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.

摘要 糖尿病显著增加动脉粥样硬化性心血管疾病（CVD）的风险。人力和 动物数据还表明，糖尿病阻止了循环中受损动脉的正常修复， LDL胆固醇（LDL-C）降低。因此，糖尿病患者仍然有更大的风险， 即使他汀类药物降低LDL-C后，心血管事件的发生率也高于无糖尿病的个体。人士 糖尿病具有更大的血小板聚集、改变的白色血细胞和更多的血管炎症， 在未受影响的个体中，通过降低LDL-C改善病理过程。我们假设 确定T1 D患者对LDL-C降低的反应，我们将确定可以治疗靶向的途径， 优化血管修复和预防CVD事件。这些数据也可以用于确定患者 与对LDL-C降低的反应缺陷相关的特征。我们建议进行一项临床研究， 1型糖尿病（T1 D）患者对LDL-C降低的反应。我们将从两个主要的 医疗中心，纽约大学Langone和西奈山，服务于纽约市内的不同社区。科目 将接受4周强效降胆固醇治疗、PCSK 9抑制剂以及他汀类药物治疗 (80 mg阿托伐他汀）或依折麦布（10 mg）。每个受试者将作为自己的对照，我们将确定 血小板和白色血细胞沿着循环炎症因子的变化，当LDL-C 明显减少。在一个受试者亚组中，血管炎症的变化将通过 评估收获的肱静脉内皮细胞和通过18F-氟脱氧葡萄糖摄取到动脉中。的 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进行分析， 这些变化与HbA 1c和葡萄糖变异性的关系，以及女性和男性之间的差异。在 此外，将T1 D中的数据与评估型糖尿病受试者对LDL-C应答的相似数据进行比较。 2型糖尿病和对照，以确定这两种形式的糖尿病之间的差异异常。