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: 8113503
• 负责人: DAVID M NATHAN
• 金额: $ 31.91万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113503
• 关键词: Glycemic; Reduction; Approaches; Treating; Diabetes

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）：在过去三十年中，2型糖尿病（T2 DM）的流行影响了美国和其他人群，是一个主要的公共卫生问题。美国最近的估计包括每年超过2100万的患病率和160万例的发病率。与这一流行病有关的主要人力和经济成本主要与长期并发症的发展有关，这些并发症造成的失明、肾衰竭和截肢病例比任何其他疾病都多。2型糖尿病还使心血管疾病增加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用各种药物降低血糖的重要性，以减少长期并发症。从业者面临的主要挑战之一是从大量的降糖药物中选择最佳方法，以实现并尽可能长时间地保持良好的血糖控制。显然缺乏证据支持选择一种或另一种药物作为初始治疗或选择序贯或联合治疗作为初始方法。比较有效性研究是改善公共卫生和最大限度地提高成本效益的一个高度优先事项。此外，几乎没有数据可以确定某些疗法是否在具有特定特征的个体中比其他人更有效;因此，个体化疗法以获得最大有效性仍处于起步阶段。 我们建议在近期发作（病程<3年）的T2 DM患者中进行一项随机临床试验来解决这些问题，该试验将比较5种常见降糖药物与二甲双胍联合使用时的代谢作用。将对招募进行分层，包括接受二甲双胍治疗长达3年的患者（n= 5，500）和首次用药患者（n= 2，000）。所有患者将被随机分配至五种药物方案之一，与二甲双胍联合给药。在二甲双胍单药治疗后血糖控制恶化后，未接受过药物治疗的受试者也将被随机分配接受指定药物序贯治疗（ST），类似于传统处方模式，或接受初始联合治疗（ICT）。分配至初始联合治疗的未接受过药物治疗的分层的一半将与二甲双胍治疗的分层一起纳入5种药物联合治疗之间差异的分析中。提出的部分析因设计是比较五种主要糖尿病药物组合并在单一试验中检查两种不同治疗策略的有效方法。 主要代谢结果将是定义为HbA 1c> 7%的失败时间，HbA 1c水平曲线下面积作为次要代谢结果。随访至少4（4-7）年。将确定和比较五种组合的其他重要属性，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，我们还将研究与代谢反应和/或个体药物组合和两种干预策略失败相关的表型和（如果资源允许）基因型特征。 申报的U34申请旨在完成设计并准备实施一项多中心研究，以确定最有效的T2 DM药物组合和治疗策略，达到并维持已知的血糖水平，以减少长期并发症。具体而言，U34期将用于：a）制定方案和操作手册; B）招募临床中心、实验室、阅读和药物配送中心;以及c）制定招募策略、确定患者人群并完成IRB和其他监管批准流程，以满足入组时间表。这项准备工作将确保大多数临床研究中心在研究获得资助后尽快准备好开始随机分配患者，最大限度地减少招募时间，最大限度地增加患者随访和研究的把握度。这项试验的结果将确定治疗T2 DM早期糖尿病的最有效方法，并将对公共卫生产生重大影响。 公共卫生关系：为了避免可能影响2型糖尿病患者的长期并发症，必须将HbA 1c测定的平均血糖水平保持在接近正常的范围内。虽然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达到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人群更好。2型糖尿病是一种常见的糖尿病，它的发病率高，发病率低。2型糖尿病是一种常见的糖尿病，在美国有2000多万人患有2型糖尿病。2型糖尿病是一种常见的糖尿病，它的发病率高，发病率低。