Cholesterol reduction and cardiovascular risk in Type 1 diabetes

摘要 糖尿病显着增加动脉粥样硬化性心血管疾病（CVD）的风险。人类和 动物数据还表明，糖尿病会阻碍循环系统中受损动脉的正常修复。 低密度脂蛋白胆固醇（LDL-C）降低。因此，糖尿病患者仍然面临更大的风险 即使在他汀类药物降低 LDL-C 后，心血管事件的发生率仍高于未患糖尿病的个体。个人有 糖尿病有更大的血小板聚集、白细胞改变和更多的血管炎症， 在未受影响的个体中，通过降低 LDL-C 可以改善病理过程。我们假设通过 确定 T1D 中 LDL-C 降低的反应后，我们将确定可作为治疗目标的途径 优化血管修复并预防 CVD 事件。这些数据还可用于确定患者 与 LDL-C 降低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 (T1D) 患者对 LDL-C 降低的反应。我们将从两个主要的领域招募患者 纽约大学朗格尼分校和西奈山医疗中心为纽约市的不同社区提供服务。科目 将接受 4 周的强力降低胆固醇疗法、PCSK9 抑制剂以及他汀类药物治疗 （80 毫克阿托伐他汀）或依折麦布（10 毫克）。每个受试者将作为自己的对照，我们将确定 当 LDL-C 降低时，血小板和白细胞以及循环炎症因子发生变化 明显减少。在受试者亚组中，血管炎症的变化将由以下因素决定 评估收获的臂静脉内皮细胞和动脉摄取 18F-氟脱氧葡萄糖。的 数据将由具有糖尿病和心血管疾病风险专业知识的经验丰富的统计学家进行分析，并确定 这些变化与 HbA1c 和血糖变异性的关系，以及女性和男性之间的差异。在 此外，T1D 中的数据将与评估 LDL-C 型受试者的反应的类似数据进行比较 2 型糖尿病和对照，以确定这两种糖尿病之间不同的异常情况。

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.