Glycemia Reduction Approaches in Diabetes: A comparative effectiveness study

描述（由申请人提供）：影响世界人口的2型糖尿病（T2 DM）流行病有可能成为本世纪的主要公共卫生问题。在美国，与该流行病相关的巨大人力和经济成本（每年约2500万人患病，190万人发病）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，这些并发症导致失明、肾衰竭和截肢的病例比任何其他疾病都多。心血管疾病（CVD）在T2 DM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定了降低血糖水平以减少长期并发症的重要性。T2 DM进展通常需要在二甲双胍（公认的一线治疗）基础上添加第二种药物。随着许多新型降糖药物的开发，缺乏指导第二种药物选择的证据，促使承认这一缺陷的相互冲突的指南的扩散。此外，虽然这些制剂通常使用多年，但没有长期使用的数据。比较有效性研究是改善公共卫生和最大限度地提高T2 DM治疗成本效益的优先事项。此外，还需要努力使T2 DM治疗个体化，并确定所选治疗在某些患者中的效果是否优于其他患者，同时还需要进行研究，以了解各种治疗随时间推移对代谢的不同影响。 糖尿病中的血糖降低方法：一项比较有效性（GRADE）研究将在6000例新发（病程<5年）T2 DM患者中进行的一项随机、实用的临床试验中解决这些问题。GRADE将比较四种常见降糖药物（磺酰脲类药物格列美脲、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）在二甲双胍基础上加用具有临床意义的持续时间内的代谢效应，平均暴露时间为4.5（3-6）年。主要结局是至原发性代谢衰竭的时间其他结果包括平均A1 C;到A1 C> 7.5%的次要代谢结果的时间，确认，之后将添加基础胰岛素“补救”疗法;和副作用，如体重增加和低血糖，对选定的微血管疾病和CVD风险因素的影响，耐受性和生活质量，以及成本和成本效益。我们还将研究与药物组合的代谢反应和/或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.