Diabetes Prevention in the Vitamin D and Omega-3 Trial

描述（由申请人提供）：我们建议在NIH资助的大规模随机试验中评估维生素D和OmegA-3 TriaL（VITAL）中维生素D3（2，000 IU/天）和海洋omega-3脂肪酸（二十碳五烯酸[EPA] +二十二碳六烯酸[DHA]，1 g/天）补充剂在降低T2 D风险方面的获益和风险平衡。VITAL试验是一项随机、双盲、安慰剂对照试验，专门用于评估维生素D和海洋omega-3脂肪酸补充剂在20，000名美国男性和女性中对癌症和心血管疾病（CVD）的一级预防的功效。我们将检验维生素D或omega-3补充剂可降低参与试验的最初非糖尿病受试者的T2 D风险的假设。我们将进一步评估维生素D或ω-3补充剂是否以及在多大程度上改善了接受这些终点生物标志物评价的队列亚组中的葡萄糖耐量和胰岛素敏感性/分泌。因此，我们提出了一种具有成本效益的策略，以评估研究干预措施预防糖尿病的疗效，并提供可能带来这种益处的生理机制的详细表征。T2 D事件的病例确认将需要从参与者的医生完成的病历审查和/或补充问卷中收集详细的诊断信息。为了补充病例验证，将通过将试验参与者与医疗保险和医疗补助服务中心（CMS）数据库相关联来检索有关糖尿病诊断和降糖药物的其他数据。在我们的子研究中，在美国的四个临床和转化科学中心（CTSC）研究中心（波士顿、芝加哥、旧金山弗朗西斯科和休斯顿）招募的基线时没有糖尿病报告的1，000名参与者将在基线（随机化前）和2年随访（按季节、按月匹配）时接受标准的2小时口服葡萄糖耐量试验（OGTT）。从而确定胰岛素和葡萄糖稳态的连续测量。还将测量糖化血红蛋白A1 c（HbA 1c）。总之，我们认为，母公司VITAL试验的研究基础设施将为我们提供一个独特的具有成本效益的机会，以及时回答有关维生素D或omega-3脂肪酸补充剂在预防T2 D方面的潜在益处的重要问题，并识别潜在风险。在这项拟议的辅助研究中，我们申请资金在VITAL队列中进行糖尿病病例验证，并在基线和随访时在子样本中进行系列葡萄糖耐量试验。为了完成CTSC研究中心受试者的葡萄糖耐量随机化前评估，至关重要的是，该辅助研究应与计划于2010年4月开始的母试验VITAL的安慰剂“导入”入组期平行进行。 公共卫生相关性：现有的生物学和观察证据强烈支持维生素D和海洋ω-3脂肪酸在预防2型糖尿病（T2 D）方面的潜在健康益处。然而，由于缺乏来自大规模临床试验的确切数据，目前尚不清楚是否可以通过使用这些补充剂来延迟或预防T2 D。

DESCRIPTION (provided by applicant): We propose to evaluate the balance of benefits and risks of vitamin D3 (2,000 IU/day) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1g/day) supplements in reducing risk of T2D in the setting of an NIH-funded large-scale randomized trial, the VITamin D and OmegA-3 TriaL (VITAL). The VITAL trial is a randomized, double-blind, placebo-controlled trial specifically designed to evaluate the efficacy of vitamin D and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease (CVD) among 20,000 U.S. men and women. We will test the hypothesis that vitamin D or omega-3 supplementation reduces the risk of T2D among initially non-diabetic subjects participating in the trial. We will further assess whether and to what extent vitamin D or omega-3 supplementation improves glucose tolerance and insulin sensitivity/secretion in a subset of the cohort undergoing biomarker evaluation for these endpoints. Hence, we propose a cost-effective strategy to evaluate the efficacy of the study interventions for diabetes prevention as well as to provide detailed characterization of the physiologic mechanisms that may impart this benefit. Case validation of incident T2D will require collection of detailed diagnostic information from medical record review and/or supplementary questionnaires completed by the participants' physicians. To complement case validation, additional data on diabetes diagnoses and hypoglycemic medication will be retrieved by linking the trial participants with the Centers for Medicare and Medicaid Services (CMS) database. In our substudy, 1,000 participants without a report of diabetes at baseline recruited at four Clinical and Translational Science Center (CTSC) sites across the U.S. (Boston, Chicago, San Francisco, and Houston) will undergo a standard 2-hour oral glucose tolerance test (OGTT) at baseline (pre- randomization) and at 2 years of follow-up (matched for season, by month). Serial measurements of insulin and glucose homeostasis will thereby be ascertained. Glycated hemoglobin A1c (HbA1c) will also be measured. In summary, we believe that the research infrastructure of the parent VITAL trial will offer us a unique cost-effective opportunity to answer important and timely questions about potential benefits of vitamin D or omega-3 fatty acid supplementation in the prevention of T2D, as well as to identify potential risks. In this proposed ancillary study, we request funds to perform diabetes case validation in the VITAL cohort and serial glucose tolerance testing at baseline and follow-up in a subsample. In order to complete pre-randomization assessment of glucose tolerance among participants at the CTSC sites, it is critically important that this ancillary study be undertaken parallel to the placebo "run-in" enrollment period for the parent VITAL trial, which is scheduled to begin in April 2010. PUBLIC HEALTH RELEVANCE: Existing biologic and observational evidence strongly supports potential health benefits of vitamin D and marine omega-3 fatty acids in preventing type 2 diabetes (T2D). However, due to lack of definitive data from large-scale clinical trials, it remains unclear whether T2D can be delayed or prevented by use of these supplements.