortspec=relevance&fdate=7/1/2004&tdate=7/31/2004&journalcode=amjepid
2. Edgar R. Miller, 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. High-dose vitamin E supplementation may increase all-cause mortality, a dose response meta- analysis of randomized trials. Annals of Internal Medicine: Online: Nov. 10, 2004: Print: 4 January 2005 | Volume 142 Issue 1 http://www.annals.org/cgi/content/full/0000605-200501040-00110v1 http://www.annals.org/cgi/content/short/142/1/37 http://www.annals.org/cgi/eletters/0000605-200501040-00110v1
3. Satia-Abouta J, Kristal AR, Patterson RE, Littman AJ, Stratton KL, White E. Dietary supplement use and medical conditions. Am Journal Preventive Medicine 24:43-51, January 2003. http://www.ajpm-online.net/article/PIIS0749379702005718/fulltext
4. Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003 Oct;133(10):3137-40 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14519797
5. The Lewin Group, DaVanzo, J. et al. Improving Public Health, Reducing Health Care Costs: An Evidence-Based Study of Five Dietary Supplements. September 22, 2004. http://www.supplementinfo.org/contentman/anmviewer.asp?a=156&z=14
6. The Lewin Group, Al Dobson, Ph.D., et al. A Study of the Cost Effects of Daily Multivitamins for Older Adults. Prepared for: Wyeth Consumer Healthcare http://www.lewin.com/NR/rdonlyres/exul3vts44kvq5kr35iw6vt3sc6nhtmj3hwope245srdtp3iw7bco4dctska6gilvhewvhivcbujnl/StudytheCostEffectsDailyMultivitaminsforOlderAdult.pdf
7. Richer S, Stiles W, Statkute L et al. Double-masked, placebo- controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75:216-30. http://www.nutrition4health.org/NOHAnews/Biographies/April%202004%20Optometry%20LAST%20Study.pdf
8. John N Hathcock, Angelo Azzi, Jeffrey Blumberg, Tammy Bray, Annette Dickinson, Balz Frei, Ishwarlal Jialal, Carol S Johnston, Frank J Kelly, Klaus Kraemer, Lester Packer, Sampath Parthasarathy, Helmut Sies and Maret G Traber. REVIEW ARTICLE: Vitamins E and C are safe across a broad range of intakes. American Journal of Clinical Nutrition, Vol. 81, No. 4, 736-745, April 2005. http://www.ajcn.org/cgi/content/full/81/4/736
Conflict of Interest:
Formulator for dietary supplement manufacturer, but this is my own response.
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Does Vitamin E Supplementation With 400 IU/d Significantly Increase All-Cause Mortality?
Submit responseA meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality among 19 clinical trials concluded that high-dosage (greater than or equal to 400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided, despite stated important limitations of the meta-analysis (1). The data suggest daily supplementation with less than 400 IU/d is not harmful and possibly slightly beneficial. The trials using 500 IU/d or more are extremely heterogeneous in risk and in summary suggest harm but with uncertain magnitude and confidence. The message for supplementation at the intermediate level 400 IU/d, commonly found in popular supplements is less clear, although the authors include it with the high-dose, possibly harmful, levels.
To explore this in an alternative analysis, we fit a Bayesian hierarchical model (2) following the authors’ model structure: a quadratic -linear segmented 2-level hierarchical logistic regression, with knot at 400 IU. To construct confidence bands for risk differences we used Bayesian credible intervals which have correct frequentist coverage probabilities in nonparametric regression (3).
Our risk difference trend agrees very closely with Miller et al in shape, including the risk difference/10,000 at low dose (20 IU/d: -28; - 22–Miller) and high dose (2000 IU/d; 56; 66–Miller). Our curve crosses from benefit to harm at 244 IU/d (150 IU/d–Miller). Specifically, we found the following unadjusted risk differences per 10,000 for different vitamin E dosages: 20 IU/d –28 (-131 to 0), 50 IU/d –24 (-131 to 0.6); 100 IU/d –15 (-84 to 6), 200 IU/d –3 , 400 IU/d 14 (-13 to 86), 500 IU/d 19 (-8 to 115), 1000 IU/d 39 (-0.2 to 219), and 2000 IU/d 56 (0 to 267). Risk ratios for the same doses were 0.95, 0.96, 0.98, 0.996, 1.02, 1.03, 1.06, and 1.10.
Our estimates of risk difference for various dosages are similar to Miller, and although our 95% Bayesian credible intervals for the risk difference are wider they (almost) achieve statistical significance at 1000 IU/d, similar to Miller. The pattern is similar for the risk ratio, in contrast to Miller who declared significance beginning at 500 IU/d.
Our similar but alternative analysis finds, as does Miller, numerically increasing mortality risk as vitamin E dosage increases. The risk estimates differ trivially in magnitude but somewhat in statistical confidence of consistency with, or of departure from, “no effect.” We find no statistically significant effect of vitamin E on mortality until 1000 IU/d. In particular, we find no persuasive statistical support for inclusion of 400 IU/d in a caution about high doses and mortality. Differences in results may reflect different software and methodology, permitting competing results where small differences are observed and further cautioning against over-interpretation. Additional analyses are required to more firmly establish dose-effect mortality characteristics of vitamin E supplementation.
Roy C. Milton Jonghyeon Kim The EMMES Corporation Rockville, MD rmilton@emmes.com
References
1. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Int Med 2005;142:37-46
2. Spiegelhalter D, Thomas A, Best N. WinBUGS Version 1.4 User Manual. Medical Research Council Biostatistics Unit. Cambridge: 2004.
3. Wahba G. Bayesian confidence intervals for the cross validated smoothing spline. Journal of Royal Statistical Society Series B 1983;45:133-150.
Conflict of Interest:
None declared
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Comment
Submit responseWith respect to the doses of this study in which the authors divide this meta analysis and beyond the expressions for Vitamin E used, the range considered does not agree with the broad safe range for this vitamin. Due to this, we believe that, better than using the number of deaths as an exclusion criteria, it would be interesting to know the causes of death.
Conflict of Interest:
None declared
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Authors response to submitted letters
Submit responseTo the Editor;
Since the publication of our vitamin E dose response meta-analysis (1), we have received hundreds of emails, letters, and phone calls as well as 38 letters to the Editor submitted electronically. Annals has asked us to prepare a written response to 10 selected letters. Blatt et al. and Krishnan et al. hypothesize that natural vitamin E supplements have greater benefit than synthetic vitamin E supplements, even though no trial has directly compared them on mortality outcomes. In response, we have performed a subgroup analysis comparing the four trials using natural supplements, all high dosage ( 400 IU/d), with high dosage trials using the synthetic form. The relative risks (95% CI) for all cause mortality in the four trials that provided natural vitamin E were 1.00 (0.89 to 1.12) in HOPE (2), 1.83 (0.88 to 3.78) in VECAT (3), 1.22 (0.86 to 1.73) in CHAOS (4,5), and 1.09 (0.72 to 1.66) in SPACE (6). The pooled relative risk comparing vitamin E to control was 1.04 (95% CI 1.00 to 1.07) in the high dosage trials of synthetic vitamin E and 1.05 (95% CI 0.97 to 1.13) in the high dosage trials of natural vitamin E. There was no evidence for a differential effect of synthetic vs. natural sources of vitamin E (P heterogeneity = 0.79).
Hemila, Krishnan et al., Lim et al., Marras et al., and Meydani et al. were concerned about the generalizability of our findings to healthy populations, since many of the high dosage vitamin E trials enrolled participants with chronic diseases. In general, trials enroll high-risk individuals to increase study power. When interventions are shown effective in high-risk populations, subsequent trials are conducted in low risk populations, and the same relative effects are often observed in low risk as in high risk populations (e.g. statin trials in primary prevention). As for vitamin E, the findings of the Women*s Health Study, a large primary prevention trial presented after the publication of our meta-analysis (7), suggest that the mortality increase that we observed with vitamin E is likely to apply to healthier groups. In this study, 39,876 healthy women were randomized to 600 IU of vitamin E on alternate days or placebo for 10 years. At the end of follow-up, there were 636 deaths in the vitamin E group and 615 in the placebo group. This increase in mortality (relative risk 1.04; 95% CI 0.93 * 1.16), albeit non significant in this individual trial, is consistent with the findings of our meta-analysis.
Meydani et al. argue that in our dose response meta-analysis we should have used a model with a constant effect of vitamin E up to a certain change-point dose and a linear effect above it. This model is problematic for a variety of reasons. First, it forces the effect of vitamin E to be constant over a wide range of low doses, an implausible assumption from a biological standpoint. Second, it forces a sharp change in effect at the chosen change-point dose, which is implausible in population studies even if there were sharp change-point effects in individual subjects (8). Finally, the conclusions from this model largely depend on the chosen change-point, but this choice is difficult from a statistical perspective, and the sequential evaluation of change-points with selection of the best fitting model underestimates the uncertainty in the final model (9). Our quadratic-linear spline model overcomes these difficulties and, contrary to the implications of Meydani et al., it does not force a harmful effect above 150 IU/d of vitamin E. Meydani argues that higher risk for mortality is not evident until the dose exceeds 400 IU/d, instead of 150 IU/d as we describe. We indicated in our paper that establishing the precise dose of vitamin E at which the relative risk of mortality increases above 1 is very difficult. However, as shown also by the findings of the large Women*s Health Study described above, it is highly likely that this threshold is below 400 IU/d.
DeZee et al. question our use of a hierarchical logistic regression model as opposed to traditional meta-regression. We believe that our model is more appropriate because it produces the same results that would be obtained if we had individual patient data on randomized treatment assignment, trial dose, and survival status. In fact, the results of their re-analysis of our data using traditional meta-analysis techniques are very similar to ours, and it is hard to believe that different conclusions should be obtained from their analysis and from ours. As argued in our paper, the dose of vitamin E is likely to be the explanation for the heterogeneity of study results identified by DeZee et al. in their letter.
Possolo re-analyzed our data using a non-parametric, locally quadratic weighted regression model and also found a positive but statistically non- significant association between vitamin E dose and increased mortality. It is difficult to evaluate this analysis based on the information provided in the letter, but we note that weighted regression routines available in general statistical packages are inadequate for meta- analysis, and specialized meta-regression programs are needed to obtain correct standard errors and confidence intervals (10).
DeZee et al., Jialal et al., and Lim et al. criticize our decision to exclude trials with less than 10 deaths total. We decided a priori to exclude studies of less than 1 year of follow-up or less than 10 deaths total as we suspected that a variety of small or short term trials, designed primarily to evaluate the effect of vitamin E on physiological intermediate outcomes, would not collect or report mortality data systematically. On the other hand, it is hard to imagine trials designed to evaluate the effect of vitamin E supplements on clinical outcomes or mortality, the objective of our meta-analysis, with less than 10 deaths total. Additionally, there is no a priori reason to believe that trials with less than 10 deaths would quantitatively differ from larger trials, or that excluding such trials would result in biased estimates of effect. Furthermore, when we compiled data from 11 trials with less than 10 deaths, the number of deaths among participants assigned to vitamin E exceeded the number of deaths among participants assigned to placebo (22 vs. 18 deaths, respectively; reference list available upon request).
Jialal et al. mention two trials of vitamin E supplementation showing a beneficial effect on surrogate markers of atherosclerosis. The Transplant -associated Atherosclerosis study, a small trial (N = 40) that reported no deaths, showed ultrasonographic evidence for benefit among heart transplant recipients (11). The Antioxidant Supplementation and Atherosclerosis Prevention study (ASAP), a 2 X 2 factorial design of vitamin E (272 IU/d) and vitamin C (1000 mg/d) in hypercholesterolemic smokers, reported that vitamin E supplementation reduced carotid artery disease progression (12,13). However, the mortality data from the ASAP trial was consistent with our findings, as there were 4 deaths in the vitamin E arms and 2 deaths in the non-vitamin E arms after 3 years of follow-up. At year 3, all participants in the vitamin arms were given an open label combination of vitamins C and E, while the placebo arm continued without supplementation. At 6 years, the relative risk for mortality was higher in those assigned to the combination of vitamins compared to placebo (19 deaths in 390 participants taking supplements vs. 3 deaths in 130 taking no supplements). On a final note, other trials have shown greater progression of atherosclerosis among those assigned to vitamin E (14-16).
Carter suggests that the HATS trial, that we excluded since it had only 2 deaths, demonstrated that antioxidant vitamin supplementation (including 800 IU/d of vitamin E) provided angiographic evidence of slowed progression of coronary artery disease (17). On the contrary, the HATS trial showed that antioxidant supplementation alone did not slow the progression of coronary plaques and that, surprisingly, antioxidants diminished the protective effect of simvastatin-niacin at slowing the progression of coronary disease.
Several authors have also expressed concerns over our choice of total mortality as an endpoint in view of the beneficial effects of vitamin E supplementation on physiological variables related to oxidative stress. While these surrogate markers can provide mechanistic insights, their clinical relevance is uncertain. In contrast, all cause mortality, the outcome used in our meta-analysis, has unambiguous clinical relevance.
In conclusion, 19 randomized trials that enrolled together over 135,000 participants have failed to document a survival benefit with vitamin E supplementation. In contrast, we have provided important evidence that high dosage vitamin E supplementation may increase total mortality. While future trials will refine the estimates of the effect of vitamin E supplementation and of the dose at which the relative risk of mortality exceeds 1, we stand by our conclusions that use of high dosage vitamin E supplementation should be avoided.
REFERENCES
(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 2005;142:37-46.
(2) 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;342:154-60.
(3) McNeil JJ, Robman L, Tikellis G, Sinclair MI, McCarty CA, Taylor HR. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology 2004;111:75-84.
(4) Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-86.
(5) Mitchinson MJ, Stephens NG, Parsons A, Bligh E, Schofield PM, Brown MJ. Mortality in the CHAOS trial. Lancet 1999;353:381-82.
(6) Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356:1213-18.
(7) Lee, I-M., Cook, N. R., Gaziano, J. M., Gordon, D., Ridker, P. M., Manson, J. E., Hennekens, C. H., and Buring, J. E. A randomized trial of vitamin E in the primary prevention of cardiovascular disease in 39,876 women: The Women's Health Study. American College of Cardiology (ACC) - Annual Scientific Session March 7, 2005. Available online at http://www.acc05online.acc.org/highlights/keyLectures.aspx?sessionId=8030&&date=7. Accessed March 23, 2005.
(8) Pastor-Barriuso R, Guallar E, Coresh J. Transition models for change-point estimation in logistic regression. Stat Med 2003;22:1141-62.
(9) Goetghebeur E, Pocock SJ. Detection and estimation of J-shaped risk-response relationships. J R Stat Soc [A] 1995;158:107-21.
(10) Egger M, Smith GD, Altman DG, eds. Systematic reviews in health care. Meta-analysis in context. 2nd ed. London: BMJ Books; 2001.
(11) Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D et al. Effect of vitamins C and E on progression of transplant- associated arteriosclerosis: a randomised trial. Lancet 2002;359:1108-13.
(12) Salonen JT, Nyyssonen K, Salonen R, Lakka HM, Kaikkonen J, Porkkala-Sarataho E et al. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Intern Med 2000;248:377-86.
(13) Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH 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;107:947-53.
(14) Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 2001;103:919-25.
(15) Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR et al. Alpha-tocopherol supplementation in healthy individuals reduces low- density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation 2002;106:1453-59.
(16) Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 2002;288:2432-40.
(17) Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
Conflict of Interest: None declared
Conflict of Interest:
None declared
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Some weaknesses in the methods of meta-analysis by Miller et al.
Submit responseA recently published meta-analysis by Miller et al. concluded that high-dosage vitamin E supplements may increase all-cause mortality (1). We question some methods of this meta-analysis. In a separate article, we will discuss some effects of vitamin E consistent with the dose-response relationships observed by Miller et al.
Supplements labeled vitamin E contain either RRR-alpha-tocopherol (the only naturally occurring stereoisomer of alpha-tocopherol) or synthetic all-rac-alpha-tocopherol (a mixture of RRR-alpha-tocopherol with seven non-natural stereoisomers). Miller et al. combined data from clinical trials that administered either RRR- or all-rac-alpha-tocopherol. This is not appropriate even though there are no known differences in the symptomatic effects of RRR- and all-rac-alpha-tocopherols. By definition, products that are different mixtures of stereoisomers are not bioequivalent and are not therapeutic equivalents (i.e., generic substitutes for each other) because most biologic processes occur in a highly stereospecific manner (2, 3). RRR- and all-rac-alpha-tocopherols are comparably potent antioxidants in vitro (4) but likely differ in their antioxidant effects in vivo because of variations in their bioavailability (5). RRR- and all-rac-alpha-tocopherols will markedly differ in their many non-antioxidant effects that involve specific interactions with chiral molecules in the cytoplasm and nuclei of most cells (6-8).
Miller et al. expressed the dosage of vitamin E supplements in international units (IU) of vitamin E activity, but by definition, IU of vitamin E activity refers only to the potency of RRR- and all-rac-alpha- tocopherols for preventing or treating symptoms of vitamin E deficiency (9, 10). The units for dosage should be milligrams in studies that assess the risk of adverse effects of RRR- or all-rac-alpha-tocopherol (10).
The meta-analysis by Miller et al. excluded 12 clinical trials that reported fewer than 10 deaths each. However, Collins states that a meta- analysis minimizes the risk of bias only if it is ¡§a systematic overview of the totality of the evidence from all relevant unconfounded randomized trials(11). In a meta-analysis intended to assess the relative risk of death, Miller et al. create the appearance of bias by excluding clinical trials that show a low rate of death.
Miller et al. only assessed the association between death and randomization to the vitamin E group, but did not assess the compliance of study participants. One method of assuring compliance in clinical trials of vitamin E supplementation is to measure the plasma concentration of alpha-tocopherol in every participant in both the vitamin E group and the placebo group. As far as we know, the Cambridge Heart Antioxidant Study (CHAOS) (12) is the only vitamin E trial that administered only alpha- tocopherol or placebo and measured plasma alpha-tocopherol concentrations in every participant. The CHAOS study found that only 6 out of 38 cardiovascular deaths in the alpha-tocopherol group were in patients known to be compliant with study protocol, 21 were in patients known to be non- compliant, and 11 were in patients for whom compliance was unknown (13).
However, CHAOS is the only trial of vitamin E supplementation that administered more than one dosage of alpha-tocopherol and some observations of the CHAOS study are consistent with the conclusion by Miller et al. that risk of mortality increases with dosages greater than 400 IU/d. The CHAOS study observed cardiovascular deaths in 2.0% of patients taking RRR-alpha-tocopherol 400 IU/day, 2.4% of patients taking placebo, and 3.1% of patients taking RRR-alpha-tocopherol 800 IU/day. Similarly, non-fatal myocardial infarction occurred in 0.20% of patients taking RRR-alpha-tocopherol 400 IU/day versus 2.0% of patients taking RRR- alpha-tocopherol 800 IU/day. We agree with Miller et al. that it is necessary to determine dose-effect relationships for vitamin E, and we recommend that future clinical trials of vitamin E use only natural RRR- alpha-tocopherol.
David H. Blatt, M.D., Good Samaritan Regional Medical Center, Corvallis, Oregon 97330
William A. Pryor, Ph.D., Biodynamics Institute, Louisiana State University, Baton Rouge, Louisiana 70803
1. Miller ER, 3rd, 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.
2. Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics. Stamford, CT: Appleton-Lange, 1999.
3. Food and Drug Administration Center for Drug Evaluation and Research. Approved Drug Products with Therapeutic Equivalence Evaluations, Preface to 24th Edition. United States Pharmacopeia Dispensing Information, 24th Edition, Volume III, Approved Drug Products and Legal Requirements. Greenwood Village, CO: Micromedex, 2004.
4. Kamal-Eldin A, Appelqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 1996; 31:671-701.
5. Blatt DH, Pryor WA, Mata JE, Rodriguez-Proteau R. Re-evaluation of the relative potency of synthetic and natural alpha-tocopherol: experimental and clinical observations. J Nutr Biochem 2004; 15:380-95. 6. Zingg JM, Azzi A. Non-antioxidant activities of vitamin E. Curr Med Chem 2004; 11:1113-33.
7. Rimbach G, Minihane AM, Majewicz J, Fischer A, Pallauf J, Virgli F, Weinberg PD. Regulation of cell signalling by vitamin E. Proc Nutr Soc 2002; 61:415-25.
8. Meydani SN, Claycombe KJ, Sacristan C. Vitamin E and Gene Expression. In: Moustaid-Moussa N, Berdanier CD, Eds. Nutrient-Gene Interactions in Health and Disease. Boca Raton: CRC Press, 2001.
9. United States Pharmacopeial Convention. The Pharmacopeia of the United States, 27th Revision, and the National Formulary, 22nd Edition. Rockville, MD: United States Pharmacopeial Convention, Inc, 2004.
10. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press, 2000.
11. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews. Stat Med 1987; 6:245-54.
12. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347:781-6.
13. Mitchinson MJ, Stephens NG, Parsons A, Bligh E, Schofield PM, Brown MJ. Mortality in the CHAOS trial. Lancet 1999; 353:381-2.
Conflict of Interest:
None declared
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Vitamin E: Good Science Requires a Precisely Defined Intervention
Submit responseTo the editor: Vitamin E is not a single entity. The vitamin E group includes alpha, beta, gamma and delta tocopherols and tocotrienols. The presence of three chiral centers (R or S forms) mean that there are also eight possible stereoisomers. Synthetic vitamin E is most often all-rac-alpha-tocopherol and thus contains equal amounts of all eight isomers (RRR to SSS). In contrast, plant-derived vitamin E is exclusively the RRR stereoisomer. This significant difference in stereospecificity appears to have clinically-relevant importance for bioavailability, receptor binding, metabolism, active metabolite creation, and excretion.$B#1(B
Even when synthetic vitamin E is available as RRR-alpha-tocopherol, it comes bound to either acetate or succinate. The functional bioavailability of each differs significantly.2
Unlike synthetic forms, dietary vitamin E consists mostly of RRR- gamma-tocopherol but also of the RRR-alpha-and delta-tocopherol isoforms and several RRR-tocotrienols. Each may be clinically important as only dietary consumption is associated with reduced cardiovascular risk. Isolated alpha-tocopherol supplementation significantly reduces both serum and tissue gamma-tocopherol but not vice-versa.3 Ironically, coronary artery disease patients already have normal RRR-alpha-but significantly reduced RRR-gamma-tocopherol levels.4 RRR-gamma-tocopherol may be clinically important in cardiovascular health as it, unlike RRR-alpha- tocopherol, safely scavenges potent reactive nitrogen species and regulates the expression of endothelial nitric oxide synthase (eNOS). It also induces significantly more NOS activity and generates more nitric oxide.5 Endogenous nitric oxide plays a crucial role in multiple vasoprotective effects including vasodilation, suppression of smooth muscle cell growth and inhibition of both inflammation and thrombosis.
Unfortunately, the alpha-:gamma-tocopherol ratios, the serum and tissue levels of the tocopherol isoforms and the serum levels of the tocopherol co-antioxidants abscorbate and ubiquinol-10, cannot be obtained retrospectively. Hopefully, future clinical trials will consider these measures. However, if the existing clinical trial data allows the clearly skilled authors of this meta-analysis to re-analyze by vitamin E composition itself, the results may indeed represent a significant contribution.
Gregory A. Plotnikoff, MD, MTS University of Minnesota Medical School Minneapolis, MN
1 Blatt DH, Pryor WA, Mata JE, Rodriquez-Proteau R. Re-evaluation of the relative potency of synthetic and natural a-tocopherol: experimental and clinical observations. J Nutr Biochem 2004; 15:380-395.
2 Hoppe PP, Krennrich G. Bioavailability and potency of natural- source and all-racemic-alpha-tocopherol in the human: a dispute. Eur J Nutr 2000; 39:183-193.
3 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;67:669-684.
4 Ohrvall M, Sundlof G, Vessby B. Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. J Intern Med 1996;239:1117.
5 Li D, Saldeen T, Romeo F, Mehta JL. Relative effects of alpha- and gamma-Tocopherol on low-density lipoprotein oxidation and superoxide dismutase and nitric oxide synthetase activity and protein expression in rats. J Cardiovasc Pharmacol Ther 1999;4:219-226.
Conflict of Interest:
None declared
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Immune-modulating properties of vitamins have been ignored
Submit responseDear Sirs, Besides the antioxidant paradigm, I think we have overlooked the effect of vitamins in modulating the immune response, which can be of crucial importance in understanding conflicting and unexpected results of vitamin supplementation trials and chronic disease. A review published in 1999 (1), showed that vitamins have specific immune- modulating properties in relation to Th1- Th2 polarized immune responses, regardless their antioxidant or water-solubility properties (i.e. vitamin A promotes a Th2 response, while vitamins C and E promote a Th1 response) (1). According to this review as well as to double-blinded, placebo controlled clinical trials in humans (2), vitamin E supplementation can improve aspects of the immune function related to cell-mediated responses, DTH to some antigens, and IL-2 production (1,2). These findings are consistent with a promotion of Th1 response by vitamin E (1). Th1, pro- inflammatory cytokines, as TNF-alpha and IL-1 stimulate the production of IL-6 and adhesion molecules by endothelial cells. Inflammation is thought to play an important role in the development of atherosclerosis, in the rupture of the atherosclerotic lesion, and in acute syndromes (3). Importantly, these same pro-inflammatory cytokines (TNF-alpha, IL-1, adn IL-6) are strong promoters for CRP production by the liver, and CRP has been strongly related to the risk of CVD and cardiac events(3,4). In summary, I suggest we better move away from the antioxidant paradigm, which has shown to be misleading, and consider immune-modulating properties of nutrients, particularly in relation to Th1-Th2 polarized immune responses. This can help to understand disparities among studies, as well as the biological mechanisms of the role of micronutrients on health and disease.
References.
1) Long KZ, Santos JI. Vitamins and the regulation of the immune response. Pediatr Infect Dis J 1999;18(3):283-290.
2) Meydani S, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA 1997;277(17):1380-1386.
3) Tousoulis D, Davies G, Stefanadis C, Toutouzas P, Ambrose JA. Inflammatory and thrombotic mechanisms in coronary atherosclerosis. Heart 2003;89:993-997.
4) Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risks of developing peripheral vascular disease. Circulation 1998;97:425-428.
Conflict of Interest:
None declared
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High-dosage vitamin E supplementation is unjustified, but will the evidence modify the custom?
Submit responseMiller's-et-al article: “High-dosage vitamin E supplementation may increase all-cause mortality” (1) and Greenberg’s accompanying editorial: “Vitamin E supplements: good in theory, but is the theory good?” (2), need a repetitive statement. Insisting in the message may reduce the resistance to change that some physician/researchers may have, because failing to abandon an esteemed idea (an human weakness) is universal.
In the case of vitamin E supplementation, some premises represent the common objections for abandoning this traditional practice:
1.- There are minimal side effects when vitamin E supplementation is taken at very high doses and for up to 11 years (3, 4).
2.- Vitamin E has a number of beneficial effects, independently of its antioxidant activity (although these supposed effects are not known) (4).
3.- While there is evidence that vitamin E may act in vitro as a prooxidant, there is little evidence that it has similar activity in vivo (4).
4.-And the worst: evidence regarding the risks of Vitamin E supplements administered in high doses, can be simply discarded
As an example, I wrote in the “Diabetes Care” issue of January 2005 (5), a commentary about the risks of administering Vitamin E in high doses (800 mg. daily) to a particularly vulnerable population (over-weighted diabetics). The response to this commentary (4) shows the abovementioned rationales (among others) and the intention to continue exploring the high -dosage vitamin E supplementation in spite of the small benefits obtained and the risks allocated to their patients.
Taking this communication as representative of the resistance to abandon a long-established idea, I believe that your statement: "High- dosage vitamin E supplementation is unjustified", must be recurrent in order to obtain in more clinicians/researchers the admission (or at least the consideration) of the evidence offered (1, 2).
Dr Salvador Vale.
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 all-cause mortality. Ann Intern Med. 2005; 142: 37-46. Epub 2004 Nov 10.
2.- Greenberg ER. Vitamin E supplements: good in theory, but is the theory good? Ann Intern Med. 2005;142: 75-6.
3.- Kappus H, Diplock AT. Tolerance and safety of vitamin E: a toxicological position report. Free Radic Biol Med 1992; 13: 55-74. Review
4.- Manning PJ, Sutherland WH, Walker RJ. Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects: response to Vale. Diabetes Care. 2005; 28: 230-231.
5.-Vale S. Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects: response to Manning et al. Diabetes Care 2005; 28: 230-231.
Conflict of Interest:
None declared
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Questions needing answers
Submit responseFor Dr. Miller, et al: This message is to request precise information regarding the "Vitamin E" that was utilized in the 19 trials selected for inclusion in the recently published meta-analysis that found a higher risk of death for persons taking Vitamin E supplements. As you must know, there are significantly varying physiological realities involved for human organisms between the ingestion of a synthetic form of alpha-tocopherol on one hand, or the naturally occurring form on another. For this reason alone, I believe that full disclosure of the exact contents and sources of the "Vitamin E" employed in each of the 19 selected trials should have been published prominently in your meta-analysis, and needs to be revealed now. I feel certain that the Roche Group, described in its own literature as "one of the world’s leading research-oriented health care groups," would expect no less in a scientific analysis for which it provided funding, nor should your University.
Among those in the population who use dietary supplements, there has been a clear and strong preference in recent years for mixed-tocopherol Vitamin E, partly as a result of the work published during the past forty years by Lester Packer, Ph.D. of the University of California at Berkeley. Packer has more recently identified the significance of tocotrienols, found in some naturally occurring Vitamin E, as being an important "cousin" to alpha- and gamma-tocopherols in the optimization of human health. Did any of the 19 trials selected for your meta-analysis involve the use of a natural form of Vitamin E that specifically included tocotrienols?
Your replies are extremely important to me, and I look forward to hearing from you.
Lawrence J. O'Brien Author
Conflict of Interest:
None declared
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Vitamin E Supplementation was not associated with mortality in the DATATOP cohort
Submit responseIn a meta-analysis of selected randomized trials Miller et al. found an increase in all-cause mortality associated with high-dosage Vitamin E supplementation for at least one year.(1) Their analysis included DATATOP, a randomized, placebo-controlled trial of selegiline and vitamin E in 800 patients with early Parkinson’s disease(2). In the DATATOP trial, 399/800 participants were randomized to receive vitamin E 2000 IU per day, the highest dosage of Vitamin E studied in the meta-analysis. Median duration of Vitamin E exposure during the randomized phase was 2.6 years. We have now accrued 13 years of follow-up and have documented 296 deaths compared with the 137 DATATOP deaths incorporated into the meta- analysis.(3)
A slightly but not significantly higher proportion of subjects randomized to Vitamin E were deceased by thirteen years after enrollment (vitamin E 154/399, 39% vs placebo 142/401, 35%, p=0.35). However, after adjusting for age and gender in a logistic regression there was no excess mortality in the group assigned to Vitamin E (OR=0.996, 95% CI 0.72-1.38, p=0.98).
We also constructed a Cox model to make full use of survival information, incorporating duration of blinded exposure to vitamin E as a time-dependent covariate. We did not observe increased mortality for each additional year of exposure to vitamin E (HR=1.05, 95% CI=0.95,1.16 p=0.31). Similar results were obtained when both blinded and subsequent open label tocopherol supplementation were considered.
We found no evidence of increased mortality in DATATOP related to 2.6 years of high dosage vitamin E exposure through 13 years of observation. The DATATOP cohort was selected for absence of serious comorbid illness and was more highly educated than the general population. These and other differences in selection may account for the discrepancy between our findings and those of Miller et al.
References:
1. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Annals of Internal Medicine. 2005;142:37-46.
2. Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med. 1993;328(3):176-83.
3. Marras C, McDermott MP, Rochon PA, Tanner CM, Naglie G, Rudolph A et al. Survival in Parkinson's disease: Thirteen year follow-up of the DATATOP cohort. Neurology. 2005;In Press.
Conflict of Interest:
None declared
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Mortality and Vitamin E ?
Submit responseTo the Editor:
Before the public embraces "high-dosage (greater than 400 IU/d) Vitamin E supplements may increase all-cause mortality. . .," several problems with this study should be addressed. First, factorial design data should not have been presented in Figure 3. The plot is much less convincing using data from Figure 4. The SPACE study is incorrectly listed as non-factorial (Table 1) when 42-57% of the Vitamin E and placebo groups were prescribed varying doses of vitamins (including 100-500 mg/d of ascorbic acid).
Second, the Vitamin E group was overweighted for diseases and mortality risk factors in the high dose VECAT and CHAOS studies. In the VECAT study, Vitamin E versus placebo had a diagnosis of ischemic heart disease (11.3 vs 9.0%), diabetes (4.9 vs 3.5%) and hypertension (38 vs 33%). Current smokers and high body mass index were also overweighted in the Vitamin E group vs placebo (2.4 vs 1.7% and 42 vs 37%, respectively). The authors of the CHAOS study state that the distribution of "five conventional coronary risk factors" favored lower mortality in the placebo group. As expected these studies show higher mortality in the Vitamin E supplemented group.
Third, a plot of mortality versus supplemental Vitamin C dose (including Linxian B at 180 mg/d) for nine studies is remarkably similar to that in Figure 3. Similarly, there is no chance that the menopausal status is the same in the low- and high-dose Vitamin E studies; there is a disproportionately higher fraction of postmenopausal women in the high- dose studies. Combining these factors and this meta-analysis may have uncovered mobilization of iron by high-dose Vitamin C and the resultant iron toxicity. These are only two of many factors that could act synergistically.
If data from pooled results (uncorrected factorial design data) results (SPACE study included) and biased results (VECAT and CHAOS) are removed, and only data from Figure 4 are used, there is no increased mortality risk for high-dose Vitamin E.
REFERENCES
1. Miller ER, Pastor-Barrivso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-Analysis: High-Dosage Vitamin E Supplementation may increase All-cause Mortality. Ann Intern Med. 2005;142:37-46.
2. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomized placebo-controlled trial. Lancet. 2000;356:1213-8. ƒËPMID: 11072938ƒÍ
3. McNeil JJ, Robman L, Tikellis G, Sinclair MI, McCarty CA, Taylor HR. Vitamin E supplementation and cataract: randomized controlled trial. Ophthalmology. 2004;111:75-84. ƒËPMID: 14711717ƒÍ
4. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-6. ƒËPMID: 8622332ƒÍ
5. Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, Ershow AG, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993;85:1492-8. ƒËPMID: 8360932ƒÍ
Conflict of Interest:
None declared
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Flaws in Vitamin E study
Submit responseAll of the studies in the recent meta-analysis you cited used alpha- tocopherol and most of those probably used the L alpha-tocopherol isomer, a form that is cheap to make but probably biologically useless. And given its ability to bind to receptor sites, potentially in favor of biologically active forms of vitamin E (d-alpha-, beta-, delta-, and gamma-tocopherol) it may even be harmful. More than two-thirds of the vitamin E in food is gamma- tocopherol, whereas most of the nutritional supplements on the market contain only alpha-tocopherol and most of those have L alpha-tocopherol.
The studies evaluated in the meta-analysis did not control for other factors that may influence vitamin E acitivity such as consumption of essential fatty acids (EFAs). More specifically in the Cambridge Heart Antioxidant Study the treatment groups had significantly more co-morbidities when compared with the placebo group. In the Age-Related Eye Disease Study (AREDS), participants received zinc and copper in addition to the vitamin E. Although the copper was added to prevent copper deficiency secondary to long-term zinc supplementation, the form of copper used was not absorbable and those subjects may have had copper deficiency as well.
There is still research to suggest that mixed tocopherol vitamin E may be useful in other diseases. And of course this study, if it is accurate, should underscore that the best source of vitamin E and all anti-oxidants is in our food, almost always the best source of nutrients. This emphasizes the importance protecting our food sources and providing high quality, nutrient- rich food. Physicians need to know more than the biochemistry of nutrition in order to incorporate this information into successful patient management.
David Riley, MD
Conflict of Interest:
None declared
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Natural or Synthetic?
Submit responseI would like to know the type of vitamin E used in the trial by Miller, et al. It is very important to know in how many studies the Vitamin E used was the Natural or synthetic form (d- or dl- tocopherols [also known as all-rac- -tocopherol], respectively), or other forms (beta, gamma, or mixed). The results of the study, especially as a meta-analysis could make a big difference in your findings. I am very concerned that the results may be confounded if we identify the types of vitamin E were used.
According to the article by Miller, et al, “the biological activities of vitamin E compounds are reported relative to all-rac- -tocopherol acetate on the basis of in vivo assays.” Also, the authors converted the vitamin E dosages of the studies included in the meta-analysis to IU/d relative to all-rac- -tocopherol acetate for standardization across studies. I am concerned about the Publication bias based on different sources.
Also, the study by Miller, et al, could not evaluate the generalizability of the findings to healthy adult populations taking high- dosage of vitamin E. Although it was mentions in the limitations section, I am curious what will the result be among healthy adults and not among patients with various chronic diseases.
Conflict of Interest:
None declared
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Re: Vitamin E & all-cause mortality
Submit responseUntil recently, recommended dietary patterns included up to 10 percent of calories from polyunsaturated oils, an unusually large quantity of these easily oxidized fats. However, during production of common polyunsaturated oils, there may be loses of about 30 percent or more of naturally-occurring vitamin E,(1) predominantly gamma-tocopherol. Additional vitamin E is destroyed in food processing, preparation and storage.(2) Although vitamin E supplementation could theoretically correct potential deficits, large doses greater than 400 mg could also exaggerate an imbalance of alpha tocopherol vs other natural vitamin E compounds, perhaps accounting for the disappointing results of the Miller et al analysis.(3)
It is possible, however, that smaller doses of vitamin E could be beneficial. In fact, in the few trials of 150 mg or less included in this meta-analysis, mortality risk was lower. Therefore, a trial of lower dose vitamin E, ideally a blend of RRR-tocopherol compounds that more closely approximates that found in natural sources, seems warranted.
1. Jung MY, Yoon SH, Min DB. Effects of processing steps on the contents of minor compounds and oxidation of soybean oil. JAOCS 1989;66:118-120.
2. Bauernfiend JB. Tocopherols in foods. In: Machlin LJ, editor. Vitamin E, a comprehensive treatise. New York: Marcel Dekker Inc; 1980. p.104-17.
3. Edgar R. Miller, III, Roberto Pastor-Barriuso, Darshan Dalal, Rudolph A. Riemersma, Lawrence J. Appel, and Eliseo Guallar.Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med 2004; 0: 0000605-200501040-00110-53.
Conflict of Interest:
None declared
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Vitamin E & all-cause mortality
Submit responseIn the recent meta-analysis that associates vitamin E (E) supplementation with all-cause mortality, Miller et al. 1 reported that supplemental intake of E at doses greater than 150 IU/d progressively increases all-cause mortality. There are several problems with the analysis and interpretation of the data. The harmful effect above 150 IU/d is an artifact of the model they chose to fit. By fitting a quadratic- linear spline, the result must be a quadratic-linear spline whether or not the data behave that way. Another reasonable model is that the favorable response to E is constant until a certain dose above which the change in all-cause mortality risk difference is linear. The constant response to E persists up to a dose of 330 IU/d and the risk difference favors E until the dose is 400 IU/d. The sum of weighted squared differences between observed and predicted all-cause mortality risk differences shows that this model fits the data better than does the quadratic-linear spline.
The modeling issue is further supported by the following re-analyses of the data presented in Figure 2 of Miller et al. 1. We grouped the data into several intermediate dose ranges of E and performed meta-analyses using a random effects model and obtained the following results:
200-500 IU 7 studies 35,595 patients RR=0.98 (0.88 - 1.09) 330-500 IU 6 studies 32,184 patients RR=0.99 (0.88 - 1.11) 400-500 IU 4 studies 16,355 patients RR=1.00 (0.80 - 1.25).
None of the subgroups that included studies with E dosage of 500 IU/d or below suggests any harmful effects. Thus, it doesn't seem plausible that increased risk occurs until at least the daily dose of 400-500 IU has been exceeded.
We also question the applicability of the data to the general population as subjects in most studies with higher doses included in the meta-analysis had cardiovascular diseases. Furthermore, we are surprised at the lack of emphasis on the benefits of reduction in all cause mortality by doses of E below 400 IU, an effect, which reached statistical significance if E alone was considered. Related to this, in a double- blind, placebo-controlled trial of E supplementation (200 IU/day for 1 year) in nursing home subjects, we observed no statistically significant difference in all cause mortality between placebo and E groups (12.5% and 14.4% in E and placebo groups, respectively). However, significantly fewer subjects in the E group acquired respiratory tract infections, an important public health problem in this age group 2.
Simin Nikbin Meydani,*§ DVM, PhD Joseph Lau,+ MD Gerard E. Dallal,* PhD Mohsen Meydani,* DVM, PhD
*Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, Massachusetts, §Department of Pathology, Sackler Graduate School of Biochemical Sciences, Tufts University, Boston, Massachusetts, +Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, Massachusetts,
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 All-Cause Mortality. Ann Intern Med 2004. 2. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA 2004; 292:828-36.
Conflict of Interest:
None declared
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High dose vitamin E supplementation: time to return to the drawing board....
Submit responseThe work of Miller et al(1) highlights the danger of assuming the safety of high dose vitamin E in the absence of definitive long-term safety data. Its impact, however, may be mitigated, by methodological concerns.
The first issue is the restrictive inclusion criteria stipulating that a trial have at least 10 deaths to be included in the meta-analysis, apparently because the authors “anticipated that many small trials did not collect mortality data”. This exclusion contradicts the raison d’être of meta-analysis, which involves the statistical pooling of multiple trials that individually have inadequate statistical power. The exclusion of at least 3 reasonably large well-conducted trials(2-4) of high dose vitamin E in which fewer than 10 deaths occurred, while including only trials meeting this arbitrary cut-off, would spuriously increase the power of the meta-analysis. We would also be interested in the funnel plot analysis to determine whether publication bias affected the study results.
Although the authors attempted to adjust for average follow-up in their analysis, a more robust statistical treatment of the variance in follow-up periods across included trials would be to express the summary statistic of pooled death risk as the number of deaths per 10,000 person- year (as opposed to per 10,000 persons).
Heterogeneity in the study populations may not have been fully accounted for despite the use of the random effects model and dosage differentiation. In particular, cardiovascular disease (CVD) may constitute a select group at distinct risk from the effects of high dose vitamin E. Seven of the eight high-dosage trials showing harmful effects of vitamin E involve subjects with vascular risk factors or who had established CVD. In contrast, the DATATOP and ADCS studies utilised mega- doses of vitamin E (2000 IU/day) in individuals with neurodegenerative disorders, rather than CVD, but did not reveal safety concerns with vitamin E. A separate meta-analysis looking solely at the group of neurodegenerative diseases (including a recent study employing 5000 mg/day of vitamin E(5)) may be warranted.
Although the focus of the Miller et al study may be on safety, the data ultimately challenges the advocates of high dose vitamin E to re- examine the evidence for its benefit. Efficacy from controlled trials ranges from minimal to modest, in contrast to the more positive results of observational studies. It is time clinicians return to the drawing board and review both the safety and efficacy data for vitamin E supplementation to determine their practice.
References: 1. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LA, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46. 2. Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel- DiFranco C, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761- 72. 3. de Waart FG, Kok FJ, Smilde TJ, Hijmans A, Wollersheim H, Stalenhoef AF. Effect of gluthathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. Atherosclerosis. 2001;158:227- 31. 4. Wluka AE, Stuckey S, Brand C, Cicuttini FM. Supplementary vitamin E does not affect the loss cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study. J Rheumatol. 2002;29:2585-91. 5. Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. The German vitamin E/ALS Study Group. J Neural Transm 2004; Oct 27 (Epub ahead of print).
Conflict of Interest:
None declared
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Not All Vitamin E Should Be Condemned : A Different Perspective
Submit responseIn light of this controversial vitamin E meta-analysis publication and the so many response by experts to it in the media, perhaps, one should look at vitamin E supplementation from a different perspective - that vitamin E should be taken as a wholesome mixture of d-mixed tocopherols and d-mixed tocotrienols.
Taking a single form of vitamin E (ie : alpha-tocopherol alone) denies the very fact that nature put seven (7) other forms on vitamin E (ie : gamma-tocopherol, beta-tocopherol, delta-tocopherol, alpha- tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol) out there for a reason.
As a matter of fact, we have seen this before - in 1996 with the beta -carotene debacle (The ATBC and CARET studies). These two studies provide evidence that taking beta-carotene alone rather than a multi-carotenoids (beta-carotene, alpha-carotene, gamma-carotene, lycopene, lutein - as produce in nature), may increase the cancer risks among smokers. This may be because all these carotenoids work synergistically as a team - recharging and supporting each other to confer the health benefits.
It goes to show that a single nutrient vitamin E (ie : alpha- tocopherol - synthetic or natural) is not the panacea. It is against conventional wisdom to take mega-doses of one nutrient without considering the potential side effects.
Similarly, high dosage of alpha-tocopherol alone has been shown to deplete the body's gamma-tocopherol. Despite alpha tocopherol's action as an antioxidant, gamma tocopherol is required to effectively remove the harmful peroxynitrite-derived nitrating species. Because large doses of dietary alpha tocopherol displace gamma tocopherol in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alpha tocopherol should be reconsidered. Other forms of vitamin E - gamma- tocopherol, delta-tocopherol and certainly tocotrienols have been proven to have unique health properties as well.
Tocotrienols on the other hand have been proven to be beneficial to the cardiovascular system. It is a potent antioxidant (40-60 times more potent) and has been proven to lower total blood cholesterol as well as reverse arterial blockage in Carotid Stenosis patients. In a recent NIH- funded study in collaboration with Ohio States University Medical Center and Carotech Inc (Tocomin®), it was found that tocotrienols especially alpha-tocotrienol are much more potent than tocopherol in protecting the neurons from glutamate-induced neuro-degeneration.
In many foods, alpha- and gamma-tocopherol account for most of the vitamin E activity. While tocopherols are generally present in common vegetable oils (i.e. soy, canola, wheat germ, sunflower), tocotrienols, on the other hand, are concentrated in cereal grains (i.e. oat, barley, and rye, rice bran), with the highest level found in crude palm oil. It is unfortunate that not many consumers are aware of tocotrienols due to the low level in the Western diets.
Looking at the whole realm of vitamin E research, it is prudent to take the wholesome full spectrum vitamin E : d mixed tocopherols + d-mixed tocotrienols - as what is produce and found in nature.
Mimicking nature is the best way for supplementation. Like the carotenoids, all these different forms of vitamin E work synergistically and depend on each other for optimum functionality.
Natural phytonutrients just don't work well in isolation from each other. I sincerely believe (from scientific evidence) that most people would benefit from taking a full spectrum Vitamin E supplement that consists of d-mixed tocopherols + d-mixed tocotrienols. And it would be safer than just the alpha-tocopherol alone.
Conflict of Interest:
Manufacturer of full spectrum tocotrienol complex
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ARBITRARY DEFINITION OF HIGH DOSE
Submit responseIn a recent vitamin E meta-analysis, authors from Johns Hopkins evaluated the results from 19 studies on vitamin E and examined whether vitamin E had an effect on total mortality. In the overall analysis, the found no effect on mortality, and in the dose-response analysis, they found a significant effect on total mortality only at intakes above 900 IU, a finding entirely lost in the furor over their third analysis.
For the main meta-analysis, the authors selected 400 IU as the dividing line between “low dose” and “high dose” trials and asserted that levels of 400 IU or more were associated with increased mortality. This is an arbitrary figure which happens to coincide with the most commonly marketed level of vitamin E. There are 2 studies at 330 IU, including the large and important GISSI study which found a decrease in total mortality. Inclusion of these 2 studies in the “high dose” category would have been logical and would have drawn the effect toward null.
There are only 2 studies at 400 IU. The largest of those is the HOPE study which found absolutely no effect on total mortality, and the other is the AREDS study which found no significant increase. The one study at 440 IU found a statistically significant decrease in total mortality in the vitamin E group. Thus, there is no evidence of an increased mortality risk in the 3 studies that actually gave 400 or 440 IU of vitamin E to more than 7500 people for a period of years.
The authors’ finding of a slightly increased risk of total mortality is driven entirely by the 8 studies using dosages of 500 IU or more. There is only one large study in this group, the MRC trial which gave 660 IU and found a slight but nonsignificant increase in risk. The other trials are all small, and five have wide confidence intervals running off the chart in one or both directions. These studies are a poor basis for the authors’ sweeping conclusions. Millions of consumers are now confused because the researchers failed to take their own good advice to use caution in generalizing the results of this meta-analysis.
Conflict of Interest:
President of a dietary supplement trade association.
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Study is too simple
Submit responseThis study fails to differentiate between:
- Types of Vitamin E used: artificial (dl) or natural(d).
- Age (old versus young) of the populations.
- Other items taken: drugs or vitamins/minerals.
- Levels of health/illness as they influence the study participant’s choices. The failure to differentiate leads me to consider: 1. The principals were too naïve to attempt this type of study; or, 2. This study has been planned in order to support (later) legal attempts to reduce Vitamin E to a prescription status.
Conflict of Interest:
None declared
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Simple Statistics support paper's findings
Submit responseIf the clinical trials are considered to be independent of each other and if the clinical trials have been selected with enough care so that the trials are representative and the administration of extra doses or not of vitamin E is the only significant variable, than it is a reasonable statistical inference that the administration of large doses of vitamin E is harmfull to patients, and by reasonable extension to the healthy as well.
Of the 11 clinical trials which administered 400 or more units of vitamin E, 8 showed "excess" mortality associated with "excess" vitamin E.
If vitamin E is considered beneficial there is only a 11% chance that this can happen by chance (3 or less adverse events in 11 trials).
While such a result is in excess of the time honored criteria of reducing chance to a 5% or 1% level,that is only a convenient rule not an absolute one.
Reference:Probability and its Engineering Uses,1928,Thornton Fry
Conflict of Interest:
None declared
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Incorrect Statistics Used in Vitamin E Report
Submit responseThe report on high dosage Vitamin E supplementation combined studies of patients with various degrees of medical conditions from healthy to seriously ill. Most of the seriously ill took high doses of Vitamin E. These combinations are statistically incompatible and the results are not reliable. Since the high doses of Vitamin E were taken mostly by seriously ill patients, the study would seem to be biased toward higher mortality rates for higher Vitamin E doses. The study does not show that high doses of Vitamin E are a risk for healthy individuals and this is admitted by the researchers. In their report the researchers write on page 9 (internet copy) that "we could not evaluate the generalizability of our findings to healthy adult populations."
High doses of Vitamin E might be harmful but this study does not provide proof.
Conflict of Interest:
None declared
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Eat an apple a day...and take your vitamins!
Submit responseThe meta-analysis by Miller et al has become part of the public landscape, because of the sensational headlines in newspapers around the world: "High Doses of Vitamin E Deadly," "Vitamin E's Fatal Flaw," "Lethal Consequences of Vitamin E Overdose." The wall-to-wall press makes it seem like one of the most important health warnings of our era, but this meta-analyses is nothing more than a tempest in a teapot brewed from a statistical study that many epidemiologists would not give much credence to.
For physicians (or their patients) unable to read past the alarming headlines, here's the story: The authors combined the findings in 19 previously published studies on vitamin E over the last 12 years. Virtually all of them failed to show any statistically significant harm--much less any increase in deaths. However, by combining the 19 old studies, the authors' believe they have found a statistically significant increase in deaths from all causes of mortality (ACM).
I believe the authors' bias is clear when they cite an apparent 0.4% increase in ACM at doses over 400 IU vitamin E while providing almost no comment on hundreds of excellent studies that show no increase in ACM--while also demonstrating benefits of vitamin E supplementation. Certainly as physicians assess the risk of vitamin E, its documented benefits muct be factored into the equation. Yet the authors fail entirely to acknowledge the benefits of vitamin E that were reported in the very same studies that they included in their own meta-analysis: Reduction in the risk of Alzheimer's disease, heart and blood vessel disease, age-related macular degeneration and several forms of cancer.
How narrowly informed is this meta-analysis? I believe the overwhelming fact is that the increase in mortality was just 39 out of 10,000 for those taking 400 IU of vitamin E or more. That's less than a one half of one percent increase in ACM, which may include floods, famine, earthquakes, homicides, suicides and accidents!
The reason why many epidemiologists do not give much credence to these types of meta-analyses is because statisticians are forced to ignore the nuances in each of the studies they have been examined. Interestingly, the data in the present statistical leap of faith suggest 400 IU vitamin E is more lethal in 1.4 - 8 years than smoking 2 packs of cigarettes for the same period of time. Clearly, this is not tenable. As a matter of fact, the Institute of Medicine has concluded that vitamin E is safe at levels as high as 1000 IU per day for the synthetic form and 1500 IU per day for the natural form.
The findings reported in this sensationalized study are really not news at all, and the headline hype would be just silly if it wasn't also a major distraction from genuinely important health news of the moment: tens of thousands of patients may have died as a result of taking Vioxx, because certain pharmaceutical firms may not have been completely honest with doctors or the public.
Read the newspapers or watch TV and anyone can see how much the drug industry influences the media with valuable advertising dollars. Drug ads have also become the economic lifeline for medical journals, which generally contain more drug advertisement pages than pages with scientific studies. Dr. Marcia Angell, the former editor of The New England Journal of Medicine, has written a book entitled, "The Truth About the Drug Companies: How They Deceive Us and What to Do About It," detailing how the companies are vast marketing empires with unprecedented control and influence over medical research, education, and how doctors do their jobs.
So in addition to scientific, evidence-based medical care, what's a sane, rational prescription for good health? Here's my "Wellness Solution:" healthy nutrition, weight management, drinking enough water, regular exercise, stress management, including being a good person, no smoking, no substance abuse, including alcohol, and taking a well-balanced vitamin and mineral supplement containing 400 IU of vitamin E every day--which is what I take myself.
Conflict of Interest: The author formulates and is a spokesperson for nutritional supplements, however the analyses and opinions expressed in this letter are solely the author's medical views as a family physician and pediatrician and do not purport to represent either the products or the companies that he is associated with.
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Interaction of drugs with vitamin E
Submit responseSince most of the subjects in these studies were older people with chronic diseases, many of them were probably taking multiple prescription drugs. Perhaps some of the mortality associated with vitamin E could be explained by an interaction of vitamin E with these drugs similar to the known interaction of an antioxidant cocktail containing vitamin E with statins and niacin that reduces the increase in HDL cholesterol.
Conflict of Interest:
None declared
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Safety of Vitamin E Supplementation in Humans
Submit responseDear Sir/Madam, We read with interest the statistically questionable and selective meta- analysis review by Miller et al (1) and as investigators of long-standing in this area, we believe that this justifies a response. In their exclusion of studies based on their arbitrary criteria, they omitted 2 studies that clearly showed the benefit of combined RRR-alpha tocopherol (natural AT) and vitamin C supplementation on the primary endpoint, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study of 440 hypercholesterolemic patients followed up for 6 years and the Transplant-associated Arteriosclerosis study (2,3). Also, in the 11 studies in which they suggested harm from high dose AT supplementation, it should be pointed out that in 5, AT was used along with other antioxidants including beta carotene, which has previously been shown to be harmful (2). In Fig 2, there does not appear to be a dose- response with high dose AT on mortality and in fact, there was a trend to benefit in the ADCS study (AT 2000 IU/day). Furthermore, in 3 of the studies, which used AT alone (CHAOS, SPACE, ADCS), there was a significant benefit on the primary endpoint without a significant increase in mortality (2,3). Since the authors do not show the data of the pooled analyses of the high dose AT studies after exclusion of the WAVE study, it is hard to determine if the questionable statistical significance could be ascribed to this chance finding as suggested by the WAVE investigators (3). Also, it should be pointed out that only 64% of the patients on antioxidants in the WAVE trial had exit angiograms. This point raises the validity of the meta-analyses with respect to the heterogeneity of the different studies including diverse populations, sample sizes, dose and duration of AT, antioxidant cocktails, form of AT (RRR- vs all rac), omission of use of biomarkers of oxidative stress and inflammation. Furthermore, it needs to be pointed out that RRR-AT at doses > 400 IU/day in human volunteers clearly demonstrates antioxidant activity (decrease in LDL oxidizability and F2-isoprostanes-a measure of in vivo lipid peroxidation) and displays anti-inflammatory activity as evidenced by decrease in pro-inflammatory cytokines and hs-C-reactive protein levels (an accepted risk marker of cardiovascular disease) (4). Thus, we believe that while the benefits of high dose RRR-AT remains to be proven, it should be pointed out that the American Heart Association, in a recent Advisory (5) reviewed in detail, antioxidant vitamin supplements and cardiovascular disease and did not conclude that alpha-Tocopherol increased mortality. 1. Miller ER 3rd, 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; 141;Epub ahead of print 2. Jialal I, Devaraj S. Antioxidants and atherosclerosis: don't throw out the baby with the bath water. Circulation. 2003;107(7):926-8. 3. Jialal I, Devaraj S. Scientific Evidence to support a vitamin E and heart disease health claim: research needs. J Nutr 2005; In Press 4. Singh U, Jialal I. Anti-inflammatory effects of alpha tocopherol. Ann NY Acad Sci 2004;1031:1-9. 5. Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL; Nutrition Committee of the American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004;110(5):637-41.
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The benefit and harm of vitamin E supplementation
Submit responseIn their important meta-analysis focusing on the potential harmful effects of vitamin E supplementation, Miller et al. (1) assumed that there may be a precise threshold level, so that larger intakes of the vitamin would progressively increase the risk of harm. However, it is possible that there is biological heterogeneity between population groups, so that the characteristics of persons would determine whether vitamin E supplementation causes net benefit or harm.
In the ATBC Study, the effect of vitamin E on the risk of pneumonia was significantly modified by the age of smoking initiation (P = 0.0007)(2). Vitamin E increased pneumonia risk in those who initiated smoking at 20 years or earlier (RR = 1.14; 95% CI: 0.98-1.32), whereas the vitamin reduced pneumonia risk in participants that initiated smoking at later ages (RR = 0.65; 95% CI: 0.49-0.86). Furthermore, in the latter subgroup the benefit was greater among those who smoked less or quit smoking during the trial. Thus, less exposure to cigarette smoking was associated with greater benefit of vitamin E.
In the ATBC Study, the vitamin E dose was 50 IU/day (50 mg/day dl- alpha-tocopheryl acetate) which is substantially less than the threshold of 150 IU/day estimated by Miller et al.(1). However, concluding from the subgroup differences described, it seems probable that some population groups suffer ill effects at this low dosage also, but the same low dose seems beneficial to other persons. Thus, assuming that there is biological heterogeneity between population groups, further studies should characterize people that obtain benefit or harm from vitamin E, instead of just estimating a uniform threshold level for harm with a presumption that the single threshold is valid for the entire population.
1. Miller ER, 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 2005;142(1):in press
2. Hemilä H, Virtamo J, Albanes D, Kaprio J. Vitamin E and beta- carotene supplementation and hospital-treated pneumonia incidence in male smokers. Chest 2004;125:557-65.
Conflict of Interest:
None declared
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Potential bias in methods may negate statistical significance of the high dose vitamin E analysis
Submit response19 Nov 04
Editor, Annals Internal Medicine
Sir or Ma’am:
We read with interest the recent article by Millar and colleagues (1). However, we question their conclusions regarding the high dose vitamin E.
First, it is not clear why the authors chose hierarchal logistic regression rather than traditional meta-analytic approaches. We reanalyzed their data from the 11 high dose trials in Figure 2 using two standard methods (Wolfe inverse variance and Mantel Haenszel). Both yielded the same point estimates as the authors, but with non-significant results (RR: 1.04, 95% CI: 0.99-1.10). Secondly, we are concerned that these results are heterogeneous. Both are borderline statistically heterogeneous (Q=16.1, d.f. = 10, p = 0.097), and there is visual evidence of heterogeneity on our Galbraith plots. Better examination of the sources of this heterogeneity is needed.
In addition, we found a suggestion of publication bias among the 11 high dose trials with Begg’s test (p=0.073) (2), which we confirmed with the trim and fill method (3). As the authors note, studies showing benefit from vitamin E are unlikely to be missing from the literature. However, small studies that demonstrate no effect could well be unpublished. It is also possible that the authors did not include these small trials because they did not search EMBASE, which may have excluded European trials. They also excluded trials with less than 10 deaths (which seems arbitrary) that, in particular, would tend to bias the results towards a finding of harm.
The authors searched for the influence of each trial and determined that “none seemed to be driving the results”. In our reanalysis, exclusion of the largest trial (MRC/BHF HPS) resulted in a wider confidence interval (95% CI: 0.96-1.13). We would like to know if the results became non-significant when the authors excluded this or other trials.
Finally, the authors did not account for study quality as a possible explanation of the results. This has been previously shown to effect the results of randomized controlled trials (4) and is recommended by the QUOROM statement (5).
In summary, we have trouble accepting the conclusions regarding high dose vitamin E due to the statistical methods used and the lack of controlling for study quality and publication or selection bias. We contend that correction of any one of these factors could negate the marginally significant results. With these problems and multiple other studies suggesting vitamin E has no effect of mortality, telling our patients that it may be harmful seems premature.
Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
References:
1. Millar ER, 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. 2004:142.
2. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994 Dec;50(4):1088 101
3. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000 Jun;56(2):455-63
4. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995 Feb 1;273(5):408-12
5. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analysis of randomized controlled trials: the QUOROM statement. Lancet 1999 Nov 27;354(9193):1896-900.
Conflict of Interest:
None declared
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VITAMIN E: Which isoform and how much?
Submit responseThere are several flaws in the meta-analysis by Miller et al. (1) that include erroneous interpretation of the pooled trials of alpha- tocopherol and lack of clarity in vitamin E nomenclature. The analysis includes trials from many time periods, with different trial designs, doses and combinations and end-points that make comparisons difficult and fallacious. Participants in several of the trials had significant medical conditions like coronary artery disease, end-stage renal disease, diabetes mellitus, Parkinson’s disease and Alzheimer’s disease. Given this heterogeneity in the participant pool, we would consider it presumptuous to draw solid conclusions of this magnitude even with complex statistical tools like meta-analysis and extend the observations to normal healthy people. In addition to clinical heterogeneity, this analysis also suffered from heterogeneity in test nutrients. In many of the trials vitamin E was used alone and in combination with another nutrient such as beta-carotene. In these cases, the authors combined the data for vitamin E alone with the data for vitamin E plus another nutrient even when the data for the other nutrient indicated that it was statistically associated with increased mortality. Moreover, those studies in which less than 10 deaths occurred were excluded from the meta-analyses giving an artificial weight to those studies in which a higher mortality occurred, i.e., those in which the subjects had serious illness as opposed to studies with healthy individuals. A close-look at the odds-ratios depicted in figure 2 does not suggest harmful effects at a dose of 400 IU of alpha-tocopherol and yet the authors conclude that harmful effects begin at a dose of 150 IU. Vitamin E is not a single compound and exists in eight different isoforms in nature (four tocopherols and four tocotrienols) and have distinct biopotencies, biokinetics and cancer preventive properties. Food sources vary in the content of the vitamin E isoforms. Gamma-tocopherol, the primary source of dietary vitamin E, is abundant in plant seeds (corn, soybean, sesame), vegetable oils and nuts (walnuts, pecans and peanuts).. It is not appropriate to “lump” all the different forms of vitamin E into a single basket and call them “vitamin E”. Natural vitamin E forms differ in their properties from synthetic vitamin E. Most of the trials cited in this analysis used synthetic alpha-tocopherol. This should have been emphasized. Dietary and supplemental sources of vitamin E isoforms possess unique properties that can influence critical pathways involved in cancer, inflammation, cardiovascular disease and neurodegenerative disease. For example, mechanistic differences between the alpha- and gamma-tocopherols and their metabolites provide a molecular basis for the superiority of gamma-tocopherol (2)(3)(4)(5). Although alpha-tocopherol has a high concentration in supplements, the primary form of vitamin E in the diet is gamma-tocopherol, which is present at 2-4 times higher concentration than alpha-tocopherol. A high intake of synthetic alpha- tocopherol can lower plasma and tissue levels of gamma-tocopherol. We believe that carefully conducted randomized studies, with long follow-up periods and well defined endpoints are required to address the potential clinical efficacy of the different isoforms of vitamin E. We also have to be clear on the terminology that is used when we discuss the properties and effects of the different forms of vitamin E.
Reference List
1. Miller ER, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142 (1): 1-11 2. Wagner KH, Kamal-Eldin A, Elmadfa I. Gamma-tocopherol-an underestimated vitamin? Ann Nutr Metab 2004; 48(3):169-188 3. Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L, Mou S, Pye QN, Stoddard MF, Wallis G, Williamson KS, West M, Wechter WJ, Floyd RA. New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic Biol Med. 2004 Jan 1;36(1):1-15 4. Stone, W.L, Krishnan, K, Campbell, S.E., Qui, M, Whaley, S.G, Yang, H: Tocopherols and the Treatment of Cancer. Ann. N.Y. Acad. Sci. 2004;1031: 1-11 5. Campbell S, Stone W.L, Whaley S, Krishnan K. Development of gamma- tocopherol as a colorectal cancer chemopreventive. Critical Reviews in Oncology/Hematology, 2003; 47: 249-259
Conflict of Interest:
None declared
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Dose-Response Analysis Reconsidered
Submit responseGiven the results of the dose-response analysis summarized in their Figure 3, the authors observe that the 95% confidence band for the risk difference does not include 0 for dosages greater than 900 IU/day, and go on (in their Table 2) to derive pooled risk differences and ratios therefrom that suggest a statistically significant relationship between vitamin E supplementation dosage and all-cause mortality.
The authors are to be commended for listing the data they used, thereby facilitating the exploration of alternative analyses: the ability to do so is especially important here because the statistical significance of the observed risk differences is not overwhelming.
If alternative analyses are just about as appropriate for the data at hand, and are generally as reasonable as those that the authors have adopted, then one might well expect that they should produce conclusions that are consistent with the authors'. This, unfortunately, is not the case for the dose-response analysis, as the following steps illustrate.
First, instead of focussing on risk difference, base the dose-response analysis on relative risk (measured by the logarithm of the odds ratio for all-cause mortality: for example, log((100*258)/(106*261))=-0.0698 for MIN.VIT.AOX in Figure 2), which rests on ample precedent and solid rationale [1].
Second, instead of the authors' spline, employ a non-parametric, locally quadratic, weighted regression [2] to model the relationship between relative risk and the logarithm of dosage.
In these circumstances, one finds that the 95% confidence band for this relationship straddles the value 0 (which corresponds to no difference in relative risk) throughout the whole range of dosages represented in the data: thus indicating that, from this viewpoint, and despite a suggestive trend, there is yet insufficient evidence incontrovertibly to establish a statistically significant difference in relative risk between the different groups that received vitamin E supplementation in different dosages.
Details of the computations aforementioned, performed using the data in the authors' Figure 2 (and also in Figure 4, with the same conclusion), using the "locfit" package for R [3], and the alternative to Figure 3 that summarizes the local regression analysis, will be produced upon request since this letter cannot accommodate them.
REFERENCES
[1] Breslow, NE, Day, NE. Statistical Methods in Cancer Research, Volume 1: The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer; 1980.
[2] Loader, C. Local Regression and Likelihood. New York, NY: Springer-Verlag; 1999.
[3] R Development Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing (http://www.R-project.org); 2004.
Conflict of Interest:
The analyses and the opinions described in this letter are solely its author's, were developed by him on his own personal time, are unrelated to the work he performs for his employer, and do not purport to represent any views or positions held by his employer (General Electric)
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Vitamin E toxicity ?
Submit responseIt has long been known that reducing agents/antioxidants such as vitamins C and E may have proxidant properties, e.g., by interacting with transition-series metals in Fenton's reactions to produce active oxygen species. Whether a reducing agent is a pro-or antioxidant depends on a complex state of circumstances such as its concnetration, that of oxygen, and so forth.
There has been at least one previous circumstance that may shed light on the possible mechanism of vitamin-E toxicity. We have found (1) that vitamin-E administered before adrimycin ameliorated intestinal toxicity of this drugs, but that continued vitamin-E treatment abolished this protective effect.
Two possible explainations of this odd finding are that "loading" a tissue in its proper tissue compartment with vitamin-E protects that tissue, but that circulating vitamin-E interacts with Adriamycin to make it more toxic (e.g., by donating electrons for redox cycling). Another possibility is some sort of hormesis. That is, vitamin-E exerts a mild oxidative stress that causes induction of further defenses against redox drugs like adriamycin.
Peter H Proctor, PhD, MD
1)McGinness JE, Grossie B Jr, Proctor PH, Benjamin RS, Gulati OP, Hokanson JA., Effect of dose schedule of vitamin E and hydroxethylruticide on intestinal toxicity induced by adriamycin. Physiol Chem Phys Med NMR. 1986;18(1):17-24. Pubmed: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3774891
Conflict of Interest:
None declared
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Lancet was correct!
Submit responseThis meta-analysis combined 19 individual studies, eighteen of which showed no statistically significant increase in mortality. This can be verified by reviewing the data in Figure 2 with a simple calculator. One study alone accounted for the entire 5% negative death rate (MRC/BHF HPS 2002 [49]).
Interestingly this Lancet study made an entirely different conclusion from your above study. Combining of 19 clinical trials into a single large cohort gave greater statistical power than the Lancet study itself concluded. And, thus, can not be justified.
Lancet reported: "There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo- allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non -vascular (568 [5.5%] vs 549 [5.3%]) causes." ... "Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe."
And, the answers that everyone has been requesting are: alpha- tocopherol along with vitamin C and beta-carotene. Their use of beta- carotene taints the whole Lancet study in my opinion.
The only thing that that the Lancet study showed was that alpha- tocopherol was not a miracle cure for gravely ill individuals with coronary disease, occlusive arterial disease, or diabetes. While not a glowing recommendation for the use of Vitamin E, it certainly did not conclude that its use increased the risk of all cause mortality.
[49]MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo- controlled trial. Lancet. 2002;360:23-33. [PMID: 12114037]
Conflict of Interest:
None declared
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Submit response
As a long-time user and occasional prescriber of high-dose vitamin E, I read with interest the meta-analysis of studies evaluating use of high- dose Vitamin E supplements. I would like to see a study or even a meta- analysis of studies of HEALTHY patients using these supplements. I agree that unmonitored usage of OTC supplements can potentially do more harm than good, especially in acutely or chronically ill elderly patients, but what about the rest of us? Unfortunately, funding for such a study would probably be difficult to obtain. Any ideas?
Conflict of Interest:
None declared
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question re: study design
Submit responseIt seems questionable that a study that was designed to determine the effects of vit E on mortality would exclude studies that did not have any mortalities. Omitting clinical trials that collected mortality data and had fewer than 10 deaths, seems like a large design flaw. Clearly, trials that did not collect mortality data would be excluded. However,in the methods of design, it was stated that of 36 identified trials to consider studying, 12 of them were excluded as they reported fewer than 10 deaths. I question the bias this creates as 30% of the available data on mortality, or lack there of, was systematically exluded. I would have to look at this study as designed and conducted with a preferred outcome. In addition, I agree, the form of Vit E tested would be helpful information.
Conflict of Interest:
None declared
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Confounders falsify conclusion
Submit responseI read with great interest the very useful paper by Miller et. al. as well as the rapid responses. I checked the type of vitamin E used in most of the studies reviewed by use of the fine review; Antioxidants and atherosclerosis: don't throw out the baby with the bath water. Jialal I, Devaraj S. PMID: 12600900 and by checking the information available on Medline for others. The use of synthetic E was not a confounder except for to possibly extremely small extent.
Beta-carotene was.
Adjustment for the concurrent use of beta-carotene with E in smokers eliminates the excess mortality entirely even after also adjusting for the positive effect of fish oil in the GISSI study.
Analysis of the relationship between mortality and the ratio of vitamin C to E given in the studies shows a strong significant trend with no effect or a small detriment possible at a ratio of less than unity and culminating in the significant 47% reduction of mortality seen at the doses of 440 for E and one gram for C in the PPS study. This relationship is consistent with in vitro and epidemiologic literature and the very corroborative HATS paper which showed a near complete stop to progression of plaque in coronary arteries with supplementation of C and E at a ration of over two.
By the way the mortality values listed for the CHAOS study in the text figure 2 seem to be incorrect. The original CHAOS study gives 36 and 27 for E and placebo.
Sinc.,
Thomas Carter
Conflict of Interest:
None declared
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Re: Natural or Synthetic?
Submit responseI have just read an article by Aileen Burford-Mason PhD, to "E" or not to "E" which appeared on the web site CTV.ca. She makes a strong arguement that because the studies did not specify whether natural or synthetic vitamin E was used the conclusions are not valid. Most people take the natural form of the vitamin but it seems that the synthetic form may have been used in the studies. It has long been known that the natural form is the preferred form. Separate trials should be done one using synthetic E and the other natural E. Only then will we be able to conclude harm or benefit and which form of the vitamin provides which.
Conflict of Interest:
None declared
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Full Disclosure regarding which form of Vitamin E
Submit responseI too, along with other concerned reponses to the study, found it very difficult to detect which form of Vitamin E was used to produce the published results. The public has a right to full disclosure in order to make educated choices regarding vitamin supplementation.
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Vitamin E study not convincing
Submit responseThe Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality, as published in ANNALS, does reveal a very slight increase in mortality at increasingly higher doses of supplemental vitamin E, which often points to a causal relationship. However, the slightly- increased mortality could also be explained by the fact that patients with cardiovascular disease take higher doses of vitamin E. A recent study, the Vitamins and Lifestyle (VITAL) study, conducted among 45,748 participants ranging in age from 50 to 75 years, revealed that persons with cardiovascular disease are more likely to be taking vitamin E supplements, presumably at the higher doses (>400 IU) attributed to the elevated mortality. (1)
Bill Sardi, Knowledge of Health, Inc., San Dimas, California.
(1) Satia-Abouta J, Kristal AR, Patterson RE, Littman AJ, Stratton KL, White E, Dietary supplement use and medical conditions: the VITAL study, Am J Prev Med. 2003 Jan;24(1):43-51.
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Natural or Synthetic E
Submit responseI am not a researcher or medical practitioner, but as an interested party and vitamin E user, I was not able to detect from the research results discussion whether it made a difference if one used natural or synthetic vitamin E. Was there a difference in the research results?
Thank You for your response.
Conflict of Interest:
None declared
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Submit response
With interest I read the online publication in the Annals of Internal Medicine concerning your meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality. You describe the pooled risk difference in the high-dosage vitamin E trials with 39 per 10.000 persons, referring to figure 2. But when I add the numbers of deaths and participants in the high-dosage vitamin E and the control groups I get a risk difference of 48 per 10.000 and I can’t explain this difference in results. May I therefore ask you to explain how you got the number of 39 per 10.000 persons.
Yours sincerely
S. SCHENK (Physician) Editorial staff arznei-telegramm
A.T.I. Arzneimittelinformation Berlin GmbH Bergstr. 38A, Wasserturm, D-12169 Berlin Fax: (0 30) 79 49 02 20 Internet: http://www.arznei-telegramm.de E-Mail: ati@berlin.snafu.de
Conflict of Interest:
None declared
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Gamma (not alpha) Tocopherol should be studied
Submit responseTo the editor:
There is a tragic flaw in Dr. Miller's meta-analysis on Vitamin E.(1) In all of the studies he referenced, Vitamin E was used alone in the "alpha-tocopherol" form. Though alpha-tocopherol may be the most common supplement form of Vitamin E, the gamma form is the one that is found in greatest concentration in the U.S. diet.(2) The "gamma" (but not alpha) form of Vitamin E is the one that protect against cancer and blocks the COX-2 enzyme that is involved in heart disease.(3,4) I prescribe Vitamin E in the "mixed tocopherols" form for these reasons. We will not know the true effects of Vitamin E unless studies are conducted properly. Until then, we should be cautious against perptuating the bias against natural medicine.(5)
1. Miller ER, et al. Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality. Ann Intern Med. 2005;142(1).
2. Jiang Q, et al. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74(6): 714-22.
3. Helzlsouer KJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24): 2018-23.
4. Jiang Q, et al. Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci U S A. 2000;97(21): 11494-9.
5. Goodwin JS. Battling quackery: attitudes about micronutrient supplements in American academic medicine. Arch Intern Med. 1998;158(20): 2187-91.
Conflict of Interest:
None declared
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Vitamin E Warning Premature
Submit responseIs Vitamin E dangerous in high doses?
In some circumstances, it may be. But these are limited conditions and there are certainly some easy ways to get around them. Let me explain.
I am writing this in response to an article published this week in Annals of Internal Medicine. Researchers at Johns Hopkins have subjected some Vitamin E studies to a meta-analysis, which is where previously published studies are re-examined and compared in order to try to mine more information out of them. These meta-analyses are often highly speculative, because the protocol for each study is different enough that it becomes a stretch to link the results and imply a common thread runs through them despite the different variables. For example, the supplement tested may be given in different forms or doses, the patient group may have significant differences, the length of time taking the supplement may vary considerably or may even include previous users and new users, etc. There are also differences between natural and synthetic Vitamin E, with most studies using only the synthetic forms that are composed of different -shaped molecules and only half as effective as natural Vitamin E. Natural Vitamin E is called d-alpha tocopherol and synthetic Vitamin E is called dl-alpha tocopherol.
Official U.S. dietary guidelines set an upper tolerable intake limit of up to 1,500 IU per day, based on the scientific record.
While these meta-analyses are academically useful to point to potential new problems or solutions, by no means are they definitive proof of anything, due to the lack of uniform protocols and patient groups. But that won’t stop the medical lobby from trying to use these results to limit potencies of vitamins to everyone “for our own good”. The doctors and researchers may be well-meaning, but results of this kind of preliminary study can be publicized and take on a life of their own, with a new role as “proof” of the dangers of taking vitamins.
One thing that many of the patients in this analysis of previous studies had in common was being elderly and sick. So the first caution issued by the report’s authors is that their speculative findings would not even apply to healthy or younger people. That’s one BIG argument against using this analysis to set general restrictions on Vitamin E dosages. We already have some evidence that taking one antioxidant, rather than antioxidant formulas or multiple vitamins, may increase the cancer risks for aged smokers. This may be because antioxidants need to recharge and support each other or else some can actually transform into pro- oxidants that can increase the damage.
I always caution against taking mega-doses of one nutrient without considering potential side effects. Taking only one antioxidant may seem to deplete others because of the way they interact, with one antioxidant chemically supporting others. A surplus of one nutrient may increase a person's need for one or more other nutrients, creating an apparent functional deficiency.
There is a recent example that illustrates my point. Some years ago an antioxidant study in Finland was halted early, with a widely reported increase in cancer rates among male smokers taking beta-carotene. Headlines associated vitamins with cancer risk. Despite objections that the study was flawed, vitamin use dropped.
Fast-forward to this year. A new analysis published in July takes another look at that same Finnish smokers' study, but now takes into account their total antioxidant intake, and clears up that whole controversy. Their risk of getting lung cancer was closely associated with total antioxidants in the diet, with more antioxidants meaning less cancer.
A composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, Vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: a combination of antioxidants lowers lung cancer risk in male smokers.
What does this all mean? I think we are in for another round of attacks on vitamins based on this crude analysis of Vitamin E, with some medical experts calling for restrictions on vitamin potency. That would be a mistake, both scientifically and from a public health viewpoint. The message should be that people should not try to take a high dose of one supplement without considering that it may increase our need for other nutrients. Elderly, sick people need a more holistic approach rather than using a single nutrient in high doses, as if it were a drug. Nutrients just don’t work well in isolation from each other. Vitamins are essential to health and life, but the average American gets only 1/3 of the recommended daily intake of Vitamin E that would prevent serious illnesses. Most people would benefit from taking a multiple vitamin and a Vitamin E supplement, and it would be safer than just the Vitamin E alone.
That shouldn’t be hard for the smart folks at Johns Hopkins to understand. But the media reporting this analysis got the facts wrong.
By Neil E. Levin, CCN, DANLA
REFERENCES:
1. July 2004 American Journal of Epidemiology
2. Poster session abstract: High-dose vitamin E supplementation may increase all-cause mortality, a dose response meta-analysis of randomized trials; Ernest N. Morial Convention Center, Exhibit Hall 1-2.) Annals of Internal Medicine, Nov. 10, 2004
Conflict of Interest:
Educator for vitamin company, but these comments are my own
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Natural or Synthetic?
Submit responseIt has been shown that synthetic Vitamin A can be quite harmful whereas natural A is very beneficial. The same is likely true with Vitamin E. Before you aggregate results across studies you must know what what types people take. Most often they themselves do not know!
Conflict of Interest:
None declared
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Type of vitamin E
Submit responsePlease report which type of vitamin E was used in the trial by Miller, et al. Whether or not d- or dl- tocopherols,beta, gamma, mixed, etc. were used could potentially be very important,indeed, make the difference in your findings altogether. I am concerned that this may be a very important study, but highly confounded if synthetic and/or various types of vitamin E were used.
Thank you Cynthia Gran
Conflict of Interest:
None declared