Is There Any Hope for Vitamin E?

Brown, Bryan P.; Crowley, John

doi:10.1001/jama.293.11.1387

Cited by 72 publications

(41 citation statements)

References 39 publications

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“…While observational studies appeared to support the notion that antioxidants might be protective against atherosclerosis, numerous prospective interventional clinical trials employing the antioxidant vitamins C and a-tocopherol have failed to show any clinical benefit (10, 16-18, 22, 35, 38, 39). To the contrary, there is strong evidence that these antioxidants may in fact be harmful and paradoxically increase mortality when given as high dose supplements (8,21,30 Examination of the results from HOPE, ICARE, and WAVE appears to provide two reasons why these trials of antioxidant vitamins may have failed to show benefit and potentially induce harm (34). First, the type of antioxidant used in these trials may not have been appropriate.…”

Section: Discussionmentioning

confidence: 99%

Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

Asleh

Levy

2010

Antioxidants & Redox Signaling

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The haptoglobin (Hp) 2-2 genotype is associated with increased risk of cardiovascular disease (CVD) in diabetes (DM). We recently proposed this increased risk arises from the tethering of redox active hemoglobin (Hb) to high density lipoprotein (HDL), thereby resulting in oxidative modification of HDL. Clinical trials have demonstrated that vitamin E (a-tocopherol) decreases while vitamin C increases CVD in Hp 2-2 DM individuals. We sought to test the hypothesis that the interaction of a-tocopherol or vitamin C on CVD in Hp 2-2 DM was due to their divergent effects on HDL oxidation and function. Vitamin C significantly increased while a-tocopherol completely blocked oxidation mediated by glycosylated Hb-Hp 2-2. Vitamin C had no benefit while a-tocopherol completely restored HDL function in Hp 2-2 DM mice. Co-administration of vitamin C mitigated the protective effects of a-tocopherol on HDL. There exists a pharmacogenomic interaction between vitamin C and a-tocopherol and the Hp 2-2 genotype on HDL function and structure. Choosing the correct antioxidant in the correct subset of patients may be critical in order to demonstrate benefit from antioxidant therapy. Antioxid. Redox Signal. 12, 209-218.

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Section: Discussionmentioning

confidence: 99%

Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

Asleh

Levy

2010

Antioxidants & Redox Signaling

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“…Our study comes in the wake of numerous large clinical trials that failed to demonstrate that vitamin E provides any protection against CVD and may be harmful (13,(15)(16)(17)(18)(19)(20). Further hampering acceptance of this paradigm is the lack of a rational pathophysiological and pharmacogenomic mechanism to explain why Hp 2-2 diabetic individuals have an increased risk of CVD and how vitamin E mitigates this risk.…”

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confidence: 99%

Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype

et al. 2008

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OBJECTIVE-Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.RESEARCH DESIGN AND METHODS-Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters.RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.CONCLUSIONS-Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

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“…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.…”

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confidence: 99%

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

Blum

Milman

Shapira

et al. 2008

ATVB

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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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Is There Any Hope for Vitamin E?

Cited by 72 publications

References 39 publications

Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

Divergent Effects ofα-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype

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

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