Antioxidant Trials: Supplements Take More Hits and Diet Stands Strong


Those of you who have read my articles in past know that I believe antioxidants are important to optimal health and may have a special role in the treatment of diabetes. My position on the topic comes from volumes of research on the role of oxidative stress in the development and progression of diabetes and its complications, and from the epidemiology research that demonstrates high antioxidant diets are protective against diabetes and cardiovascular disease.

However, the gold standard of medical science remains the randomized clinical trial. In recent years, several large, well-designed studies have been published investigating antioxidant supplementation and have resulted in neutral or negative results. Where does this discrepancy come from? What lessons should be learned and, for those of us activated to optimize our health, what should we do? This article will highlight some recent studies and suggest what we have known to be true all along is still true.


Vitamin E - Is All HOPE Lost?

The HOPE trial evaluated 400 IU of vitamin E (RRR-alpha tocopheryl acetate) per day in over 3,600 people with diabetes for an average of 4.5 years. The findings of the trial were that vitamin E had a neutral effect on risk for renal disease (nephropathy) or cardiovascular events, including heart attack and stroke[1].

The HOPE study arguably started the controversy of whether antioxidant supplements are effective, or even safe, for routine use by patients with diabetes or others at risk for cardiovascular events. There are many ways to criticize the HOPE trial, including the fact that there are eight forms of vitamin E (four tocopherols and four tocotrienols -- at least!) and only one form was studied, yet generalized statements about vitamin E not being safe resulted from the trial. Vitamin E occurs in alpha, beta, delta, and gamma tocopherols and tocotrienols. Therefore, global statements about the safety and efficacy of “vitamin E” are misguided and not accurate. In fact, a recent study investigating a dose response to vitamin E suggested that up to 3,200 IU per day were required to reduce blood markers of oxidative stress[2].

If you are following the logic here, not only has only one form of vitamin E been thoroughly tested but it may have been underdosed. Similarly available research suggests overconsumption of alpha-tocopherol may reduce levels of other tocopherols, including gamma-tocopherol which may impact the clotting rate of blood and increase risk for cardiovascular disease [3]. Have we learned all there is to learn about “vitamin E”? I think not. We have learned that one form, in low doses, is not protective.


What About Selenium?

Although selenium is a mineral and not an antioxidant by itself, selenium is a necessary and limiting cofactor in the operation of the glutathione antioxidant system. Specifically it is necessary for the function of glutathione peroxidase; a small protein, or peptide, in the body that functions as a keystone of several antioxidant pathways.

Research shows that people with diabetes, and especially people with diabetic complications, have lower glutathione levels that those without diabetes [4, 5]. Therefore it is tempting to believe that taking more selenium would increase glutathione levels, or at least activity, in the body. However recent studies suggest this isn’t the case.

In a recent epidemiologic study, those people with the highest selenium levels in their blood actually had a 50% increased chance of having diabetes compared to those with the lowest concentration[6]. Results from epidemiologic studies like this one need to be interpreted with caution because they cannot show causality, only association. However, a recent clinical trial of selenium (200 mcg/day) given to 1200 people without diabetes showed that after 7.7 years (a long trial!), those who took selenium actually had a 50% increased risk of developing diabetes[7]!

All studies have there limitations; in this case the study was actually performed on a population at high risk for recurrent skin cancer (they had already had one skin cancer to be included in the trial) and therefore the population may have some health compromises at baseline that contributed to the results. However, I believe it is fair to say that for otherwise healthy adults with history of skin cancer, selenium supplementation does not reduce the risk for developing diabetes!


Other Recent Antioxidant Findings

Two other studies, of very different designs, also found little or negative results when looking at antioxidant supplementation.

One study was a recent meta-analysis, or systematic summary, published in the New England Journal of Medicine, of antioxidant clinical trials which found that antioxidant supplementation may actually increase mortality, i.e. death[8]. This study was very weak and very biased in that many of the studies included in the analysis were clinical trials of antioxidants in cancer treatment, including one very large study that found an increase risk of lung cancer in smokers who took beta-carotene supplements. The inclusion of the cancer trials seemed to heavily influence the findings and really cannot be generalized to the average population. Yet, I still think the study had value because, although I do not believe the findings that antioxidants increase risk of death, the results did not show a protective effect either. If there is a strong protective effect of antioxidants, some trend should have emerged.

Another recently published antioxidant trial was the Women’s Antioxidant Cardiovascular (WAC) Study[9]. This study followed over 8000 women with or at risk for cardiovascular events for 9.4 years (another very long study!). The women in the study were given either vitamin E (600 IU every other day), vitamin C (500mg per day), beta-carotene (50 mg every other day), or combinations of the three. The findings of the study were very neutral; neither antioxidants or combinations of antioxidants reduced nor increased the risk of cardiovascular events including heart attack, stroke, revascularization, or death (there was a very small protective trend for the combination of vitamin E and vitamin C on stroke risk).


Why Such a Discrepancy?

Oxidative stress runs rampant throughout the body in those with diabetes; it impacts the pancreas, the vasculature, the insulin receptors, etc, yet the seemingly obvious “treatment” does not appear to impact the development of diabetes nor the risk of vascular events in diabetes.

We are all exposed to oxidative stresses throughout the day due to our diet, our environment, and our normal metabolic functions, yet clinical research results suggest no benefit from supplementation from some antioxidants. I agree it is confusing and I believe the discrepancy creates a charge for more research. Unfortunately because of the negative results from clinical trials, there is little interest in continuing down the path of antioxidant research, except from innovative organizations like the Diabetes Action Research and Education Foundation!


What are the Lessons to be Learned?

In my opinion the lessons to be learned from findings like those discussed above include:

1. Don’t believe everything you read about natural health products. There is a reason to be critical of all hype, whether for a drug or for a supplement. Find doctors and advisors who know the research and ask them challenging questions.

2. More research needs to be done on antioxidants and it needs to be precise. Unfortunately negative (and positive!) findings in research often get generalized inaccurately.

3. Life and health is all about balance. Overconsumption of anything leads to poor health. This rule applies to sugar, fat, alcohol, protein, salt and even water! It appears as though it may apply to antioxidants as well. Every process in the body is a coordinated dance of cellular pathways and hormonal signals, oxidative and antioxidation balanced in a yin-yang sort of way. In diabetes, we believe the oxidation overpowers the antioxidation, yet the trick remains to find out where these pathyways are out of balance and supply just the right nutrients to correct the imbalance.


So What Can I Do?

I understand this article is a bit ominous and may challenge some beliefs you hold true; believe it or not, I am going through this process too! So what can be done?

For me, it has added precision to my practice because I focus more now on antioxidants which have more proven roles in the treatment of diabetes such as alpha-lipoic acid, CoQ10, pycnogenol, etc.

More importantly, I focus more on dietary antioxidant intake.Dietary antioxidant intake shows much more consistency in the literature for cardiovascular and cancer prevention. The Mediterranean Diet is a high antioxidant diet that is also high in healthful unsaturated fats, whole grains, legumes and is rich in vegetables and phytonutrients. The Mediterranean Diet demonstrated remarkable success in reducing the risk of heart attacks and strokes in people with previous heart disease (more than most statin research!)[10]. A recent study of dietary patterns and cardiovascular disease death suggested a Mediterranean Diet plan may offer the most protection for those with diabetes[11].

The fundamental strategy to reach optimal health remains the same: a good diet rich in diverse vegetable foods, quality oils, and lean protein, combined with a regular exercise program, stress reduction activities, and time with friends and family is the only guaranteed approach to good health!


Ryan Bradley, ND, MPH     September,  2007


1. Lonn, E., et al., Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care, 2002. 25(11): p. 1919-27.

2. Roberts LJ, O.J., Linton MF, Fazio S, Meador B, Gross M, Shyr Y, Morrow J., The Relatioship Between Dose of Vitamin E and Suppression of Oxidative Stress in Humans. Free Radic. Biol. Med., 2007.

3. Clarke, M.W., et al., Supplementation with mixed tocopherols increases serum and blood cell {gamma}-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes. Am J Clin Nutr, 2006. 83(1): p. 95-102.

4. Komosinska-Vassev, K., et al., Effects of metabolic control and vascular complications on indices of oxidative stress in type 2 diabetic patients. Diabetes Res Clin Pract, 2005. 68(3): p. 207-16.

5. Tagliabue, M., et al., Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus. Int J Androl, 2005. 28(3): p. 156-62.

6. Bleys, J., A. Navas-Acien, and E. Guallar, Serum selenium and diabetes in U.S. adults. Diabetes Care, 2007. 30(4): p. 829-34.

7. Stranges, S., et al., Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med, 2007. 147(4): p. 217-23.

8. Bjelakovic, G., et al., Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Jama, 2007. 297(8): p. 842-57.

9. Cook, N.R., et al., A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med, 2007. 167(15): p. 1610-8.

10. de Lorgeril, M., et al., Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation, 1999. 99(6): p. 779-85.

11. Hodge, A.M., et al., Dietary patterns and diabetes incidence in the Melbourne Collaborative Cohort Study. Am J Epidemiol, 2007. 165(6): p. 603-10.