Precision medicine with vitamin E for the prevention of diabetic cardiovascular disease

There are two common alleles in the Haptoglobin (Hp) gene defined by the presence (Hp 2) or absence (Hp 1) of a 1.7kb in frame duplication of exons 3 and 4 of the Hp 1 allele. In Israel, approximiately 50% of the population has the Hp 2-2 genotype. The primary function of the Hp protein is to control how extracorpuscular hemoglobin is disposed of and to protect against hemoglobin driven oxidative stress. Numerous epidemiological studies have demonstrated that Hp 2-2 individuals with Diabetes have a 2-4 fold increased risk of myocardial infarction and death from cardiovascular disease. Genetically altered mice with the Hp 2-2 genotype display more advanced atherosclerosis, plaque instability and dysfunctional HDL , findings that have all been confirmed in man. Both in mice and man vitamin E supplementation has been shown to correct HDL dysfunction associated with the Hp 2-2 genotype. Several small clinical studies have demonstrated that supplementation of vitamin E to Hp 2-2 individuals significantly reduces the incidence of myocardial infarction and cardiovascular death. In the context of the Israeli SPHERE center for diabetes we have recentl begun establishing the framework for a randomized placebo controlled clinical trial seeking to prevent Diabetic cardiovascular disease in over 6000 Hp 2-2 participants. The study will be powered to determine whether daily supplementation with vitamin E in Hp 2-2 individuals can reduce the incidence of myocardial infarction and cardiovascular death. The public health implications and health care savings of this precision medicine approach will be discussed.