on November 21, 2007
Published online before print November 21, 2007, doi: 10.1161/ATVBAHA.107.153965
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Submitted on August 19, 2007
Accepted on November 14, 2007
Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype. A Prospective Double-Blinded Clinical Trial
Uzi Milman ;
From Clalit Health Services (U.M., C.S., L.B., M.K., A.K., A.R.), Haifa and Western Galilee, Israel; Technion Faculty of Medicine (S.B., R.M.L., Y.A., J.A., A.P.L.), Technion-Israel Institute of Technology, Haifa, Israel; Cardiology Department (D.A.), Rambam Medical Center, Haifa, Israel; Internal Medicine (S.K., Y.L.), Rambam Medical Center, Haifa, Israel; and PharmaBrains Israel (M.L.), Tel Aviv, Israel.
* To whom correspondence should be addressed. E-mail: alevy{at}tx.technion.ac.il.
Objective—Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). The Hp gene is polymorphic with 2 common alleles, 1 and 2. The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product. We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population.
Methods and Results—1434 DM individuals 
55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; P=0.01) and led to early termination of the study.
Conclusions—Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2-2 genotype (ClinicalTrials.gov NCT00220831).
Key words: diabetes mellitus • vitamin E • cardiovascular events • pharmacogenomics • haptoglobin genotype
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  S. Blum, U. Milman, C. Shapira, R. Miller-Lotan, L. Bennett, M. Kostenko, M. Landau, S. Keidar, Y. Levy, A. Khemlin, et al. Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): e18 - e20. [Full Text] [PDF]
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