Health system based clinical trial recruitment

描述(由申请人提供)：尽管临床试验一般不支持补充1-生育酚对心血管疾病结局的保护作用，但活性氧与糖尿病并发症的病因和进展有关。最近有人提出，抗氧化剂治疗的成功可能仅限于易感人群，如糖尿病患者和结合珠蛋白(HP)2-2基因。幽门螺杆菌与游离的血红蛋白结合，从而抑制血红蛋白对组织的氧化损伤。已有研究表明，HP2-2基因作为一种抗氧化剂效果较差，与糖尿病状态相互作用，促进高密度脂蛋白氧化修饰和功能障碍。事实上，对2型糖尿病的纵向研究表明，携带HP2-2基因的人患心血管疾病的风险增加，对HOPE试验的回顾分析表明，只有在糖尿病和HP2-2基因携带者中，服用维生素E才能降低心肌梗塞和心血管疾病的死亡率。重要的是，在一项针对2型糖尿病和Hp 2-2基因携带者的前瞻性随机双盲临床试验中，每日补充400IU维生素E可在18个月内将心血管事件显著减少53%。与单独使用他汀类药物相比，维生素E和他汀类药物的双重治疗提供了更好的心血管保护。匹兹堡糖尿病并发症流行病学研究还表明，与1型糖尿病患者的Hp1-1基因相比，携带Hp2-2基因的人患冠状动脉疾病的风险增加了两倍。在这个1型糖尿病队列中，HP预测早期肾功能下降和终末期肾病(ESRD)，但不能预测蛋白尿本身。到目前为止，除了强化胰岛素治疗外，对于1型心血管疾病的预防存在有限的直接试验证据。 糖尿病和照顾这些患者的医生不得不从2型糖尿病研究中进行推断。不幸的是，与其他并发症(如肾脏疾病)相比，这一策略可能导致1型糖尿病患者心血管疾病发病率的下降幅度较小。因此，评估维生素E降低1型糖尿病患者糖尿病血管疾病发生率的潜力提供了一个独特的机会，既解决了这一不平等问题，也解决了1型糖尿病患者被忽视的主要需求。因此，我们的长期计划是进行一项随机(在Hp基因范围内)、双盲、安慰剂对照的临床试验，每日补充 400IU 1-生育酚对1型糖尿病心血管事件的影响。已经向NIDDK提交了一份U34规划赠款。然而，主要关注的是增加1型糖尿病患者(3,000名)的必要数量的可行性，这些受试者有足够的风险进行为期5年的试验。因此，我们的R03应用程序的目标是在美国最大的医疗保健系统之一匹兹堡大学医学中心(UPMC)内建立糖尿病患者的登记，从而评估在1型糖尿病人群中招募此类临床试验的可行性。 公共卫生相关性：一项针对2型糖尿病的前瞻性临床试验显示，在HP2-2基因携带者中，每日补充维生素E可降低53%的心血管疾病风险，HP2-2基因是糖尿病心血管疾病风险增加的一个亚群。试验结果是否可以推断为1型糖尿病目前尚不清楚。因此，这项拟议的研究为预防心血管疾病提供了一个独特的机会，在很大一部分1型糖尿病患者中，使用维生素E补充剂进行简单而廉价的治疗，因为44%的人患有这种基因。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.