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.

Figure 1. Discontinuation of vitamin E was associated with a 4.5-fold increase in the incidence of myocardial infarction in Hp 2-2 diabetes mellitus individuals in ICARE

In the Tx phase of Israel Cardiovascular Events Reduction with Vitamin E (ICARE), Hp 2-2 diabetes mellitus (DM) individuals who received vitamin E had a significantly lower rate of MI as compared with Hp 2-2 DM individuals who received placebo (* denotes comparison by: 2.7% on placebo vs 0.4% on vitamin E, p = 0.003). At the conclusion of the ICARE study the study drug (placebo or vitamin E) was D/C in all Hp 2-2 DM individuals, but surveillance of all participants for cardiovascular disease events was continued for an additional 18 months. The rate of MI was 4.5-fold higher in the post-treatment phase for those individuals who had been previously treated with vitamin E (** denotes comparison by: 0.4% on vitamin E vs 1.8% after discontinuation of vitamin E, p = 0.03). There was no change in the rate of MI in individuals who had been treated with placebo after the placebo was discontinued (2.7% on placebo vs 2.1% after discontinuation of placebo; p = 0.55). D/C: Discontinued; MI: Myocardial infarction; Tx: treatment.

Figure 2. Simulation of the long-term effects of Hp typing all diabetes mellitus individuals and providing vitamin E to those with the Hp 2-2 genotype in Kaiser Permanente (CA, USA) Northwest region

All subjects were simulated for 50 years of treatment or until death. 50-year simulation results are shown for Hp 2-2 individuals only. Results when treated with vitamin E are shown in black and results when not treated with vitamin E are shown in gray. For survival (A) the incremental benefit of vitamin E therapy was ascertained by determining the area between the two survival curves. For cumulative qualityadjusted life-years (QALYs) per person (B) and for cumulative MI admissions per 1000 starting persons (C), differences between policies are summarized by the differences in the values at year 50. (A) Percentage survival. The cumulative gain in life expectancy in Hp 2-2 individuals treated with vitamin E was 3.04 years (gray) as compared with Hp 2-2 individuals who were not treated with vitamin E (black). (B) Cumulative QALYs. Total QALYs were increased 2.49 years in Hp 2-2 individuals treated with vitamin E (gray) as compared with Hp 2-2 individuals who were not treated with vitamin E (black). (C) Cumulative hospital admissions for MI. For every 1000 Hp 2-2 diabetes mellitus individuals treated with vitamin E, for up to 50 years, 75 hospital admissions for MI would be prevented (gray) as compared with not treating with vitamin E (black). MI: Myocardial infarction.