There was some big news in this week’s issue of Journal of the American Medical Association (JAMA): results were published1 from the
Physician’s Health Study II, a well designed long-term controlled trial of multivitamins for cancer prevention. It is very hard to come by large, prospective controlled supplement trials, so this was exciting! Almost 15,000 men over age 50 were randomized to take either placebo or a combination of the following supplements: Centrum Silver daily 400 IUs of synthetic alpha tocopherol every other day 500mg Vitamin C daily 50mg beta carotene daily The men were then followed for over 11 years. Here is what they found: Compared with placebo, men taking the supplement combination had a statistically significant reduction in the incidence of total cancer. To be clear, it was a small reduction (about 8%), but it was significant… and I’ll tell you in a minute how they could have gotten even better results (and so can you). There was no significant reduction in prostate or colon cancer. Half of all the cancers they found were prostate cancer. This is not surprising, since this was a men-only study and prostate cancer is among the most common cancers in men. However, most of the prostate cancers were early grade with high survival rates—cancers that these days might be addressed with a “watch and wait” mentality rather than any intervention. Thus, the authors point out that daily multivitamin use may have an even greater benefit on more clinically relevant cancer diagnoses—the cancers we are really worried about. But there is another possibility: There is good reason to believe that they would have had even better results if they had not used high doses of synthetic alpha-tocopherol or beta carotene. As I wrote last year in my comments on the SELECT trial, there is no reason to expect a good outcome from the use of high doses of synthetic alpha tocopherol. In fact, SELECT2 found an increase in prostate cancer in patients that took high doses of synthetic alpha tocopherol, so perhaps it is no surprise that this new study found no decrease in prostate cancer. As I said then,
The SELECT Trial shows yet again that high doses of synthetic 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.
The Physician’s Health Study II now reinforces that impression. Patients took high dose synthetic alpha tocopherol, just like in the SELECT trial, and so in fact we might have expected prostate cancer incidence to increase—however, they also took multiple other antioxidants (including selenium) along with it—and thus while prostate cancer incidence was not reduced (like other cancers were), it was also not increased. For a much more extensive look at the data on various forms of Vitamin E, please see my review, Does Vitamin E Cause Prostate Cancer? In addition, I would point out that this trial used 50mg (quite a high dose) of beta carotene– and the data behind using high doses of beta carotene is questionable at best. Unlike most supplements, beta-carotene has been studied in several large randomized, placebo-controlled clinical trials: The “Beta-Carotene and Retinol Efficacy Trial,” called CARET for short, was stopped early in 1996 because initial results showed that smokers and asbestos workers taking beta-carotene had a 28% increase in lung cancer and a
17% increased risk of death over those taking placebo.3 And in Finland, the Alpha-Tocopherol Beta-Carotene (ATBC) cancer prevention
trial evaluated the effects of beta-carotene and/or alpha-tocopherol on more than 29,000 male smokers4 – and there too, after six years the risk of lung cancer in the groups taking beta-carotene increased by 16%. In fact, a 2011 review paper5 looked at six randomized controlled trials, including 40,544 total participants (half in beta-carotene supplement groups, and half in placebo groups). They found that beta-carotene supplements had no preventive effect on either cancer incidence or cancer mortality. (And they noted similar findings whether the trials were for primary prevention or secondary prevention.) Subgroup analyses by various factors revealed that actually beta carotene significantly increased the risk of bladder cancer (RR = 1.52, 95% CI = 1.03-2.24). Also, it marginally increased the overall risk of cancer among current smokers (RR = 1.07, 95% CI = 0.99-1.17). Furthermore, lutein (which is also in Centrum Silver) may also be ill-advised: A study published in 2008 looked at 77,000 people who took supplements, and found that, whether or not they smoked, taking lutein supplements doubled their risk of lung cancer—and beta carotene tripled it!17 We aren’t sure yet what the reasons are for this increased cancer risk with beta carotene and lutein (both of which have similar chemical structures). However, further investigation by McNulty et al.5 reveals a possible explanation: the molecular structure of carotenoids actually can be very disruptive to the cell membrane, and thus it is plausible that they may cause an increase in cancer risk over time. Therefore at
PhysioAge we decided to completely remove beta carotene and lutein from our new Premium Packs. We have replaced them with a special carotenoid called astaxanthin, which
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has numerous human trials supporting its use. But, you may ask: if Astaxanthin is another carotenoid, won’t it just cause the same problems? Actually, no: because of its unique molecular structure, astaxanthin is different from other carotenoids. For the whole story on astaxanthin and how it differs from beta carotene and lutein, see my blog post, Astaxanthin: King of the Carotenoids. Thus, I believe that the data supports two important points:
- Multiple antioxidants used together, in their natural form, with doses of natural alpha-tocopherol not exceeding 100 IUs, are likely to produce significant health benefits.
- Large doses of beta carotene—such as the 50mg used in this trial—should be avoided.
Have any human trials tested these ideas? Yes. The SU.VI.MAX Study: The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study was a randomized, double-blind, placebo-controlled primary prevention trial of the health effects of antioxidant vitamins and minerals. More than 13,000 French adults took a daily capsule 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).8 As you can see, the decreased cancer incidence in the SuViMax trial was far greater than in the current Physician’s Health Study II! One may well wonder what the Physician’s Health Study would have found if they had left out the synthetic alpha tocopherol and lowered the dose of beta carotene. What’s the bottom line?
- For long term health benefits, including cancer prevention, the Physician’s Health Study II provides additional support for the concept of using multiple antioxidants in combination.
- However, at least a dozen prior studies on alpha tocopherol indicate the authors would have had even better results had they replaced synthetic alpha tocopherol with no more than 100 iu’s of natural alpha tocopherol.
- Prior studies also suggest that large doses of beta carotene may increase the risk of cancer; lab studies indicate that astaxanthin does not disrupt cell membranes the way other carotenoids do, and multiple human studies have shown significant benefit from the use of astaxanthin.
- For these reasons, astaxanthin remains my ‘carotenoid of choice.’
For more thoughts and analysis on what the ideal multivitamin should look like, see my blog post, Is Your Multivitamin Doing More Harm Than Good? All of the data mentioned above, and a lot more, went into formulating the new PhysioAge Premium Pack and Premium Pack Plus, which I’m pleased to announce will be available in just a few weeks!
[dropdown_box expand_text=”” show_more=”Show me the REFERENCES.” show_less=”Hide references, please.” start=”hide”] 1. Multivitamins in the Prevention of Cancer in Men: The Physicians’ Health Study II Randomized Controlled Trial. JAMA, Published online October 17, 2012 2. Vitamin E and the Risk of Prostate Cancer; The Selenium and Vitamin E Cancer Prevention Trial (SELECT) JAMA. 2011;306(14):1549-1556. 3. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155. 4. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330(15):1029-1035 5. Nutr Cancer. 2011 Nov;63(8):1196-207. Epub 2011 Oct 7. Effects of Beta-carotene supplements on cancer prevention: meta-analysis of randomized controlled trials 6. Long-term Use of b-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study Am J Epidemiol 2009;169:815–828 7. McNulty HP, Byun J, Lockwood SF, et al. Differential effects of carotenoids on lipid peroxidation due to membrane interactions. X-ray diffraction analysis. Biochim Biophys Acta 2007;1768:167-174. 8. 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. [/dropdown_box]