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

项目总结 心血管疾病(CVD)和糖尿病肾病(DKD)是发病率和 青年和成年1型糖尿病(T1D)患者过早死亡。连续葡萄糖的研究进展 监测(CGM)和自动胰岛素输送系统促进了血糖控制的改善，但 心血管疾病和DKD的残余风险仍然很高。肥胖和胰岛素抵抗(IR)也伴随着 强化血糖治疗，可能会加剧动脉僵硬和内皮功能障碍，这两种情况都是 已知可预测T1D的心血管疾病。因此，需要研究来探索新的辅助剂对心脏和肾脏的影响。 由2型糖尿病(T2D)的变革性心血管结局试验(T2D)得知的T1D治疗。 胰升糖素样肽-1受体激动剂(GLP-1RAs)可减轻成人高血压患者的主要不良心脏事件 T2D和支持减肥。我们小组的特点是年轻人的亚临床心肾疾病。 对于T1D，报告心功能、中央动脉僵硬、内皮功能、肾脏异常 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。我们的 该小组还记录了使用GLP-1RA可减轻亚临床心功能障碍和主动脉僵硬 在患有T2D的成人和动物模型中，没有增加低血糖或糖尿病酮症酸中毒的风险 糖尿病的症状。到目前为止，关于患有T1D的年轻人的心血管疾病、IR或DKD相关结局的数据有限 对GLP-1RA的反应。事实上，在T1D中，对GLP-1RA的研究主要集中在体重和血糖上 放低。因此，我们对这些药物在T1D中对心脏和肾脏的影响的理解存在差距。 探讨GLP-1RA对心血管和肾功能的影响及其机制 对于T1D的胰岛素敏感性，我们建议在52名患者中进行为期6个月的随机、安慰剂对照、双盲研究 青壮年T1D(年龄18-40岁)每周皮下注射一次半乳糖作为治疗机制 探测器。主要结果是主动脉MRI显示中心和外周脉搏波速度(PWV)的改变 和SPhygmoCor。其他结果将包括心脏MRI、内皮细胞检测的亚临床心功能 血流介导的血管扩张(FMDBA)功能，高胰岛素正血糖钳夹的胰岛素敏感性， 碘海醇和对氨基马尿酸清除肾小球内血流动力学功能，尿白蛋白尿 白蛋白/肌酐比率和CGM的血糖变异性。创新的硝酸盐翻译评估 一氧化氮(NO)生物利用度、内皮型一氧化氮合酶(ENOS)活性、活性氧物种 血管内J钢丝活检的(ROS)/氧化应激和舌下内皮细胞糖基化反应 评估将提供机械性的洞察力。

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.