The role of alpha-aminoadipic acid (2-AAA) in residual CVD risk in T2D

α-氨基己二酸 (2-AAA) 在 T2D 残余 CVD 风险中的作用

• 批准号: 10713291
• 负责人: Jane F Ferguson
• 金额: $ 13.13万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713291
• 关键词: Acids; Address; Affect; Aftercare; Animal Model; Atherosclerosis; Attenuated; Biological Markers; Blood; Blood Glucose; Cardiovascular Diseases; Cell model; Cholesterol; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Outcome; Disease Progression; Event; Fenofibrate; Functional disorder; Future; Glucose; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hyperinsulinism; Hypertriglyceridemia; Hypoglycemia; Individual; Insulin; Kidney Diseases; Knowledge; Learning; Lipids; Measures; Mediator; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Persons; Pharmaceutical Preparations; Plasma; Population; Residual state; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Simvastatin; Stroke; Triglycerides; cardiovascular disorder risk; cardiovascular risk factor; data resource; disorder risk; effective therapy; experience; follow-up; high risk; improved; insulin secretion; mitochondrial metabolism; mortality; new therapeutic target; novel; optimal treatments; response; secondary outcome; targeted treatment; treatment arm

PROJECT SUMMARY / ABSTRACT Cardiovascular disease (CVD) kills 1 in 3 individuals and affects >2 in 3 individuals diagnosed with type 2 diabetes (T2D). Despite optimization of available therapies, CVD remains the leading cause of mortality in T2D, highlighting the considerable burden of residual risk. Achieving further reduction in CVD morbidity and mortality in people with T2D requires advancing promising candidate mediators of residual risk. The metabolite α-aminoadipic acid (2-AAA) predicts the development of both T2D and atherosclerosis, independent of other known risk factors. This may represent a novel independent risk mechanism for the development of CVD, particularly among individuals with T2D. Our overarching hypothesis is that 2-AAA is an independent mediator of CVD risk among individuals with T2D. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, both intensive glucose-lowering therapy, and intensive lipid management failed to attenuate CVD risk in individuals with T2D, and indeed showed evidence of increased risk. We hypothesize this was, in part, due to residual risk factors, including 2-AAA. We propose an analysis of 2-AAA in existing plasma samples from N=1,757 participants of the ACCORD study lipid treatment arms, with the following aims: 1) Define the effects of lipid- and glucose-lowering therapies on plasma 2-AAA, and address whether plasma 2-AAA changes in response to lipid-targeted therapy or intensive glycemic management. 2) Address the hypothesis that plasma 2-AAA is a CVD risk mechanism among individuals who experienced events despite optimal therapy. Successful completion of the aims will determine whether 2-AAA levels are impacted by lipid and glycemic management in T2D and establish whether elevated 2-AAA associates with CVD risk. This will provide important information on the utility of 2-AAA as a biomarker of risk and plausibility as a novel therapeutic target, allowing us to refine specific hypotheses to be probed in future studies. These aims represent novel and important questions and use existing NHLBI-supported sample and data resources to add considerable scientific value and address a key knowledge gap.

项目概要/摘要 心血管疾病 (CVD) 导致三分之一的人死亡，并影响超过三分之二的 2 型患者 糖尿病（T2D）。尽管优化了现有的治疗方法，CVD 仍然是导致死亡的主要原因 T2D，凸显了残余风险的巨大负担。进一步降低 CVD 发病率 T2D 患者的死亡率需要推进有希望的残余风险候选调节剂。代谢物 α-氨基己二酸 (2-AAA) 可预测 T2D 和动脉粥样硬化的发展，独立于其他因素 已知的风险因素。这可能代表了 CVD 发展的一种新颖的独立风险机制， 尤其是 T2D 患者。我们的首要假设是 2-AAA 是一个独立的介体 T2D 患者的 CVD 风险。控制糖尿病心血管风险行动 (ACCORD) 试验表明，强化降糖治疗和强化血脂管理均未能降低 CVD 风险 患有 T2D 的人，并且确实显示出风险增加的证据。我们假设这部分是由于 残余风险因素，包括 2-AAA。我们建议对现有血浆样本中的 2-AAA 进行分析 N=1,757 名 ACCORD 研究脂质治疗组的参与者，其目标如下： 1) 定义效果 降脂和降糖疗法对血浆 2-AAA 的影响，并解决血浆 2-AAA 是否发生变化 对脂质靶向治疗或强化血糖管理的反应。 2) 解决等离子体的假设 2-AAA 是尽管接受最佳治疗但仍经历事件的个体的 CVD 风险机制。 目标的成功完成将决定 2-AAA 水平是否受到血脂和血糖的影响 T2D 管理并确定 2-AAA 升高是否与 CVD 风险相关。这将提供 关于 2-AAA 作为风险生物标志物和作为新型治疗方法的合理性的重要信息 目标，使我们能够完善未来研究中要探讨的具体假设。这些目标代表了新颖和 重要问题并使用 NHLBI 支持的现有样本和数据资源来添加大量 科学价值并解决关键的知识差距。