22/22 Diabetes Prevention Program Outcomes Study (DPPOS) Phase 3 - Biostatistics Center

 描述(由申请人提供)：血糖调节异常(“血糖异常”)有一个非常长的过程，从其最早的阶段，标记为糖尿病前期，到2型糖尿病(T2D)的发病，到临床可检测到的微血管变化和可测量的动脉粥样硬化的发展，到临床表现出并发症并伴随着发病率和死亡率。糖尿病预防计划(DPP)侧重于糖尿病前阶段的血糖紊乱，与安慰剂(PLBO)相比，生活方式干预(ILS)和二甲双胍(MET)在预防或推迟高危人群(n=3234)3年T2D发病方面具有强大的有益效果。DPP还调查和描述了与T2D发展相关的干预措施、表型和遗传型风险因素、干预措施在这些风险因素设置中的影响、T2D预防的健康经济学影响以及其他感兴趣的结果。基于这些结果，民进党生活方式计划得到了广泛的实施。这项为期11年的后续DPP结果研究(DPPOS)探索了T2D预防的长期效果，跨越了糖尿病前期和T2D之间的时期，并检查了与相对短暂的DPP 3年相比需要更多时间才能形成的结果。DPPOS显示了原始干预在T2D预防和心血管疾病(CVD)危险因素方面的长期有益效果。使用MET可节省成本，使用ILS可节约成本。总体而言，发生T2D的受试者发生微血管疾病的风险明显更大，并且随着病程的延长和血红蛋白A1C(A1C)的升高而增加。不同治疗组的总微血管结果发生率没有显著差异；然而，与PLBO和MET相比，ILS显著降低了女性和研究结束时A1C≥为6.5%的女性微血管疾病的风险。拟议的DPPOS第三阶段将再研究DPPOS队列10年，利用长期随机暴露于MET和密集表型和基因分型的DPPOS队列(n=2778)，其中包括近1600名已知T2D病程的患者和约1200名尚未发展为T2D的患者，以解决在糖尿病前期开始的长期暴露于MET和ILS的尚未回答的问题。DPPOS第三阶段将审查在患有糖尿病前期和T2D的老年人口中日益引起公共健康关注的结果，包括MET在心血管疾病和癌症发展方面的推定益处。DPPOS第三阶段的主要目标是有效地检查：1)从糖尿病前期开始的二甲双胍治疗对风险的长期影响 这些研究包括：1)ILS和MET对心血管疾病和癌症的治疗意向的长期影响；2)ILS和MET对T2D的进一步发展和对传统的和新近发现的血糖异常并发症的长期影响，以及它们的经济影响；3)通过分类诊断(糖尿病前期与糖尿病)和作为一个连续体来评估血糖异常的临床病程及其与并发症发展的关系，包括与DPP干预措施和已确定的和新的危险因素相互作用的分析。

 DESCRIPTION (provided by applicant): Abnormal regulation of glycemia ("dysglycemia") has a very long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The 11-year follow-up DPP Outcomes Study (DPPOS) explored the longer-term effects of T2D prevention, bridging the period between pre-diabetes and T2D, and examined outcomes that required more time to develop than the relatively brief 3-years of DPP. DPPOS showed longer- term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. Prevention was cost-saving with MET and cost-effective with ILS. Overall, the risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (A1C). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those who had A1C ≥6.5% at study end. The proposed DPPOS Phase 3 will study the DPPOS cohort for 10 more years, taking advantage of the long- term randomized exposure to MET and the densely phenotyped and genotyped DPPOS cohort (n=2778), which includes nearly 1600 patients with known T2D duration and ~1200 who have not developed T2D, to address yet unanswered questions about long-term exposure to MET and ILS initiated during pre-diabetes. DPPOS Phase 3 will examine outcomes that are of increasing public health concern in the aging population with pre- diabetes and T2D, including the putative benefits of MET on development of CVD and cancer. The main goals of DPPOS Phase 3 are to examine efficiently: 1) the long-term effects of metformin therapy begun in the pre- diabetic phase on risk for CVD and cancer; 2) the long-term effects by intention-to-treat of ILS and MET on further development of T2D and on traditional and more recently recognized complications of dysglycemia, and of their economic impact; and 3) the clinical course of dysglycemia, evaluated by categorical diagnoses (pre-diabetes vs diabetes) and as a continuum, and their associations with the development of complications, including analyses of interactions with DPP interventions and established and novel risk factors.