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）：2 型糖尿病 (T2DM) 的流行在过去三十年中影响了美国和其他人群，是一个重大的公共卫生问题。美国最近的估计包括每年超过 2100 万例患病率和 160 万例病例。与该流行病相关的主要人员和经济损失主要与长期并发症的发生有关，与任何其他疾病相比，这些并发症导致更多的失明、肾衰竭和截肢病例。 T2DM 还会使心血管疾病增加 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证实了使用各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从可供使用的大量降糖药物中选择最佳方法，以实现并尽可能长时间地维持良好的血糖控制。显然缺乏支持选择一种药物与另一种药物作为初始治疗或选择序贯治疗与联合治疗作为初始方法的证据。比较效果研究是改善公共卫生和最大化成本效益的首要任务。此外，几乎没有数据可以确定某些疗法是否对具有特定特征的个体比其他人更有效。因此，个体化治疗以获得最大效果仍处于起步阶段。 我们建议在近期发病（病程<3年）T2DM患者中进行一项随机临床试验来解决这些问题，该试验将比较五种常见降糖药物与二甲双胍联合使用时的代谢效应。招募对象将分层，包括已接受二甲双胍治疗长达三年的患者 (n=5,500) 和未接受过药物治疗的患者 (n=2,000)。所有患者都将被随机分配到五种药物治疗方案中的一种，与二甲双胍联合给药。与传统处方模式类似，在二甲双胍单药治疗血糖控制恶化后，未用药层的受试者也将被随机分配接受指定药物的序贯治疗 (ST)，或接受初始联合治疗 (ICT)。在分析五种药物组合之间的差异时，分配给初始联合治疗的一半未接受过药物治疗的群体将包括在二甲双胍治疗的群体中。所提出的部分因子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治疗策略的有效方法。 主要代谢结果是衰竭时间，定义为 HbA1c >7%，HbA1c 水平曲线下面积作为次要代谢结果。随访时间至少为四 (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 危险因素的影响和成本。此外，我们将检查与单个药物组合和两种干预策略的代谢反应和/或失败相关的表型和基因型特征（在资源允许的情况下）。 拟议的 U34 申请的目标是完成设计并为实施多中心研究做好准备，以确定最有效的 T2DM 药物组合和治疗策略，以达到并维持已知可减少长期并发症的血糖水平。具体来说，U34时期将用于： a) 制定操作规程和手册； b) 招募临床中心、实验室、阅片中心和药品分配中心； c) 制定招募策略，确定患者群体并完成 IRB 和其他监管审批流程，以满足招募时间表。这一准备工作将确保大多数临床中心准备好在研究资助后尽快开始对患者进行随机分组，从而最大限度地缩短招募时间并最大限度地提高患者随访率和研究效力。该试验的结果将确定治疗 T2DM 早期血糖的最有效方法，并将对公共卫生产生重大影响。 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，通过 HbA1c 测定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，但我们并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，我们不知道特定药物或药物组合是否更适合特定人群。拟议的研究将比较治疗 2 型糖尿病的两种不同策略和五种不同药物，以确定最佳治疗方法。由于 2 型糖尿病现已流行，影响美国超过 2000 万人，因此比较和选择最有效的治疗方法将对公共健康产生重大影响。