Personalized Medicine for Individuals with Diabetes Mellitus.
The public health burden of cardiovascular and renal complications from Diabetes Mellitus (DM) is over $100 billion dollars per year in the USA alone and the problem is increasing. Medications to treat these complications are extremely expensive and require lifetime use. The purpose of this diagnostic test is to provide a once in a lifetime test that will indicate whether a particular individual suffering from Diabetes Mellitus will benefit from an extremely inexpensive, easy to use treatment to reduce complications including death from myocardial infarction (heart attack), and end stage renal disease requiring dialysis. This test will permit the care of an individual with Diabetes Mellitus to be personalized as it is based on his or her own phenotype.
Should Vitamin E be Given to Individuals with Diabetes? It May Depend on your Haptoglobin Phenotype.
Over the past 10 years multiple prospective, randomized clinical trials have investigated whether Vitamin E supplementation provides protection against cardiovascular disease (myocardial infarction and stroke). The overwhelming consensus from these studies is that vitamin E supplementation does not provide cardiovascular benefit. To the contrary, meta-analysis of these studies suggests that high dose vitamin E supplementation may increase mortality and several opinion based articles have called for a moratorium on prescription of high dose vitamin E supplements. A possible explanation for why these studies failed in spite of solid pre-clinical and observational data was the inadequate nature of patient selection in these studies. High dose antioxidant supplementation with vitamin E may only provide benefit to individuals who suffer from particularly high levels of oxidative stress.
The Hp gene is polymorphic with two common classes of alleles denoted 1 and 2. The Hp 2 allele protein is an inferior
antioxidant compared to the Hp 1 allele protein. We have published eleven peer-reviewed, longitudinal studies in diverse ethnic groups showing that individuals suffering from Diabetes Mellitus (both Type I and Type II Diabetes Mellitus) who have the Hp 2-2 phenotype, have a 3 fold increased risk of developing cardiovascular disease and end stage renal disease, compared to Hp 2-1 and Hp 1-1 DM individuals. These data prompted us to examine whether vitamin E administration prevents cardiovascular events in Hp 2-2 DM individuals in the HOPE study. Upon analysis of stored samples from the HOPE study we demonstrated that in Hp 2-2 DM individuals, vitamin E reduced myocardial infarction and cardiovascular death by 43% and 55%, respectively.
We sought to validate these findings in a prospective, double blinded, placebo controlled trial called ICARE –ISRAELI CARDIOVASCULAR VITAMIN E study (www.ClinicalTrials.gov number NCT00220831). Approximately 1500 DM individuals with the Hp 2-2 phenotype were randomized to vitamin E or placebo treatment groups. One year after initiating ICARE the primary composite outcome of cardiovascular death, stroke and myocardial infarction was reduced by over 50% (log rank p=0.004) in Hp 2-2 DM individuals receiving vitamin E, compared to placebo. Furthermore, in a meta analysis examining the interaction between Hp type and vitamin E on diabetic vascular disease, vitamin E was shown to be harmful in non Hp 2-2 individuals.
We propose an algorithm whereby all individuals with Diabetes Mellitus should be tested for the Hp phenotype and vitamin E prescribed only to those with the Hp 2-2 phenotype (see references 1-10 below for clinical data and mechanistic studies supporting this claim).
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