Cholesterol reduction and cardiovascular risk in Type 1 diabetes

1 型糖尿病的胆固醇降低和心血管风险

• 批准号: 10510217
• 负责人: Ira J Goldberg
• 金额: $ 86.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10510217
• 关键词: Abnormal Endothelial Cell; American Heart Association; Animal Model; Arteries; Atherosclerosis; Biological Markers; Biological Process; Blood Platelets; Blood Vessels; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Characteristics; Cholesterol; Clinic; Clinical Research; Clinical Trials; Communities; Cytometry; Data; Dendritic Cells; Development; Diabetes Mellitus; Endothelial Cells; Epinephrine; Event; Failure; Female; Gene Expression; Glucose; Glycosylated hemoglobin A; Harvest; Health care facility; Impairment; Individual; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; LDL Cholesterol Lipoproteins; Leukocytes; Low-Density Lipoproteins; Measurement; Measures; Medical center; Methods; Natural Killer Cells; New York City; Non-Insulin-Dependent Diabetes Mellitus; PET/CT scan; Pathologic Processes; Pathway interactions; Patient Recruitments; Patients; Peripheral Blood Mononuclear Cell; Platelet aggregation; Positron-Emission Tomography; Process; RNA; Research; Research Design; Residual state; Risk; Subgroup; Techniques; Testing; Time; Vascular Endothelial Cell; Veins; Woman; abdominal aorta; animal data; atorvastatin; blood glucose regulation; cardiovascular disorder risk; cardiovascular risk factor; diabetes control; experience; ezetimibe; fluorodeoxyglucose; glucose monitor; glycemic control; human data; improved; inflammatory marker; inhibitor; mRNA sequencing; macrophage; male; medical schools; men; neutrophil; platelet function; predictive marker; prevent; recruit; repaired; response; single-cell RNA sequencing; therapeutic target; transcriptome; treatment response; ultrasound; underserved community; uptake; vascular inflammation

ABSTRACT Diabetes markedly increases risk of development of atherosclerotic cardiovascular disease (CVD). Human and animal data also show that diabetes prevents the normal repair of damaged arteries that occurs upon circulating LDL cholesterol (LDL-C) reduction. Because of this, patients with diabetes still have greater risk of a cardiovascular event even after statin reduction of LDL-C than individuals without diabetes. Individuals with diabetes have greater platelet aggregation, altered white blood cells, and more vascular inflammation, pathological processes that are improved by LDL-C reduction in unaffected individuals. We hypothesize that by determining response to LDL-C reduction in T1D, we will identify pathways that can be therapeutically targeted to optimize vascular repair and prevent CVD events. These data can also be used to determine patient characteristics that associate with defective response to LDL-C reduction. We propose a clinical study of response to LDL-C reduction in patients with Type 1 diabetes (T1D). We will recruit the patients from two major medical centers, NYU Langone and Mount Sinai that serve diverse communities within New York City. Subjects will be treated for 4 weeks with robust cholesterol-reducing therapies, PCSK9 inhibitors and also either statin (80 mg atorvastatin) or ezetimibe (10 mg). Each subject will serve as their own control and we will determine changes in platelets and white blood cells along with circulating inflammatory factors that occur when LDL-C is markedly reduced. In a subgroup of subjects, changes in vascular inflammation will be determined by assessment of harvested brachial vein endothelial cells and by uptake of 18F-fluordeoxyglucose into arteries. The data will be analyzed by an experienced statistician with expertise in diabetes and CVD risk and will identify the relationship of these changes with HbA1c and glucose variability, and differences between women and men. In addition, the data in T1D will be compared with similar data assessing response to LDL-C in subjects with Type 2 diabetes and controls to determine abnormalities that differ between these two forms of diabetes.

抽象的 糖尿病明显增加了动脉粥样硬化心血管疾病（CVD）的发展风险。人类和 动物数据还表明，糖尿病可防止循环时发生的受损动脉的正常修复 LDL胆固醇（LDL-C）还原。因此，糖尿病患者仍然有更大的风险 与没有糖尿病的人相比，即使他汀类药物降低了他汀类药物，心血管事件也是如此。有个人 糖尿病具有更大的血小板聚集，白细胞改变和更血管炎症， 通过减少未受影响的个体LDL-C减少的病理过程。我们通过 确定对T1D降低LDL-C的反应，我们将确定可以针对治疗的途径 优化血管修复并防止CVD事件。这些数据也可用于确定患者 与降低LDL-C响应有缺陷的特征。我们提出了一项临床研究 1型糖尿病患者（T1D）患者对LDL-C减少的反应。我们将从两个主要的 医疗中心，纽约大学兰蒙和西奈山，为纽约市境内的不同社区提供服务。主题 通过鲁棒胆固醇疗法，PCSK9抑制剂和他汀类药物的稳健疗法将治疗4周 （80 mg atorvastatin）或ezetimibe（10 mg）。每个主题都将作为自己的控制，我们将确定 血小板和白细胞的变化以及LDL-C为循环的炎症因子 明显减少了。在受试者的亚组中，血管炎症的变化将由 评估收获的臂静脉内皮细胞，并通过将18F氟氧基葡萄糖摄入动脉。这 数据将由具有糖尿病和CVD风险专业知识的经验丰富的统计学家分析，并将确定 这些变化与HBA1C和葡萄糖变异性以及男女之间的差异的关系。在 此外，将T1D中的数据与类型受试者中对LDL-C的相似数据进行比较 2种糖尿病和对照，以确定这两种形式的糖尿病之间有所不同的异常。