Type 1 Diabetes Impacts of Semaglutide on Cardiovascular Outcomes (T1-DISCO)

项目摘要 心血管疾病（CVD）和糖尿病肾病（DKD）是发病的主要原因， 1型糖尿病（T1 D）患者中的年轻人和成年人过早死亡。动态葡萄糖的研究进展 血糖监测（CGM）和自动胰岛素输注系统有助于改善血糖控制，但 CVD和DKD的剩余风险仍然很高。肥胖和胰岛素抵抗（IR）也伴随着 强化血糖治疗，并可能加重动脉僵硬和内皮功能障碍，其中每一个都是 已知可预测T1 D患者的CVD。因此，需要进行研究以探索新的维生素E对心肾的影响。 2型糖尿病（T2 D）的变革性心血管结局试验为T1 D治疗提供了信息。 胰高血糖素样肽-1受体激动剂（GLP-1 RA）可减轻成人中的主要不良心脏事件， T2 D和支持减肥。我们的研究小组已经在年轻人中发现了亚临床心肾疾病的特征 T1 D患者，报告心脏功能、中心动脉僵硬度、内皮功能、肾脏 功能和胰岛素敏感性。这些心肾异常也随着BMI的增加而加重。我们 GLP-1 RA组还记录了亚临床心功能不全和主动脉僵硬的减轻 在T2 D成人患者和动物模型中，低血糖或糖尿病酮症酸中毒的风险不增加 糖尿病迄今为止，关于年轻T1 D患者中CVD、IR或DKD相关结局的数据有限 对GLP-1 RA的反应。事实上，在T1 D中，GLP-1 RA研究主要关注体重和血糖 降低。因此，我们对这些药物在T1 D中的心肾影响的理解存在差距。 评价GLP-1 RA对心血管和肾功能的影响及其潜在机制 作为T1 D的胰岛素敏感性，我们提出了一项为期6个月的随机、安慰剂对照、双盲研究， 使用每周一次皮下semaglutide作为机制的T1 D年轻成人（18-40岁） 探针主要结局将是主动脉MRI显示的中心和外周脉搏波速度（PWV）的变化 和SphygmoCor。其他结局将包括通过心脏MRI检查的亚临床心功能、内皮 通过血流介导的血管舒张（FMDBA）的功能，通过高胰岛素血正葡萄糖钳夹的胰岛素敏感性， 通过碘海醇和对氨基马尿酸清除率测定肾小球内血流动力学功能，通过尿测定白蛋白尿 白蛋白/肌酐比值和CGM血糖变异性。创新的氮转化评估 一氧化氮（NO）生物利用度，内皮型NO合酶（eNOS）激活，活性氧 (ROS)/来自血管内J形针活检的氧化应激和来自舌下的内皮糖萼 评估将提供机械的洞察力。

PROJECT SUMMARY Cardiovascular disease (CVD) and diabetic kidney disease (DKD) are the leading causes of morbidity and premature death in youth and adults with type 1 diabetes (T1D). Recent advances in continuous glucose monitoring (CGM) and automated insulin delivery systems have facilitated improved glycemic control, but the residual risk of CVD and DKD remains high. Obesity and insulin resistance (IR) have also accompanied intensive glycemic therapy and may accentuate arterial stiffness and endothelial dysfunction, each of which is known to predict CVD in T1D. Thus, studies are needed to explore the cardio-renal impact of new adjunctive therapies in T1D informed by the transformative cardiovascular outcome trials in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) mitigate major adverse cardiac events in adults with T2D and support weight loss. Our group has characterized subclinical cardiorenal disease in young persons with T1D, reporting abnormalities in cardiac function, central arterial stiffness, endothelial function, kidney function, and insulin sensitivity. These cardiorenal abnormalities were also worse with increasing BMI. Our group has also documented attenuated subclinical cardiac dysfunction and aortic stiffness with GLP-1RA without increased risk of hypoglycemia or diabetic ketoacidosis, in both adults with T2D and in animal models of diabetes. To date, limited data exist regarding CVD, IR or DKD-related outcomes in young adults with T1D in response to GLP-1RA. Indeed in T1D, studies with GLP-1RA have focused primarily on weight and glucose lowering. Thus, there is a gap in our understanding of the cardiorenal impact of these agents in T1D. To evaluate the effects and underlying mechanisms of GLP-1RA on cardiovascular and kidney function as well as insulin sensitivity in T1D, we propose a 6-month randomized, placebo-controlled, double-blind study in 52 young adults with T1D (ages 18-40 years) using once weekly subcutaneous semaglutide as a mechanistic probe. The primary outcomes will be change in central and peripheral pulse wave velocity (PWV) by aortic MRI and SphygmoCor. Additional outcomes will include subclinical cardiac function by cardiac MRI, endothelial function by flow mediated vasodilatation (FMDBA), insulin sensitivity by hyperinsulinemic euglycemic clamps, intraglomerular hemodynamic function by iohexol and p-aminohippurate clearance, albuminuria by urine albumin-to-creatinine ratio, and glycemic variability by CGM. Innovative translational assessments of nitric oxide (NO) bioavailability, endothelial NO synthase (eNOS) activation, reactive oxygen species (ROS)/oxidative stress from endovascular J-wire biopsies and endothelial glycocalyx from sublingual assessments will provide mechanistic insight.