Cumulative Glycemic Burden and Cardiovascular Disease Risk in Type 2 Diabetes

描述（由申请人提供）：我们试图提供证据证明，在首次诊断2型糖尿病（DM）时开始并在DM患者的整个生命周期内维持长期、持续、严格的血糖控制，可以降低心血管疾病（CVD）的风险。目前对糖尿病患者的护理建议包括严格控制糖化血红蛋白（A1 C）（<7%），以降低CVD和其他并发症的风险。最近的研究对这一建议提出了质疑，因为未能证明严格的A1 C控制可为DM患者提供CV获益，但这些研究无法解释试验开始前的血糖控制。其他研究支持随着时间的推移严格控制血糖的好处，并表明即使A1 C水平在“正常”范围内适度升高也表明长期CVD风险。为了解决这些看似矛盾的观点，如何优化DM护理，我们建议测试的假设，严格的血糖控制确实可以降低CVD的风险，如果早期开始，并持续整个过程中的DM。我们还将评估在糖尿病患者中，随着时间的推移累积血糖负荷是否比当前A1 C水平或随着时间的推移平均A1 C更好地预测长期CVD风险，并确定CVD风险显著升高的累积血糖负荷阈值水平。我们将使用Kaiser Permanente西北糖尿病登记处的数据进行拟议的分析。自1988年以来，KPNW开发并维护了这一高度具体、敏感、数据丰富的糖尿病患者登记册;截至2009年12月，该登记册载有超过70 000人的数据。在1995-2010年加入登记的成年人中，我们将识别出经历过CVD事件的个体，并将其与5名未经历CVD事件的对照组进行匹配。然后，我们将对A1 C、平均A1 C和累积A1 C负荷预测首次CVD事件发生时间的程度进行多变量logistic回归分析，并描述从DM诊断日期到2010年CVD几率的差异，以确定CVD风险增加的临界点（A1 C、随时间推移的平均A1 C和累积血糖负荷水平）。这些发现的临床应用将证明长期以来的怀疑-累积血糖负荷是一个关键的CVD风险因素-从而为DM诊断后立即启动严格的血糖控制并严格保持这种控制的重要性提供关键支持。尽管累积血糖负荷作为CVD风险因素具有生物学可接受性，但既往没有研究将累积血糖负荷单独或与随时间推移的平均A1 C相比作为DM的CVD风险指标进行评估。拟议的工作建立在我们以前开发的测量累积血糖负荷的方法的基础上。 公共卫生相关性：这项研究将使用1995- 2010年Kaiser Permanente Northwest糖尿病患者的现有数据，评估早期开始并持续控制高血糖是否会降低心血管疾病风险。我们将使用一种新的测量高血糖的方法，即血糖负担，它可以解释血糖有多高以及高血糖持续了多长时间。我们的研究结果将显示糖尿病诊断后立即积极治疗血糖的重要性，并严格维持这种积极的治疗。

DESCRIPTION (provided by applicant): We seek to provide evidence that prolonged, continuous, tight glycemic control, initiated when type 2 diabetes (DM) is first diagnosed and maintained throughout patients' DM lifetime, can reduce the risk of cardiovascular disease (CVD). Current recommendations on care for persons with DM include tight glycated hemoglobin (A1C) control (<7%) as a means to reduce risk of CVD and other complications. Recent studies raised questions about this recommendation by failing to demonstrate that tight A1C control provides CV benefit in persons with DM, but these studies could not account for glycemic control prior to trial initiation. Other research supports the benefit of tight glycemic control over time, and suggests that even moderately elevated A1C levels in the 'normal' range indicate long-term CVD risk. To address these seemingly contradictory perspectives on how to optimize DM care, we propose to test the hypothesis that tight glycemic control does indeed reduce CVD risk, if begun early and continued throughout the course of DM. We will also assess whether cumulative glycemic burden over time, predict long-term CVD risk better than current A1C level or mean A1C over time, and to identify threshold levels of cumulative glycemic burden at which CVD risk becomes markedly elevated, among persons with DM. We will conduct the proposed analyses using data from the Kaiser Permanente Northwest Diabetes Registry. Since 1988, KPNW has developed and maintained this highly specific, sensitive, data-rich registry of members with DM; as of December 2009, it contained data on >70,000 persons. Among adults who joined the registry in 1995-2010, we will identify individuals who experienced a CVD event and match them to 5 controls who did not. We will then conduct multivariate logistic regression analyses of the extent to which A1C, mean A1C, and cumulative A1C burden predict time until first CVD event, and describe differences in the odds of CVD from date of DM diagnosis through 2010, to identify cut-points (of A1C, mean A1C over time, and cumulative glycemic burden levels) where CVD risk increases. The clinical application of such findings would lie in proving what has long been suspected - that cumulative glycemic burden is a critical CVD risk factor - thus providing critical support for the importance of initiating tight glycemic control immediately upon DM diagnosis and maintaining such control rigorously. No previous studies have evaluated cumulative glycemic burden as an indicator of CVD risk in DM, alone or in comparison to mean A1C over time, despite cumulative burden's biological plausibility as a CVD risk factor. The proposed work builds on our previous development of methods for measuring cumulative glycemic burden. PUBLIC HEALTH RELEVANCE: This study will use existing data on Kaiser Permanente Northwest members with diabetes from 1995- 2010 to assess whether control of high blood sugar, if begun early and continued over time, reduces cardiovascular disease risk. We will use a novel measure of high blood sugar, glycemic burden, which accounts for how high blood sugar is and how long it has been high. Our results would show the importance of treating blood sugar aggressively immediately upon diabetes diagnosis and maintaining such aggressive treatment rigorously.