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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
High dose vitamin E supplementation and all-cause mortality.
New Evidence on Vitamin E Safety
Does Vitamin E Supplementation With 400 IU/d Significantly Increase All-Cause Mortality?
Comment
Authors response to submitted letters
Some weaknesses in the methods of meta-analysis by Miller et al.
Vitamin E: Good Science Requires a Precisely Defined Intervention
Immune-modulating properties of vitamins have been ignored
High-dosage vitamin E supplementation is unjustified, but will the evidence modify the custom?
Questions needing answers
Vitamin E Supplementation was not associated with mortality in the DATATOP cohort
Mortality and Vitamin E ?
Flaws in Vitamin E study
Natural or Synthetic?
Re: Vitamin E & all-cause mortality
Vitamin E & all-cause mortality
High dose vitamin E supplementation: time to return to the drawing board....
Not All Vitamin E Should Be Condemned : A Different Perspective
ARBITRARY DEFINITION OF HIGH DOSE
Study is too simple
Eat an apple a day...and take your vitamins!
Simple Statistics support paper's findings
Incorrect Statistics Used in Vitamin E Report
Interaction of drugs with vitamin E
Safety of Vitamin E Supplementation in Humans
Lancet was correct!
Untitled
question re: study design
Confounders falsify conclusion
The benefit and harm of vitamin E supplementation
Potential bias in methods may negate statistical significance of the high dose vitamin E analysis
VITAMIN E: Which isoform and how much?
Dose-Response Analysis Reconsidered
Vitamin E toxicity ?
Re: Natural or Synthetic?
Full Disclosure regarding which form of Vitamin E
Natural or Synthetic E
Vitamin E study not convincing
Untitled
Gamma (not alpha) Tocopherol should be studied
Vitamin E Warning Premature
Natural or Synthetic?
Type of vitamin E
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Simin N. Meydani, DVM,PhD JM USDA-HNRCA at Tufts University, Gerard E. Dallal, Joseph Lau, Mohsen Meydani
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simin.meydani{at}tufts.edu Simin N. Meydani, et al.
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Dear 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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Neil E. Levin, CCN, DANLA
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neil.levin{at}fruitfulyield.com Neil E. Levin
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New 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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Roy C Milton , Jonghyeon Kim
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rmilton{at}emmes.com Roy C Milton, et al.
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A 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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M Joyanes, unknown CNA-AESA
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gjoyanes{at}isciii.es M Joyanes
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With 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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Edgar R Miller III, MD PhD Johns Hopkins University, Roberto Pastor-Barriuso, Lawrence J Appel, Eliseo Guallar
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emiller{at}jhmi.edu Edgar R Miller III, et al.
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To 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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David H. Blatt, MD Good Samaritan Center, William A. Pryor PhD
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davidblatt{at}comcast.net David H. Blatt, et al.
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A 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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Gregory A. Plotnikoff, MD, MTS University of Minnesota Medical School
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gregory{at}sc.itc.keio.ac.jp Gregory A. Plotnikoff
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To 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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Mario E Flores, MD, MSc National Institute of Public Health, Cuernavaca, MEXICO.
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mflores{at}correo.insp.mx Mario E Flores
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Dear 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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Salvador Vale, MD INDESALUD, Departamento de Investigación, Campeche, México
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svalemayorga{at}yahoo.com.mx Salvador Vale
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Miller'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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Lawrence J. O'Brien, MA None-Author, n/a
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inlob{at}comcast.net Lawrence J. O'Brien, et al.
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For 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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Connie Marras, MD Division of Neurology, Toronto Western Hospital, University of Toronto, David Oakes, Michael P. McDermott, Anthony E. Lang, Caroline M. Tanner, Karl Kieburtz, Stanley Fahn, Ira Shoulson and the Parkinson Study Group
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connie.marras{at}utoronto.ca Connie Marras, et al.
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In 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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Joseph E. Baggott, Ph.D. Department of Nutrition Sciences, University of Alabama at Birmingham
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bbrannum{at}uab.edu Joseph E. Baggott
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To 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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David S Riley, MD University of New Mexico
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dsrileymd{at}earthlink.net David S Riley
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All 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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Samer Koutoubi, MD, PhD Bastyr University
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skoutoub{at}bastyr.edu Samer Koutoubi
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I 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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Rachel G Stern, RD
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Sternworks{at}att.net Rachel G Stern
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Until 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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Simin N. Meydani, DVM, PhD JM USDA/HNRCA at Tufts University, Joseph Lau, Gerard E. Dallal, Mohsen Meydani
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simin.meydani{at}tufts.edu Simin N. Meydani, et al.
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In 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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Wee-Shiong Lim, M.D. Alzheimer's Disease Research Center, Washington University School of Medicine, Rajka Liscic, Chengjie Xiong, and John C. Morris
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lwees{at}yahoo.com Wee-Shiong Lim, et al.
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The 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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WH LEONG, B. Applied Science Carotech Inc
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carot3{at}aol.com WH LEONG
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In 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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Annette Dickinson, Ph.D. Council for Responsible Nutrition
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annette{at}crnusa.org Annette Dickinson
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In 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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