Reactive oxygen species have been implicated in the etiology and progression of diabetes complications, although clinical trials generally have not supported a protective effect of 1-tocopherol supplementation on CVD outcomes. It has recently been proposed that the success of antioxidant therapy may be limited to susceptible subgroups, such as individuals with diabetes and the Haptoglobin (Hp) 2-2 genotype. Hp binds to free hemoglobin, thereby inhibiting hemoglobin-induced oxidative damage to tissues. It has been shown that the Hp 2-2 genotype is less effective as an antioxidant, interacting with the diabetic state to promote HDL oxidative modification and dysfunction. Indeed, longitudinal studies in type 2 diabetes have shown increased CVD risk in those with the Hp 2-2 genotype and retrospective analyses of the HOPE trial showed a reduction in MI and CVD death rates with vitamin E only in the group with diabetes and the Hp 2-2 genotype. Importantly, daily supplementation with 400 IU vitamin E significantly reduced CVD events by 53% within 18 months in a prospective randomized double-blinded clinical trial in those with type 2 diabetes and the Hp 2-2 genotype. Dual therapy with vitamin E and statins provided superior cardiovascular protection compared to statin therapy alone. The Pittsburgh Epidemiology of Diabetes Complications study has also shown a twofold increased coronary artery disease risk in those with the Hp 2-2 compared to the Hp 1-1 genotype in type 1 diabetes. In this type 1 diabetes cohort, Hp predicted early renal function decline and end-stage renal disease (ESRD) but not albuminuria per se. To date, beyond intensive insulin therapy, limited direct trial evidence exists for CVD prevention in type 1 diabetes and physicians caring for these patients have been left having to infer from type 2 diabetes studies. Unfortunately, this strategy may have contributed to a smaller decline in the incidence of CVD in type 1 diabetes than seen for other complications (e.g. renal disease). Thus, evaluating the potential of vitamin E to reduce rates of diabetic vascular disease in type 1 diabetes provides a unique opportunity to address both this inequity and a major neglected need for those with type 1 diabetes. Our long term plan is therefore to conduct a randomized (within Hp genotype), double-blind, placebo controlled clinical trial of daily supplementation with 400 IU 1-tocopherol on CVD events in type 1 diabetes. A U34 planning grant has already been submitted to NIDDK. However, the major concern is the feasibility to raise the needed number of subjects (>3,000) with type 1 diabetes at sufficient risk for a 5 year trial to be conducted. Thus, our aim for this R03 application is to develop a registry of individuals with diabetes treate within one of the largest U.S. health care systems, the University of Pittsburgh Medical Center (UPMC) and thus assess the feasibility of recruiting for such a clinical trial in the type 1 diabets population.
A prospective clinical trial in type 2 diabetes showed a 53% reduction in CVD risk with daily vitamin E supplementation in those with the Hp 2-2 genotype, a subgroup at increased CVD risk in diabetes. Whether trial results can be extrapolated to type 1 diabetes is currently unknown. The proposed study therefore offers a unique opportunity for CVD prevention with a simple and inexpensive treatment with vitamin E supplementation in a large proportion of individuals with type 1 diabetes as 44% of individuals have this genotype.
