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; 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.

项目摘要 心血管疾病（CVD）和糖尿病肾病（DKD）是发病率和 1型糖尿病（T1D）的青年和成人过早死亡。连续葡萄糖的最新进展 监测（CGM）和自动胰岛素输送系统促进了血糖控制的改善，但是 CVD和DKD的残留风险仍然很高。肥胖和胰岛素抵抗（IR）也伴随 强化血糖疗法，可能会强调动脉僵硬和内皮功能障碍，每种功能障碍 已知可以预测T1D中的CVD。因此，需要研究来探索新辅助性的心肾脏影响 T1D中的疗法通过2型糖尿病（T2D）的转化性心血管结局试验告知。 胰高血糖素样肽-1受体激动剂（GLP-1RA）减轻成年人的重大不良心脏事件 T2D和支持减肥。我们的小组表征了年轻人的亚临床心脏疾病 与T1D有关心脏功能异常，中央动脉僵硬，内皮功能，肾脏的报告异常 功能和胰岛素敏感性。随着BMI的增加，这些心脏异常也更糟。我们的 小组还记录了与GLP-1RA的减弱亚临床心脏功能障碍和主动脉僵硬 在患有T2D和动物模型的成年人中，没有增加血糖或糖尿病性酮症酸中毒的风险 糖尿病。迄今为止，对于T1D的年轻人，有关CVD，IR或DKD相关结果的数据有限 响应GLP-1RA。实际上，在T1D中，GLP-1RA的研究主要集中于体重和葡萄糖 降低。因此，我们对这些药物在T1D中的心脏影响的理解存在差距。 评估GLP-1RA的影响和潜在机制对心血管和肾功能也 作为T1D胰岛素敏感性，我们提出了一个6个月的随机，安慰剂对照，双盲研究，52 T1D的年轻人（18-40岁）使用曾经每周皮下semaglutide作为机械 探测。主要结果将是主动脉MRI的中央和外围脉冲波速度（PWV）的变化 和血压点。其他结果将包括心脏MRI，内皮的亚临床心脏功能 通过流动介导的血管扩张（FMDBA）的功能，高胰岛素血糖夹的胰岛素敏感性，胰岛素敏感性， iohexol和p-氨基磷酸清除，尿液的依克己醇和p-氨基硫酸盐的血液动力学功能 CGM的白蛋白与共氨酸比例和血糖变异性。一氮的创新翻译评估 氧化物（NO）生物利用度，内皮NO合酶（ENOS）激活，活性氧 （ROS）/内血管内生活检中的氧化应激和舌下的内皮糖脂 评估将提供机械洞察力。