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

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.2–11 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 …