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 Ն55 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%; Pϭ0.01) and led to early termination of the study. xtensive preclinical and observational studies showing the apparent benefit from vitamin E in preventing cardiovascular events created an atmosphere in which more than 40% of cardiologists were routinely prescribing high dose vitamin E. 1 Over the past 10 years, several prospective randomized clinical trials have investigated whether vitamin E supplementation provides cardiovascular protection. 2-9 The overwhelming consensus from these studies is that vitamin E supplementation does not provide cardiovascular benefit. 10 -11 To the contrary, meta-analysis of these studies suggests high dose vitamin E supplementation may increase mortality, 12 and several opinion articles have called for a moratorium on prescription of high dose vitamin E supplements. 10 -12 A possible explanation for why these studies failed in spite of solid preclinical data are the inadequate nature of patient selection in these studies. 13 High-dose antioxidant therapy may only provide benefit to individuals who suffer from particularly high levels of oxidative stress. Conclusions-VitaminThe haptoglobin (Hp) genotype may help identify patients with high levels of oxidative stress and who may benefit from antioxidant therapy with vitamin E. 14 The Hp gene is polymorphic with 2 common classes of alleles denoted 1 and 2. 15 We and others have demonstrated that the Hp 2 allele protein product is an inferior antioxidant compared with the Hp 1 allele protein product. 16 -20 These differences in antioxidant protection are profoundly accentuated in the diabetic state resulting in a marked relative increase in oxidative stress in Hp 2 transgenic mice and Hp 2-2 individuals with DM. 16 -20 The distribution of the 3 Hp genotypes in Western societies is approximately 16% Hp 1-1, 36% Hp 2-2, and 48% Hp 2-1. 15 We have demonstrated an interaction between the Hp genotype and DM on the development of cardi...

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress. 1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials. [2][3][4][5][6][7][8][9][10][11] However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress. 12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy. 13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein. 14 -18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD. 19 -22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype. 13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events. 22 However, only about half of the Hp 2-2 DM participants in ICARE received statin therapy. Because statin therapy is currently recommended for all DM individuals we sought to determine whether antioxidant therapy could still be demonstrated to provide benefit to Hp 2-2 DM individuals also taking statins in ICARE. We believed that this analysis would be of particular interest and importance because of previous work demonstrating that the addition of antioxidant vitamins to simvastatin-niacin therapy blunted the rise in protective subfractions of HDL with an apparent adverse effect on the progression of coronary artery disease. 23,24 Research Design and MethodsThe study protocol of the ICARE study has previously been reported in detail. 22 Briefly, participants were drawn from 47 primary health clinics of the Clalit Health Services in the northern sector of Israel. Patients were eligible for the study if they had Type II DM and were 55 years of age or older. 3054 individuals underwent Hp genotyping, and of these 1434 were found to have the Hp 2-2 genotype. These Hp 2-2 individuals were randomly assigned to treatment with either vitamin E or placebo. Hp 1-1 and Hp 2-1 individuals were not enrolled in the treatment phase of the study but were followed in a study registry for all major cardiovascular events using the same methodology for outcomes adjudication as for individuals with the Hp 2-2 genotype. The major study outcomes (MI, stroke, CVD death) were identified prospectively in this population over an 18-month period. A preplanned secondary analy...

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