Cholesterol reduction and cardiovascular risk in Type 1 diabetes

摘要 糖尿病显著增加患动脉粥样硬化性心血管疾病(CVD)的风险。人与人 动物数据还表明，糖尿病会阻止循环时发生的受损动脉的正常修复 降低低密度脂蛋白(LDL-C)。正因为如此，糖尿病患者仍然有更大的风险 即使在他汀类药物降低低密度脂蛋白胆固醇后发生心血管事件的患者也比无糖尿病患者少。具有以下特征的个人 糖尿病有更大的血小板聚集，白细胞改变，以及更多的血管炎症， 在未受影响的个体中，通过降低低密度脂蛋白-C而改善的病理过程。我们假设，通过 确定T1D对低密度脂蛋白-C降低的反应，我们将确定可以作为治疗靶点的途径 优化血管修复，预防心血管事件。这些数据也可用于确定患者 与低密度脂蛋白降低反应缺陷相关的特征。我们建议进行一项临床研究 1型糖尿病患者对低密度脂蛋白胆固醇降低的反应。我们将从两个主要的医院招募病人 为纽约市不同社区提供服务的医疗中心、纽约大学朗格尼和西奈山。科目 将使用强有力的降胆固醇疗法、PCSK9抑制剂和他汀类药物治疗4周 (阿托伐他汀80 mg)或依折麦布(10 Mg)。每个受试者都将充当自己的控制者，我们将确定 当低密度脂蛋白-C升高时，血小板和白细胞以及循环炎症因子的变化 明显减少。在一组受试者中，血管炎症的变化将由以下因素决定 通过动脉摄取18F-脱氧葡萄糖对收获的臂静脉内皮细胞进行评估。这个 数据将由在糖尿病和心血管疾病风险方面具有专业知识的经验丰富的统计学家进行分析，并将确定 这些变化与糖化血红蛋白和血糖变异性的关系，以及男女之间的差异。在……里面 此外，T1D中的数据将与评估类型受试者对低密度脂蛋白-C的反应的类似数据进行比较 2糖尿病和对照组，以确定这两种形式的糖尿病之间的不同异常。

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.