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

1 型糖尿病索马鲁肽对心血管结局的影响 (T1-DISCO)

• 批准号: 10672454
• 负责人: Petter M Bjornstad
• 金额: $ 61.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672454
• 关键词: Adipose tissue; Adult; Age; Agonist; Albumins; Albuminuria; Animal Model; Aorta; Attenuated; Biological Availability; Biopsy; Blood Vessels; Body Weight decreased; Body mass index; Cardiac; Cardiopulmonary; Cardiorenal syndrome; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Clinical Trials; Continuous Glucose Monitor; Creatinine; Data; Diabetes Mellitus; Diabetic Ketoacidosis; Diabetic Nephropathy; Disease Outcome; Double-Blind Method; Endothelium; Event; Fatty acid glycerol esters; Frequencies; GLP-I receptor; Glomerular Filtration Rate; Glucose; Glucose Clamp; Glycocalyx; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Iohexol; Kidney; Magnetic Resonance Imaging; Medial; Mediating; Metabolic; Metformin; Methods; Morbidity - disease rate; Myocardial dysfunction; NOS3 gene; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Stress; Peripheral; Persons; Physiologic pulse; Placebo Control; Placebos; Population; Positioning Attribute; Randomized; Reactive Oxygen Species; Renal function; Reporting; Residual state; Risk; Safety; Structure; System; Thick; Urine; Vascular resistance; Vasodilation; Weight; Youth; arterial stiffness; cardiac magnetic resonance imaging; cardiometabolism; cardioprotection; cardiovascular disorder risk; disorder risk; endothelial dysfunction; glycemic control; heart function; hemodynamics; improved; innovation; insight; insulin sensitivity; intravital microscopy; kidney vascular structure; pilot trial; premature; pressure; primary outcome; response; shear stress; subcutaneous; young adult

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.

项目概要 心血管疾病（CVD）和糖尿病肾病（DKD）是发病率和死亡率的主要原因 患有 1 型糖尿病 (T1D) 的青少年和成人过早死亡。连续血糖的最新进展 监测（CGM）和自动胰岛素输送系统促进了血糖控制的改善，但 CVD 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度和内皮功能障碍，这两种情况都是 已知可以预测 T1D 的 CVD。因此，需要研究探索新辅助药物对心肾的影响 2 型糖尿病 (T2D) 的变革性心血管结果试验为 T1D 治疗提供了信息。 胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 可减轻患有以下疾病的成人的主要不良心脏事件 T2D 并支持减肥。我们的小组已对年轻人的亚临床心肾疾病进行了表征 患有 T1D，报告心脏功能、中央动脉僵硬度、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体重指数的增加而恶化。我们的 小组还记录了 GLP-1RA 可减轻亚临床心脏功能障碍和主动脉僵硬 在患有 T2D 的成人和动物模型中，不会增加低血糖或糖尿病酮症酸中毒的风险 糖尿病。迄今为止，关于年轻 T1D 患者 CVD、IR 或 DKD 相关结局的数据有限 响应 GLP-1RA。事实上，在 T1D 中，GLP-1RA 的研究主要集中在体重和血糖上 降低。因此，我们对这些药物对 T1D 心肾影响的理解存在差距。 评估 GLP-1RA 对心血管和肾功能的影响和潜在机制 作为 T1D 中的胰岛素敏感性，我们建议对 52 名患者进行为期 6 个月的随机、安慰剂对照、双盲研究 患有 T1D 的年轻成人（18-40 岁）使用每周一次皮下注射索马鲁肽作为机制 探测。主要结果是主动脉 MRI 测得的中央和外周脉搏波速度 (PWV) 的变化 和 SphygmoCor。其他结果将包括通过心脏 MRI 检测的亚临床心脏功能、内皮细胞 通过血流介导的血管舒张（FMDBA）来调节功能，通过高胰岛素正常血糖钳夹来调节胰岛素敏感性， 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，通过尿液测定白蛋白尿 白蛋白与肌酐的比率以及 CGM 的血糖变异性。硝酸的创新转化评估 氧化物 (NO) 生物利用度、内皮一氧化氮合成酶 (eNOS) 激活、活性氧 (ROS)/来自血管内 J 线活检和舌下内皮糖萼的氧化应激 评估将提供机制洞察。