Are Antioxidants Finished as Dietary Supplements?

by Paul Rogers on June 2, 2009

Pic (c) Stoic / Flickr

Pic (c) Stoic / Flickr

Twenty years ago, antioxidant supplements ruled. The famous, now infamous, supplement combination of vitamins A, C and E, was supposed to be a miracle supplement combo that would fight everything from heart disease to cancer. Famous cardiologists started to take vitamin E — and say so — and the whole ACE thing boosted the reputation and sales of supplements the world over.

Vitamin A and beta-carotene

Then things started to go seriously wrong. In 1996, the Beta-Carotene and Retinol Efficacy Trial (CARET) reported on a test of the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit, and substantial evidence of possible harm: there was 28% more lung cancers and 17% more deaths in the group that received the beta carotene and vitamin A. These results were similar to those produced in a trial of beta carotene in smokers in Finland.

Strangely, the trial had been prompted by the observation that increased consumption of carotenes (orange to purple colours) in fruit and vegetables might provide protection against lung cancer. This observation seems to hold to this day for food sources of beta carotene — but not for supplements.

Vitamin E

Well, what about vitamin E then? Surely that has some benefit as a supplement? Probably not; in fact, vitamins E, A and beta-carotene supplements may increase mortality. The latest Cochrane review (Bjelakovic) of ACE supplements said this:

“We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomised trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.”

(Cochrane reviews provide systematic evaluation of the evidence for various biomedical interventions. See http://www.cochrane.org/)

Vitamin C

Vitamin C supplementation seems not to do serious harm but provides little benefit either for most end points, including cancer, heart disease and immunity. Even the early promise of ACE supplements for the prevention of age-related macular degeneration of the eyes has not been confirmed; and in the light of potential harm from E, A and B-C, this course is not recommended, even though a high dietary intake of whole plant foods may be beneficial.

There may still be health niches where vitamin C supplementation is useful — in smokers with poor dietary intake and in low-dose supplements and multivitamins for example — but the good old days of vitamin C as a miracle vitamin is long gone. High and megadoses >200 milligrams/day may even be limiting for athletes and regular exercisers by interfering with energy systems and oxidative metabolism — but that’s another story.

Selenium

Selenium, not so long ago, was the new kid on the block with promise of prevention of prostate cancer, cancer in general, and heart disease. But now, it seems that the infamous J curve could be at work again. In sufficient amounts, selenium might do all of these things or at least not be toxic, but at higher supplement doses, perhaps even under the upper limit of safety in the recommended dietary intakes (400 mcg/day), selenium might cause type 2 diabetes (Bleys) in long-term consumers. This data has been somewhat of a shock to researchers and will surely be followed up for confirmation.

After early promise, recent trials of selenium supplements have not shown that selenium supplements reduce prostate cancer risk either.

While it’s obviously still important to get the RDI for selenium (15 to 70 mcg/day infants to adults), supplementation with higher doses does not seem wise.

B vitamins – folate

While not strictly an antioxidant, folate supplementation advice for heart disease and cancer prevention reached a crescendo in the 1990s. Another magic bullet it seemed. Folate’s apparent long-term success in preventing neural tube defects in childbirth added to its reputation as an important vitamin in preventive health.

In a new approach, folate supplementation was supposed to reduce blood levels of the protein homocysteine, high levels of which were thought to contribute to heart disease risk. Reduced heart disease risk has not been borne out in supplement trials, and homocysteine as a risk factor in cardiovascular disease has turned out to be something of a dud (apparently more a marker rather than a cause) — and so has supplementary folate as a useful tool in lowering heart disease risk.

Further, folate works to prevent birth defects by protecting cell division and differentiation. But what if certain cells — colon, prostate, breast — are cancerous or pre-cancerous? Could high folate intakes actually promote cancer by protecting the aberrant cell division? This is the question being considered by cancer researchers. It is not proven, but some are cautious. The evidence for protection or causation with folate, especially for colon and breast cancer, seems mixed. High doses of folate can also mask vitamin B12 deficiency.

Summing up

While various trials will continue to test the value of dietary antioxidant supplements in preventive health, the writing is surely on the wall for their demise for many of the traditional uses for which they acquired reputation — cancer and heart disease. This does not mean that diets high in antioxidant status from plant food consumption may also be harmful. I’ve not seen any evidence that that is true, or even defensible, and most evidence suggests the reverse is true and diets high in natural plant foods are protective.

- Omenn GS, Goodman GE, Thornquist MD, et al.  Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.  J Natl Cancer Inst. 1996 Nov 6;88(21):1550-9.
– Lin J, Cook NR, Albert C et al.  Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial.  J Natl Cancer Inst. 2009 Jan 7;101(1):14-23.
– Bjelakovic G, Nikolova D, Gluud LL, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007176.
– Evans JR, Henshaw K. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD000253.
– Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008 Nov 12;300(18):2123-33.
– Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2009 Jan 7;301(1):52-62.
– Lee IM, Cook NR, Gaziano JM, Gordon D et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005 Jul 6;294(1):56-65.
– Sauer J, Mason JB, Choi SW et al. Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):30-6.
– Bleys J, Navas-Acien A, Guallar E. Selenium and diabetes: more bad news for supplements. Ann Intern Med. 2007 Aug 21;147(4):271-2.
– Marcus J, Sarnak MJ, Menon V et al. Homocysteine lowering and cardiovascular disease risk: lost in translation. Can J Cardiol. 2007 Jul;23(9):707-10.
– Lonn E, Yusuf S, Arnold MJ et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77.

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