Disputed Meta-Analyses

Good Stress, Bad Stress—The Delicate Balance in the Vasculature by Dr. rer. nat. Kirstin Wingler, Prof. Dr. med. Harald H. H. W. Schmidt in volume 42/2009

This is not an attempt to forcefully rehabilitate studies with the “old” antioxidants. However, two of the meta-analyses that Wingler and Schmidt cited in their very readable article (1) have come under strong criticism. The main result of the study reported by Bjelakovic et al (2007) was that in the total analysis of all 68 studies, intake of the 5 implicated micronutrients (vitamin E, vitamin C, vitamin A, beta-carotene, and selenium) had no significant effect on mortality (relative risk 1.02). Only when the authors subcategorized the 68 studies according to their own criteria into 47 with low bias and 21 with high bias, they found that mortality was slightly raised (RR 1.05) for the studies with low bias and reduced for those of “low” quality (RR 0.91).

Bjelakovic et al have ignored further fundamental principles of meta-analysis by categorizing 4 physiochemically entirely different molecules and a trace element as “antioxidants” and by including studies with observational periods of between 1 day and 12 years. For 2 studies they used incorrect mortality data and were forced to publish a comprehensive correction in JAMA when prompted by the author of this commentary (2).

The allegedly raised total mortality in the subgroup of “methodically sound” studies went down by another percentage point. The results were also driven by the negative results of known studies of beta-carotene and vitamin A in male smokers who consumed vast amounts of alcohol. The cited Miller study into vitamin E was examined in detail and almost discredited (3).

The question that remains to be asked is why the important links between ã-tocopherol and the NO metabolism were not explained—the substitution of ã-tocopherol (by á-tocopherol) would even offer an explanation for the failure of the decades of á-tocopherol monomania (4).
DOI: 10.3238/arztebl.2010.0224b

Dr. med. M. P. Look
Clemens-August Str. 39, 53115 Bonn, Germany
[e-mail]

Conflict of interest statement
The author provides advice on supplementation with micronutrients, including antioxidants, as a private medical service. He has received consultancy fees for advising manufacturers of food supplements and balanced diets (Orthomol GmbH and Vitamin Shop Direct Inc) regarding scientific questions.

References

1. Wingler K, Schmidt H: Good stress, bad stress—the delicate balance in the vasculature [Guter Stress, schlechter Stress: Die feine Balance in Blutgefäßen]. Dtsch Arztebl Int 2009; 106(42): 677–84.

2. Bjelakovic, et al.: Erratum zu: Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2008; 299(7): 756–6.

3. Bell SJ, Grochoski GT: How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008; 48, 760–74.

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: 111–7.