Vitamin E Reduces Cardiovascular Disease in Individuals with Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Abstract

Aims Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. Materials & methods We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). Results Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40–0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. Conclusion A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

“…Hp polymorphism has been documented as a major determinant for determining the risk of developing cardiovascular diseases in diabetes mellitus patients. However, the increased risk of cardiovascular disease was most prevalent in patients who possessed the Hp-2 gene, with the highest risk for individuals who carried the Hp2-2 allele [17]. Individuals with the Hp-2 gene experienced more risk for developing diabetic retinopathy, diabetic nephropathy, and atherosclerosis compared to those who carried the Hp-1 gene [18].…”

“…Diabetes mellitus with cardiovascular diseases increases the burden of patient health through increased free radical oxygen species in the body. Although several clinical trials did not show that additional benefit of Vitamin E helps patients, it left researchers to investigate the possible polymorphism in the genetic profile of patients [17].…”

“…The Hp gene contains several louses including the Hp1 (Hp1-1 allele), which is more prevalent in Western populations, and the Hp2 gene (Hp2-2 and Hp2-1 alleles), the later is present only in humans and provides less beneficial effects of antioxidant protection against Hb when compared to Hp1 [17]. Hp polymorphism has been documented as a major determinant for determining the risk of developing cardiovascular diseases in diabetes mellitus patients.…”

“…In addition, Vitamin E supplementation has shown to reduce atherosclerotic lesion size and progression, platelet adhesion, and protein kinase C activation [18]. In addition, the use of Vitamin C showed to have a harmful effect on the genotype, increasing the oxidative activity of the lipids and blocked the activity of Vitamin E to correct HDL dysfunction [17] …”

Understanding the Genome: Implications for Human Nutrition?

“…It was subsequently shown that the risk of CVD in T2D patients was five times higher if they had a dysfunctional allelic mutation in a gene encoding for haptoglobin [9]. Supplementation with vitamin E in these individuals was able to compensate the impaired antioxidant function of haptoglobin, thereby reducing their risk of stroke, myocardial infarction and cardiovascular mortality [10]. No such benefit was observed in patients with other haptoglobin genotypes.…”