(The essay below was written for PhysioAge patients in response to the SELECT trial. As such, it is not as “engaging” as a typical blog post but rather serves as a literature review, and also provides insight on my approach to supplements.) From time to time a medical paper comes out that “makes the headlines.” This week the news cycle focused briefly on a trial known as SELECT: the Selenium and Vitamin E Cancer Prevention Trial. SELECT was a study of 35,000 men over age 50, initiated back in 2001. The men were given either 200mcg/day of selenium, 400 IUs/day of vitamin E, both, or neither (two placebo pills). They were then checked for prostate cancer every six months, for the next ten years. In 2008 the researchers reported that, after 5.5 years of supplementation, there was no benefit from either supplement in the prevention of prostate cancer. Last week, JAMA published a follow-up report: having followed the men for a few more years, it now appeared that dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. This hit the 24-hour news cycle hard and fast: ABC World News reported that the study shows “vitamin E significantly raises the risk of prostate cancer in healthy men by 17%.” CBS Evening News agreed. The Washington Post (10/12/11, Stein) reported on its front page(!), “Just because it’s ‘only a vitamin’ or ‘it’s natural,’ we assume it must be safe. But over and over again, we see that’s not necessarily the case.’ And so on. Not surprisingly, we received a number of emails from concerned patients. Let me start by making clear that the PhysioAge Supplement Packs do not contain any of the type of vitamin E that was used in the SELECT study. And with good reason: it’s been apparent for well over a decade that high doses of that type of vitamin E may be harmful. If we had been asked to write the news story on SELECT, it would have sounded something like this: The SELECT Trial shows yet again that high doses of synthetic d,l-alpha tocopherol are probably harmful— a finding that has been observed in close to a dozen previous trials. SELECT did not investigate natural alpha-tocopherol, nor did it look at any of the seven other forms of vitamin E. Of note, trial participants who also took selenium were protected from the ill effects of high-dose synthetic alpha-tocopherol, suggesting that multiple anti-oxidants used in combination (similar to how they are ingested in food) are more beneficial than single anti-oxidants in high doses. This too is consistent with multiple previous trials. That story is a bit less exciting, but it has the benefit of being accurate. To put the SELECT trial in context, we need to back up and look at vitamin E research as a whole. Epidemiologic data from cross-sectional, case-controlled, prospective studies have shown a connection between the consumption of antioxidant vitamins and minerals— or foods with high concentrations of these nutrients— and reduction in the incidence of cancer and cardiovascular disease. Some examples: A 1993 study, published in the New England Journal of Medicine, looked at 40,000 men over the course of four years, and concluded:
For men consuming more than 60 IU per day of vitamin E, the relative risk [of coronary disease] was 0.64 as compared with those consuming less than 7.5 IU per day.”1
(95 percent confidence interval 0.49 to 0.83) (Note: the cutoff for a beneficial effect in this study was 60 IUs of vitamin E per day—quite a low dose compared to what is found in most multivitamins. Remember this as you read on.) Other epidemiologic studies found similar results:
- “Epidemiologic data support the association between high intake of vegetables and fruits and low risk of chronic disease.” 2
- “…the results are consistent with a strong protective effect of fruit and vegetables for stroke and a weaker protective effect on coronary heart disease.” 3
- “This overview of prospective cohort studies indicates that high dietary intake of flavonols from a small number of fruits and vegetables, tea and red wine may be associated with a reduced risk from CHD mortality.” 4
- “Epidemiological studies suggest that low levels of antioxidants are associated with increased risk for cardiovascular disease, and that increased intakes appear to be protective.”5
However, randomized, placebo-controlled, primary prevention trials using vitamin E, either alone or paired with other antioxidant micronutrients, have produced conflicting results regarding clinical benefit.6,7,8,9,10,10a How do we explain that? Why is it that the epidemiologic studies show benefit, yet the primary prevention trials do not? The answer is, vitamin E primary prevention trials frequently suffer from one or more key issues that negatively affect outcome:
- They use synthetic
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rather than natural vitamin E
- They use natural vitamin E, but only one form of it, d-alpha-tocopherol, while ignoring the other seven forms
- They use alpha-tocopherol doses that are excessively high, thereby inhibiting utilization of more beneficial forms of E
- They study single antioxidants in isolation, the way they would study a pharmaceutical drug. Antioxidants work better in concert with one another.
Allow me to explore these issues a bit further, starting with the first two, which are intertwined: Synthetic vs. Natural E, and the Eight Isomers of E It is important to understand that Vitamin E is not a single vitamin. There are, in fact, at least eight forms of Vitamin E. Four of these are called tocopherols: alpha, beta, gamma and delta tocopherol, and four are called tocotrienols (again, alpha through delta). The eight forms are not inter-convertible in humans, and all have different chemical structures, functions, biological activity and clinical effects. In food, we generally find much higher concentrations of gamma-tocopherol than alpha. However, nearly all of the large trials that have been performed on vitamin E (including SELECT) have studied just one vitamin E isomer: alpha-tocopherol. Gamma-tocopherol, and the other six tocopherol and tocotrienol isomers, have been virtually ignored. To confuse things further, natural alpha-tocopherol found in food is not the same as the type found in many supplements. Natural alpha-tocopherol is known as d-alpha tocopherol; the “d” refers to chemistry nomenclature indicating the orientation of the molecule. But synthetic alpha-tocopherol contains both the d-form and its mirror image, the l-form. This synthetic mixture of “d and l”-alpha tocopherol (also called ‘racemic’ alpha tocopherol) is cheaper than natural d-alpha-tocopherol—and therefore is quite often the form used in large trials, even though it’s not the kind we ingest in food. Is the difference between synthetic and natural alpha-tocopherol clinically relevant? There is reason to believe it is. Natural d-alpha tocopherol is more potent than the synthetic form in its anti-inflammatory, antioxidant and cell signaling effects.11,12,13 In addition, synthetic d,l-alpha-tocopherol may have adverse effects. Studies suggest that when administered alone at high doses, all-racemic (synthetic) alpha-tocopherol may:
- interfere with the biological activity of natural d-alpha tocopherol and reduce HDL-cholesterol in humans, potentially increasing cardiovascular risk14
- inhibit glutathione S-transferases important in the detoxification of drugs and endogenous toxins15
- produce other adverse effects: in the Alpha Tocopherol Beta Carotene (ATBC) Cancer Prevention study, synthetic alpha tocopherol increased the risk of intra-cranial hemorrhage in patients who were smokers.16
And what about the other seven forms of vitamin E? The foods we eat do not contain much alpha-tocopherol: natural d-alpha-tocopherol comprises only about 15% of total vitamin E found in the U.S. diet (and synthetic d,l-alpha tocopherol isn’t found in food at all). Gamma-tocopherol is the most common form of vitamin E in the US diet (70%) and in many plant seeds. And there is a growing body of data to suggest that gamma-tocopherol has a much more important role in cancer prevention than alpha-tocopherol.9,13
Gamma-tocopherol has some unique properties that alpha-tocopherol does not have, including the ability to reduce nitrogen dioxide to the antioxidant nitric oxide17, along with the ability to suppress the expression of the ras-p21 gene, which encodes a protein known to promote cancer.
In colon cancer cell studies, scientists have found that while both gamma- and alpha-tocopherol could upregulate PPAR-γ protein expression (produce more of the protein), gamma-tocopherol was much better at this task than its alpha cousin (BMC Cancer. 2003;3:25). So, when we use only alpha-tocopherol in studies, we are likely ignoring a much more powerful anti-cancer agent. The problem with high doses of alpha-tocopherol This brings us to Problem #3 from our list above: Many studies on vitamin E—even those that used natural alpha-tocopherol—used high doses (over 400 IUs a day). Why is this a problem? It’s a problem because the hepatic tocopherol transfer protein (TTP) is crucial for the relative percent of transport of the various forms of vitamin E in the plasma lipoproteins— and it has a 10-fold greater affinity for alpha tocopherol compared to gamma tocopherol. So by taking too much alpha tocopherol, you are likely reducing your ability to utilize gamma-tocopherol, as well as the tocotrienols.18,19 This means that taking high doses of alpha-tocopherol isn’t just “neutral”: it may decrease your ability to fight cancer—as apparently occurred in the SELECT trial. This is not new information, though: In 2006 Wright et al reviewed the ATBC data and found that higher levels of (natural) serum alpha-tocopherol are associated with lower mortality — but only to a point:
“…regression analysis of continuous serum alpha-tocopherol values indicated greater risk reductions with increasing concentrations up to 13–14 mg/L (30-33 uM/L), after which no further benefit was noted. Conclusion:
Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.20
And how much alpha-tocopherol would be needed to keep your serum level at that “sweet spot” of 13-14mg/L? That has been studied as well. In an extensive comment on the above article, it was noted:
We now have a critical piece of information—that is, serum alpha-tocopherol concentrations of 13–14 mg/L (30–33 µmol/L) optimally reduce mortality due to chronic disease. Now all we have to do is estimate how much alpha-tocopherol to consume to achieve that serum concentration. …Deveraj showed that serum alpha-tocopherol concentrations… could be raised to 14.2 mg/L (33 µmol/L) by the consumption of 100 IU (alpha tocopherol) supplements.21
In other words, we have an analysis indicating that perhaps 100 IUs/day should be the upper limit of your alpha-tocopherol supplementation.
With that in mind, let’s get more supporting evidence: Further data showing gamma is good, synthetic is bad A large trial completed a decade ago followed 11,000 men for eleven years and found that increased serum levels of gamma-tocopherol were associated with a significantly reduced risk of prostate cancer:22 Men with the highest levels of gamma-tocopherol, had a fivefold reduction in the risk of developing prostate cancer compared to men with the lowest levels (P (trend) =.002). Selenium was also protective, with one important caveat:
Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high.
The researchers drew a very reasonable conclusion:
The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium.”23
That study was published eleven years ago in the Journal of the National Cancer Institute! So we have suspected for 11 years that, at least in the case of prostate cancer, it doesn’t make sense to do trials with high doses of alpha tocopherol alone.
And we’ve known for even longer that using synthetic alpha tocopherol is a bad idea: as far back as 2003, an editorial in Circulation looked at eleven Vitamin E studies done to that point, and stated:
…of the 7 studies with a negative result, five used [synthetic] all-rac-Alpha Tocopherol… whereas all 4 studies showing a positive effect used [natural d-alpha tocopherol]. 5
So what have we learned so far? We’ve seen that– for well over a decade– the evidence has shown two things about Vitamin E:
- synthetic alpha tocopherol may be harmful and should not be used
- even natural alpha-tocopherol should not be supplemented alone or in high doses: gamma-tocopherol should be included– perhaps in higher concentrations than alpha, similar to the ratios found in food.
Over the many years since, these observations have been validated again and again: In 2005, a meta-analysis of 19 vitamin E studies conducted between 1993 and 2004 was published in Annals of Internal Medicine. Authors Miller et al concluded that people who take daily doses of 400 iu’s or more of “Vitamin E” have a 10% increase in all-cause mortality compared to people who take smaller doses or no “Vitamin E”.24 Of course, what made the news? Simply that “Vitamin E” increases the risk of death. But which type of E was used in those trials? In his rebuttal to the Annals article, Dr Mark Houston pointed out that the Vitamin E used in Miller’s meta-Analysis was entirely alpha-tocopherol, and mostly synthetic d,l-alpha tocopherol:
None of the 19 studies in Miller’s review included any of the other seven forms of vitamin E, and, in fact, most of them used synthetic d,l-alpha tocopherol.25
Yet researchers seem fixated on re-testing the same point: even after that 2005 meta-analysis, another “negative” vitamin E study was published by Sesso in JAMA Nov 9, 2008– again using high-dose synthetic d,l-alpha tocopherol.26
And to that we can now add this week’s paper on the SELECT study: yet another trial of high-dose (400 IU/day) synthetic, dl-alpha tocopherol with a negative outcome. Not news at all—simply leftovers from a meal
that has been reheated one too many times. Selenium lends a hand There is one other interesting note within the small print of the SELECT study: The patients that took BOTH selenium and synthetic alpha tocopherol did NOT have an increased risk of prostate cancer:
After adjustment for the marginal effects of vitamin E and selenium, the interaction between vitamin E and selenium was statistically significant (P = .02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together.”29
And that gets to the crux of why most studies of high-dose anti-oxidant therapy using a single supplement are likely to fail: Our bodies do not rely on one antioxidant. There are hundreds of naturally occurring antioxidants, but there is dynamic interplay between five key antioxidants in particular: Vitamins C and E, CoQ10, lipoic acid, and glutathione. In his book “The Antioxidant Miracle”, these are referred to by Lester Packer as the “anti-oxidant network”. In combination, they greatly enhance the activity of one another, and are able to ‘recycle’ each other after a free-radical has been bound. This ‘recycling’ is crucial, because without it, the anti-oxidant itself becomes a free-radical once it has acted on the offending molecule. So vitamin E, for example, benefits from having CoQ10 around to recycle it. Furthermore: Vitamin E and CoQ10 are lipid soluble, and therefore may be beneficial within the lipophilic cell membrane, but may be of little help in the hydrophilic interior of the cell or in the blood. For those areas, we need Vitamin C and glutathione. Because of this dynamic interplay, it is not surprising that in the SELECT study, those taking two antioxidants (E and selenium) fared better than those taking just E. What is the take-home message? All available evidence strongly suggests that if the SELECT study had been done using low-dose natural d-alpha tocopherol, the outcome would have been better, and if they had used gamma-tocopherol (as we do in our Supplement Packs), the incidence of prostate cancer might have decreased, just as it did in the gamma-tocopherol and selenium study mentioned above.23 To summarize: I believe that multiple antioxidants used together, in their natural form, with doses of alpha-tocopherol not exceeding 100 IUs, are likely to produce significant health benefits. Have any human trials tested this hypothesis? Yes. Here are two human trials illustrative of these principles: 1. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13,017 French adults took a single daily capsule of a combination of 120 mg of Vitamin C, 30 mg (45 IUs) of natural vitamin E, 6 mg of beta carotene, 100 mcg of selenium, and 20 mg of zinc, or a placebo. After 7.5 years, total cancer incidence and all cause mortality in men was reduced by 31% and 37% respectively (p = 0.004).27 2. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study: In the ASAP trial, participants supplementated with 136 IU of alpha-tocopherol (a bit higher than our “suggested upper limit” of 100 IUs) plus 250 mg of vitamin C. At three years and again at six years, they noted that the regimen slowed down the progression of carotid atherosclerosis, in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not significant). The effect was larger in subjects with low baseline plasma vitamin C levels.28 We are in the process now of reviewing the PhysioAge Packs again, and will likely make some changes as we assess what the data dictates. Eventually, the goal is to be able to measure each person’s intracellular vitamin and micronutrient needs individually, and tailor a program to them. We can do this already with CoQ10 and Vitamin D, for which supplementation based on serum levels has been clinically validated. As other such tests become available, we will certainly adopt them; currently we are looking into the data behind testing F2-isoprostanes and Omega-3 fatty acid testing. Meanwhile, it is our belief that current literature supports the use of antioxidants and other micronutrients in concert with one another, in doses that can be justified with the available data. In some cases that means limiting your intake (alpha-tocopherol below 100 IUs per day and selenium below 200 mcg/day) and in some cases it means making sure you take enough (e.g., curcumin needs to be dosed higher to achieve absorption). As always, if you have questions about any part of your treatment plan, please don’t hesitate to ask. [expandsub1 title=”Show me the REFERENCES.”] 1. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993; 328:1444-1449. 2. Lampe JW. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr 1999; 70(Suppl):475S-490S. 3. Ness AR, Powles JW. Fruit and vegetables and cardiovascular disease: a review. Int
J Epidemiol 1997; 26(1):1-13. 4. Huxley RR, Neil HAW. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2003; 57:904-908. 5. Jialal I, Devaraj S. Antioxidants and atherosclerosis. Don’t throw out the baby with the bath water. Circulation 2003; 107:926-928. 6. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta- analysis of randomized trials. Lancet 2003; 361-423. 7. Morris CD, Carson S. Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003; 139:56-70. 8. U.S. Preventative Task Force. Routine vitamin supplementation to prevent cancer and cardiovascular disease. Nutrition in Clinical Care 2003; 6(3):102-107. 9. Friedrich MJ. To “E” or not to “E”, Vitamin E’s Role in Health and Disease is the Question. JAMA 2004; 292(6):671-673. 10. Kris-Etherton P, Lichtenstein AH, Howard BV, et al. Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004; 110:637-641. 10a. Abudu N, Miller JJ, Attaelmannan M, et al. Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin Chim Acta 2004; 339:11-25. 11. Devaraj S, Traber MG. Gamma-tocopherol, the new vitamin E? Am J Clin Nutr 2003; 77:530-531. 12. Chopra RK, Bhagavan HN. Relative bioavailabilities of natural and synthetic vitamin E formulations containing mixed tocopherols in human subjects. Int J Vitam Nutr Res 1999; 69(2):92-95. 13. Qing J, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the U.S. diet, deserves more attention. Am J Clin Nutr 2001; 74(6):714-722. 14. Abudu N, Miller JJ, Attaelmannan M, et al. Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin Chim Acta 2004; 339:11-25. 15. van Haaften RI, Haenen GR, van Bladeren PJ, et al. Inhibition of various glutathione S-transferase isoenzymes by RRR- alpha-tocopherol. Toxicol In Vitro 2003; 17:245-251. 16. Roberts HJ. Perspective on vitamin E as therapy. JAMA 1981; 246:129-131 17. Cooney RV,
et al. gamma tocopherol detoxification of nitrogen dioxide: superiority to alpha tocopherol. Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1771-5. 18. Hosomi A, et al. Affinity for alpha-tocopherol transfer protein as a determinant for the biological activities of vitamin E analogs. FEBS Lett 1997; 409:105-108. 19. Huang HY, Appel LJ. Supplementation of diets with alpha- tocopherol reduces serum concentrations of gamma- and delta- tocopherol in humans. J Nutr 2003; 133(10):3137-3140.
20. Wright ME, Lawson KA, et al: Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 2006 Nov;84(5):1200-7.
21. Traber MG. How much vitamin E? … Just enough! Am J Clin Nutr. 2006 Nov;84(5):959-60.
22. (Helzlsouer KJ et al, Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92:2018-2023) 23. Helzlsouer KJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. 24. http://www.annals.org/cgi/content/full/142/1/37 High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality Edgar R. Miller et al. Annals of Internal Medicine 4 January 2005 25. JANA Vol. 8 No. 1, 2005, “Meta-Analysis, Metaphysics and Mythology” Scientific and Clinical Perspective on the Controversies Regarding Vitamin E for the Prevention and Treatment of Disease in Humans. Mark Houston, MD. http://www.antiaging.com/white_papers/vitamin_e_jana.html 26. http://jama.ama-assn.org/cgi/content/full/300/18/2123 Vitamins E and C in the Prevention of Cardiovascular Disease in Men. The Physicians’ Health Study II Randomized Controlled Trial. Howard D. Sesso et al JAMA. 2008;300(18):2123-2133. 27. Hercberg S, Galan P, Preziosi P, et al. The SU.VI. MAX Study. A randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med 2004; 164:2335-2342. 28. Circulation. 2003 Feb 25;107(7):947-53. 29. Vitamin E and the Risk of Prostate Cancer; The Selenium and Vitamin E Cancer Prevention Trial (SELECT) JAMA. 2011;306(14):1549-1556. [/expandsub1]