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

项目总结/摘要 心血管疾病（CVD）导致1/3的人死亡，并影响2/3诊断为2型的人 糖尿病（T2 D）。尽管优化了现有的治疗方法，CVD仍然是死亡的主要原因， T2 D，突出了剩余风险的巨大负担。进一步降低CVD发病率， T2 D患者的死亡率需要推进有希望的剩余风险候选介质。代谢物 α-氨基己二酸（2-AAA）预测T2 D和动脉粥样硬化的发展，与其他因素无关。 已知的风险因素。这可能代表了CVD发展的一种新的独立风险机制， 特别是在患有T2 D的人中。我们的总体假设是，2-AAA是一个独立的调解人 2型糖尿病患者的心血管疾病风险控制糖尿病心血管风险行动（雅阁） 在一项试验中，强化降糖治疗和强化血脂管理均未能降低 T2 D患者，并且确实显示出风险增加的证据。我们假设这部分是由于 剩余风险因素，包括2-AAA。我们建议分析现有血浆样品中的2-AAA， N= 1，757例雅阁研究脂质治疗组的受试者，目的如下：1）确定影响 降脂降糖治疗对血浆2-AAA的影响，并探讨血浆2-AAA是否会在 对脂质靶向治疗或强化血糖管理的反应。2)提出血浆 2-AAA是尽管接受了最佳治疗但仍发生事件的个体的CVD风险机制。 目标的成功完成将决定2-AAA水平是否受脂质和血糖的影响 T2 D的管理，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的效用的重要信息和作为一种新的治疗方法的可行性 目标，使我们能够完善具体的假设，在未来的研究中进行探讨。这些目标代表了新颖和 重要的问题，并使用现有的NHLBI支持的样本和数据资源， 科学价值和解决一个关键的知识差距。

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.