The LIMIting AAA with meTformin (LIMIT) Trial

项目摘要 腹主动脉瘤（AAA）疾病是成人过早死亡的常见原因 美国人到目前为止，没有医疗（例如，非手术）治疗已证明可有效限制AAA疾病 进展，或降低AAA破裂或动脉粥样硬化相关猝死的风险。 认识到糖尿病个体不太可能发展为AAA，当存在于糖尿病患者中时， AAA扩大速度较慢，破裂频率较低，为医学AAA疾病带来了新的可能性 管理最近的回顾性研究表明，二甲双胍，世界上最常用的口服 降血糖剂，可能与AAA扩大率降低有关。然而，到目前为止， 二甲双胍抑制AAA疾病的作用尚未以科学严谨的前瞻性方式进行评估。 在现有观测证据和为支持这一提议而产生的新的初步数据的基础上， 我们的基本假设是二甲双胍治疗可以安全地抑制非腹主动脉瘤患者的疾病进展， 糖尿病患者为了验证这一假设，提出了两个具体目标。第一个目标将评估 二甲双胍在非糖尿病AAA患者中的耐受性和安全性。耐受性将由 生活质量调查的连续管理和跟踪参与者的遵守和保留。安全将是 通过半年一次的检查、原始病历审查、补充血液学检查和 根据需要进行代谢小组调查。第二个目标将检测二甲双胍XR（缓释）的能力 将现有中小型AAA的平均年扩张率降低≥ 30% 与安慰剂相比。为此，480名受试者将以1：1的比例随机分配至二甲双胍组或安慰剂组。的 主要终点将是24个月内平均最大正交AAA直径的增加， 通过计算机断层摄影术（CTA）确定。这些目标的成功实现将推动 对AAA疾病的理解以及二甲双胍治疗的转化效用， 非糖尿病患者的心血管疾病。 这些目标具体涉及NIH的战略愿景目标：1）了解人类生物学，2） 减少人类疾病，3）推进转化研究，以及1）了解 正常的生物功能和恢复力，2）研究新发现的病理生物学机制，以及3） 开发和优化新的治疗策略，以预防、治疗和治愈HLBS疾病。

Project Summary Abdominal aortic aneurysm (AAA) disease is a common cause of premature death in adult Americans. To date, no medical (e.g., non-surgical) therapies have proven effective at limiting AAA disease progression, or reducing the risk of AAA rupture or aneurysm-related sudden death. The recognition that diabetic individuals are less likely to develop AAAs and when present in diabetics, AAAs enlarge less rapidly and rupture less frequently, introduces new possibilities for medical AAA disease management. Recent retrospective studies suggest that metformin, the world’s most commonly prescribed oral hypoglycemic agent, may be associated with reduced rates of AAA enlargement. To date, however, the ability of metformin to suppress AAA disease has not been evaluated in a scientifically rigorous, prospective fashion. Building off existing observational evidence and novel preliminary data, generated to support this proposal, it is our fundamental hypothesis that metformin therapy will safely suppress AAA disease progression in non- diabetic patients. To test this hypothesis, two Specific Aims are proposed. The First Aim will evaluate the tolerability and safety of metformin in nondiabetic patients with AAA disease. Tolerance will be assessed by the serial administration of quality of life surveys and tracking participant compliance and retention. Safety will be assessed by semi-annual examinations, review of the source medical record, supplementary hematologic and metabolic panel surveys as needed. The Second Aim will test the ability of metformin XR (extended release) to reduce the average annual rate of enlargement of existing small to intermediate size AAAs by ≥ 30% compared to placebo. For this Aim, 480 participants will be randomized 1:1 to metformin or placebo. The primary endpoint will be the increase in mean maximal orthogonal AAA diameter through 24 months, as determined by computed tomographic aortography (CTA). Successful completion of these Aims will advance the understanding of AAA disease as well as the translational utility of metformin therapy to treat cardiovascular diseases in nondiabetic patients. These Aims specifically address the NIH Strategic Vision Goals of 1) understanding human biology, 2) reducing human disease, and 3) advancing translational research, as well as Objectives of 1) understanding normal biologic function and resilience, 2) investigating newly discovered pathobiological mechanisms, and 3) developing and optimizing novel therapeutic strategies to prevent, treat and cure HLBS diseases.