Glycemic Reduction Approaches for Treating Diabetes: An Effectiveness Study

治疗糖尿病的降血糖方法：有效性研究

• 批准号: 8152144
• 负责人: DAVID M NATHAN
• 金额: $ 30.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8152144
• 关键词: Address; Adherence; Affect; Amputation; Area Under Curve; Biological Assay; Blindness; Blood Glucose; Body Weight Changes; Cardiovascular Diseases; Cause of Death; Cessation of life; Characteristics; Clinical; Clinical Trials; Combination Medication; Combined Modality Therapy; Contracts; Data; Data Reporting; Development; Diabetes Mellitus; Disease; Drug Combinations; Effectiveness; Enrollment; Ensure; Epidemic; Failure; Funding; Glucose; Glycosylated hemoglobin A; Goals; Human; Hypoglycemia; Incidence; Individual; Institutional Review Boards; Intervention; Kidney Failure; Laboratories; Manuals; Measures; Metabolic; Metformin; Methods; Multicenter Studies; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Preparation; Prevalence; Process; Protocols documentation; Public Health; Quality of life; Randomized; Randomized Clinical Trials; Reading; Recruitment Activity; Regimen; Resources; Risk; Risk Factors; System; Time; TimeLine; Work; base; clinical research site; comparative effectiveness; cost; cost effectiveness; design; drug distribution; economic cost; effective therapy; effectiveness research; follow-up; glycemic control; improved; infancy; meetings; operation; patient population; premature; public health relevance; response; secondary outcome; treatment strategy

DESCRIPTION (provided by applicant): The epidemic of type 2 diabetes (T2DM) that has affected the US and other populations in the last thirty years is a major public health problem. The most recent US estimates include a prevalence of more than 21 million and incidence of 1.6 million cases per year. The major human and economic costs associated with the epidemic are related primarily to the development of long-term complications that cause more cases of blindness, renal failure, and amputations than any other disease. T2DM also increases cardiovascular disease by 2-5 fold and is the leading cause of death and premature death in persons with diabetes. High quality clinical trials have established the importance of lowering glycemia with a variety of medications to reduce the long-term complications. One of the major challenges for practitioners is to choose, from the large armamentarium of glucose-lowering medications at their disposal, the optimal approach to achieve and then maintain good glycemic control for as long as possible. Evidence supporting the choice of one versus another agent as initial therapy or the choice of sequential versus combination therapy as an initial approach is clearly lacking. Comparative effectiveness research is a high priority to improve public health and maximize cost- effectiveness. Moreover, there are little data available to determine whether some therapies work better in individuals with particular characteristics compared to others; therefore, individualizing therapies to obtain maximum effectiveness remains in its infancy. We propose to address these questions in a randomized clinical trial in patients with recent onset (<3 years duration) T2DM that will compare the metabolic effects of five common glucose- lowering drugs when combined with metformin. Recruitment will be stratified to include patients who have been treated with metformin (n=5,500) for up to three years, and patients who are drug-naive (n=2,000). All will be randomly assigned to one of five drug regimens to be administered in combination with metformin. Subjects in the drug naive stratum will also be randomly assigned to be treated with the assigned drug as sequential therapy (ST) after glycemic control has deteriorated with metformin monotherapy, similar to traditional prescribing patterns, or to receive initial combination therapy (ICT). The one-half of the drug-naive stratum assigned to initial combination therapy will be included with the metformin-treated stratum in the analyses of the differences among the five drug combinations. The proposed partial factorial design is an efficient way to compare the five major diabetes drug combinations and examine two different treatment strategies in a single trial. The primary metabolic outcome will be time to failure defined as a HbA1c >7%, with area- under-the-curve HbA1c levels as a secondary metabolic outcome. Follow-up will be for a minimum of 4 (4-7) years. Determination and comparison of the other important attributes of the five combinations, including weight change, hypoglycemia, tolerability, effects on CVD risk factors, and cost will be performed. In addition, we will examine the phenotypic and, resources permitting, genotypic characteristics that are associated with metabolic response to and/or failure of the individual medication combinations and the two intervention strategies. The goal of the proposed U34 application is to complete the design and prepare for the implementation of a multicenter study to determine the most effective drug combinations and treatment strategies for T2DM that achieve and maintain the glycemic levels known to reduce long-term complications. Specifically, the U34 period will be used to: a) develop the protocol and manual of operations; b) recruit the clinical centers, laboratories, and reading and drug distribution centers; and c) establish recruitment strategies, identify patient populations and complete the IRB and other regulatory approval process to meet enrollment timelines. This preparation will ensure that the majority of clinical sites are ready to start randomizing patients as soon as possible after the study is funded, minimizing recruitment time and maximizing patient follow-up and power of the study. The results of this trial will identify the most effective means of treating glycemia in T2DM early in its course and will have major public health implications. PUBLIC HEALTH RELEVANCE: In order to avoid long-term complications that may affect people with type 2 diabetes, average blood sugar levels, as measured with the HbA1c assay, must be maintained in a near-normal range. Although there are many medications that are currently available to treat type 2 diabetes, we don't understand the most effective means of achieving and maintaining the target blood sugar levels over time. In addition, we don't know whether specific medications, or combinations of medications, are better for specific groups of people. The proposed study will compare two different strategies and five different medications for treating type 2 diabetes in order to determine how best to treat it. Since type 2 diabetes is now epidemic, affecting more than 20 million people in the US, comparing and selecting the most effective treatment methods will have a major public health impact.

描述（由申请人提供）：在过去30年中影响美国和其他人群的2型糖尿病（T2DM）的流行是一个主要的公共卫生问题。美国最近的估计包括超过2100万的患病率和每年160万例的发病率。与流行病相关的主要人类和经济成本主要与长期并发症的发展有关，这些并发症会导致盲目性，肾衰竭和截肢的病例比任何其他疾病。 T2DM还将心血管疾病增加2-5倍，是糖尿病患者死亡和过早死亡的主要原因。高质量的临床试验已经确定了使用多种药物降低血糖以减少长期并发症的重要性。从业者面临的主要挑战之一是，可以从降低葡萄糖药物的大型武器库中选择，这是达到尽可能长时间的最佳方法，然后尽可能长期保持良好的血糖控制。显然缺乏支持选择一种与另一种药物作为初始疗法或连续疗法作为初始方法的选择与另一个药物的选择的证据。比较有效性研究是提高公共卫生并最大化成本效益的高度优先事项。此外，与其他疗法相比，与其他人相比，一些疗法在具有特定特征的个体中是否效果更好。因此，获得最大有效性的个性化疗法仍处于起步阶段。 我们建议在一项随机临床试验中解决这些问题（近3年）T2DM的患者，该试验将比较五种常见的葡萄糖降低药物与二甲双胍的代谢作用。招募将分层为包括二甲双胍治疗（n = 5,500）长达三年的患者，而药物不接受的患者（n = 2,000）。所有这些都将随机分配给与二甲双胍结合使用的五种药物方案之一。药物天真层中的受试者还将随机分配给分配的药物作为顺序治疗（ST）在血糖控制后使用二甲双胍单一疗法恶化，类似于传统的处方模式，或接受初始组合疗法（ICT）。分配给初始组合疗法的药物层的一半将与二甲双胍处理的层中包括在五种药物组合之间的差异分析中。拟议的部分阶乘设计是比较五种主要糖尿病药物组合并在一次试验中检查两种不同的治疗策略的有效方法。 主要的代谢结果将是将失败定义为HbA1c> 7％的时间，而面积下方的HBA1C水平为次级代谢结果。随访至少为4（4 - 7）年。将执行五种组合的其他重要属性的确定和比较，包括体重变化，低血糖，耐受性，对CVD风险因素的影响和成本。此外，我们将研究与对单个药物组合和两种干预策略的代谢反应和/或失败有关的表型和资源，基因型特征。 提出的U34应用的目的是完成设计并为实施多中心研究做准备，以确定T2DM的最有效的药物组合和治疗策略，以实现和维持已知可减少长期并发症的血糖水平。具体而言，U34时期将用于：a）制定操作协议和手册； b）招募临床中心，实验室以及阅读和药物分配中心； c）建立招聘策略，确定患者人群并完成IRB和其他监管批准过程，以满足入学时间。这项准备工作将确保大多数临床部位准备在研究后尽快开始随机对患者进行随机，最大程度地减少招聘时间，并最大程度地提高患者的随访和研究的能力。该试验的结果将确定在其课程初期治疗T2DM中治疗血糖的最有效方法，并将具有重大的公共卫生影响。 公共卫生相关性：为了避免可能影响2型糖尿病患者的长期并发症，必须维持使用HBA1C测定法测量的平均血糖水平，必须保持在接近正常的范围内。尽管目前有许多药物可用于治疗2型糖尿病，但我们不了解随着时间的推移实现和维持目标血糖水平的最有效方法。此外，我们不知道特定的药物或药物组合是否对特定的人群更好。拟议的研究将比较两种不同的策略和五种治疗2型糖尿病的药物，以确定如何最好地治疗它。由于现在流行2型糖尿病，在美国影响超过2000万人，比较和选择最有效的治疗方法将对公共卫生产生重大影响。