Cumulative Glycemic Burden and Cardiovascular Disease Risk in Type 2 Diabetes

描述(由申请人提供)：我们寻求提供证据，证明在2型糖尿病(DM)首次诊断并在患者一生中保持血糖控制时，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(A1C)(&lt；7%)，作为降低心血管疾病和其他并发症风险的手段。最近的研究对这一建议提出了质疑，因为未能证明严格的A1C控制为糖尿病患者提供心血管益处，但这些研究不能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A1C水平在“正常”范围内适度升高也表明存在长期的心血管疾病风险。为了解决这些关于如何优化DM护理的看似矛盾的观点，我们建议测试这样一个假设，即严格的血糖控制确实降低了心血管疾病风险，如果及早开始并持续到整个DM过程。我们还将评估随时间推移的累积血糖负荷，预测长期心血管风险是否比当前的A1C水平或随时间推移的平均A1C水平更好，并确定糖尿病患者中心血管风险显著升高的累积血糖负荷的阈值水平。我们将使用Kaiser Permanente西北糖尿病注册中心的数据进行拟议的分析。自1988年以来，KPNW开发和维护了这一高度具体、敏感、数据丰富的DM成员登记册；截至2009年12月，它包含了70,000人的数据。在1995-2010年间加入登记的成年人中，我们将确定经历过心血管疾病事件的个人，并将他们与5名没有经历过心血管疾病事件的对照组进行匹配。然后，我们将对A1C、平均A1C和累积A1C负荷预测到第一次CVD事件的时间的程度进行多变量Logistic回归分析，并描述从糖尿病确诊之日到2010年发生CVD的几率的差异，以确定CVD风险增加的临界点(A1C、随时间变化的平均A1C和累积血糖负荷水平)。这些发现的临床应用将在于证明人们长期以来一直怀疑的--累积血糖负担是关键的心血管危险因素--从而为糖尿病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心血管危险因素在生物学上是可信的，但之前没有研究单独或与随时间推移的平均A1C比较，将累积血糖负荷作为糖尿病心血管疾病风险的指标进行评估。这项拟议的工作建立在我们之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年间Kaiser Permanente Northwest成员患有糖尿病的现有数据，以评估如果及早开始并持续一段时间的高血糖控制是否可以降低心血管疾病风险。我们将使用一种新的高血糖测量方法，即血糖负荷，它解释了血糖有多高以及高血糖持续了多久。我们的结果将显示在糖尿病确诊后立即积极治疗血糖的重要性，并严格保持这种积极治疗。

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.