Several clinical trials (1) have demonstrated that vitamin E does not reduce future major cardiovascular (CV) events. However, these trials could not rule out the potential benefit for high-risk subgroups. Diabetic individuals who are homozygous for the haptoglobin 2 allele (Hp 2-2) are at high risk for CV events (2–4); moreover, the Hp 2-2 protein product is an inferior antioxidant compared with the Hp 1 allele (5). We therefore hypothesized that vitamin E may reduce CV events in Hp 2-2 diabetic individuals.

Hp type was measured in 3,167 participants (1,078 with diabetes) of the Heart Outcomes Prevention Evaluation (HOPE) trial, which evaluated the 4.5-year effects of 400 IU vitamin E daily on the primary composite of CV death, myocardial infarction, and stroke (1). No significant benefit of vitamin E supplementation was detected in either the entire group or in the diabetic subset, consistent with what was previously reported for the entire HOPE cohort (1). In Hp 2-2 diabetic participants, there was a trend toward a reduced primary composite outcome (relative risk 0.70 [95% CI 0.45–1.10]) and a statistically significant reduction in the risk of CV death (0.45 [0.23–0.90]) and nonfatal myocardial infarction (0.57 [0.33–0.97]). However, this trend was not observed for strokes (1.15 [0.47–2.82]), and there was no statistical interaction between vitamin E use and haptoglobin type for either the composite outcome or any of its components.

In conclusion, the absence of any statistical interaction indicates that these data do not support the hypothesis that the effects of vitamin E differed by Hp phenotype. Therefore, the results noted above in Hp 2-2 diabetic individuals demonstrating a significant reduction in CV death and myocardial infarction could be spurious and clearly require prospective testing in future trials.

This study was funded by the Kennedy-Leigh Trust and the Israel Science Foundation.

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Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P, for the Heart Outcomes Prevention Evaluation Study Investigators: Vitamin E supplementation and cardiovascular events in high-risk patients.
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Levy AP, Hochberg I, Jablonski K, Resnick H, Best L, Lee ET, Howard BV: Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the Strong Heart Study.
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Roguin A, Koch W, Kastrati A, Aronson D, Schomig A, Levy AP: Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes.
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Suleiman M, Kapeliovich MR, Roguin A, Aaronson D, Meisel SR, Shochat M, Reisner SA, Hammerman H, Levy NS, Levy AP: Haptoglobin phenotype and mortality in the 30-day period following acute myocardial infarction (Letter).
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Asleh R, Marsh S, Shilkrut M, Binah O, Guetta J, Lejbowicz F, Enav B, Shehadeh N, Kanter Y, Lache O, Cohen O, Levy NS, Levy AP: Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease.
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A.P.L is the author of a patent that claims to predict diabetic vascular disease on the basis of haptoglobin phenotyping.

DIABETES CARE
2004