Glycemia Reduction Approaches in Diabetes: A comparative effectiveness study

描述（由申请人提供）：2型糖尿病（T2DM）的流行已经影响到世界人口，有可能成为本世纪主要的公共卫生问题。在美国，与该流行病相关的巨大人力和经济成本（患病率约为2500万，每年发病率为190万）主要与长期并发症的发展有关，包括视网膜病变、肾病和神经病变，这些并发症导致的失明、肾衰竭和截肢病例比任何其他疾病都多。心血管疾病（CVD）在T2DM中增加2-5倍，是过早死亡的主要原因。高质量的临床试验已经确立了降低血糖对减少长期并发症的重要性。T2DM的进展通常需要在二甲双胍（公认的一线治疗）的基础上再加一种药物。随着许多新型降糖药物的发展，指导第二种药物选择的证据缺乏，促使承认这一缺陷的相互矛盾的指南激增。此外，虽然这些药物通常使用多年，但没有长期使用的数据。比较有效性研究是改善公众健康和最大限度地提高治疗2型糖尿病的成本效益的重中之重。此外，需要对2型糖尿病患者进行个体化治疗，并确定某些治疗方法是否对某些患者比其他患者更有效，同时也需要研究不同治疗方法对代谢的不同影响。糖尿病降糖方法：一项比较有效性（GRADE）研究将在一项随机、实用的临床试验中解决这些问题，该试验涉及6000名新近发病（持续时间<5年）的T2DM患者。GRADE将比较四种常见降糖药物的代谢作用，磺脲类格列美脲、DPP-4抑制剂西格列汀、GLP-1激动剂利拉鲁肽和基础甘精胰岛素，添加到二甲双胍中，在有临床意义的持续时间内，平均暴露时间为4.5（3-6）年。主要转归是发生原发性代谢衰竭的时间（随后确认的血红蛋白A1c （A1c）达到7%）。其他结果包括平均糖化血红蛋白；确认为A1C bb0 7.5%的继发性代谢结局，之后将添加基础胰岛素“拯救”治疗；和副作用，如体重增加和低血糖，对特定微血管疾病和心血管疾病风险因素的影响，耐受性和生活质量，以及成本和成本效益。我们还将研究与代谢反应和/或药物组合失败相关的表型特征和病理生理因素。

DESCRIPTION (provided by applicant): The epidemic of type 2 diabetes (T2DM) that has affected the world's populations threatens to become this century's major public health problem. The enormous human and economic costs associated with the epidemic in the US (prevalence of ~25 million, incidence 1.9 million per year) are related primarily to the development of long-term complications including retinopathy, nephropathy, and neuropathy that cause more cases of blindness, renal failure, and amputations than any other disease. Cardiovascular disease (CVD) is increased 2-5 fold in T2DM and is the leading cause of premature death. High quality clinical trials have established the importance of lowering glycemia to reduce long-term complications. Progression of T2DM usually requires addition of a second agent to metformin, the accepted first line treatment. With the development of numerous new classes of glucose-lowering drugs, evidence to guide the choice of the second agent is lacking, prompting the proliferation of conflicting guidelines that acknowledge this deficiency. Moreover, while these agents are typically used for many years, data on long-term use are non-existent. Comparative effectiveness research is a high priority to improve public health and maximize cost-effectiveness in the treatment of T2DM. In addition, efforts to individualize T2DM therapy and determine whether selected therapies work better in some patients than others are needed, as are studies to understand differential effects of various therapies on metabolism over time. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study will address these questions in a randomized, pragmatic clinical trial in 6000 patients with recent-onset (<5 years duration) T2DM. GRADE will compare the metabolic effects of four common glucose-lowering medications, the sulfonylurea glimepiride, DPP-4 inhibitor sitagliptin, GLP-1 agonist liraglutide, and basal insulin glargine, added to metformin, over a clinically meaningful duration, with a mean exposure of 4.5 (3-6) years. The primary outcome is the time to primary metabolic failure (hemoglobin A1c (A1C)>7%, subsequently confirmed).Other outcomes include mean A1C; time to a secondary metabolic outcome of A1C>7.5%, confirmed, after which basal insulin "rescue" therapy will be added; and adverse effects such as weight gain and hypoglycemia, effects on selected microvascular disease and CVD risk factors, tolerability and quality-of-life, and cost and cost-effectiveness. We will also examine the phenotypic characteristics and pathophysiologic factors associated with metabolic response to and/or failure of the drug combinations.