Impact of Biological Variation in A1c on Mortality, Cardiovascular Events, and Hy

描述（由申请方提供）：雅阁研究检验了强化葡萄糖管理可减少具有已知心血管风险因素的2型糖尿病患者心血管疾病的假设。尽管针对接近正常血红蛋白A1c水平（6%）的强化治疗并未减少主要心血管事件，但该研究记录了死亡率增加，这是先前未被认识到的2型糖尿病高危患者强化降糖治疗的危害。强化血糖控制和血脂异常的联合治疗降低了糖尿病视网膜病变的进展速度，并延迟了蛋白尿的发生。然而，强化治疗的这些微血管获益并未明显超过伴随的重度低血糖或总死亡率或心血管疾病相关死亡率的风险增加。在强化治疗组和标准治疗组中，症状性重度低血糖与死亡风险增加相关，但不能解释强化治疗组中观察到的较高死亡率。本提案将评估雅阁研究的数据，以确定血红蛋白A1c的生物学变异是否与2型糖尿病强化血糖控制的临床结局相关。一些个体、家庭和种族群体的A1c水平始终高于平均水平，与血糖浓度的影响无关。血红蛋白糖化指数（HGI）测量控制血糖的血红蛋白A1c，是血糖浓度影响之外微血管并发症风险的生物标志物。HGI与糖尿病并发症（微血管除外）之间的潜在相关性尚未研究。高HGI的特征是持续高于平均A1c水平，与血糖浓度无关。值得注意的是，雅阁研究报告称，在强化治疗组中，较高的A1c水平与较高的死亡风险相关。我们假设HGI反映了遗传对代谢的影响，这种影响有助于血红蛋白糖化和大血管和微血管并发症的风险。由于高HGI患者的血糖水平低于具有相似A1c的低HGI患者，我们推测，将高HGI患者强化管理至低A1c目标可能会无意中产生低于预期的血糖水平。我们的具体目标是确定高HGI是否与1）死亡率和心血管事件，2）微血管疾病进展和3）低血糖的风险增加相关。这些结果有助于解释雅阁强化治疗组的死亡率过高。该结果也可能验证HGI用于评估2型糖尿病并发症风险的临床用途。高HGI患者更容易发生低血糖的证据将推荐临床使用HGI来识别高风险个体，这将允许医生个性化治疗，以达到个性化的低A1c目标，从而最大限度地减少急性（低血糖）和慢性（大血管和微血管）糖尿病并发症。1 公共卫生相关性：本提案将评估雅阁研究的数据，以确定血红蛋白A1c的生物学变异是否与2型糖尿病强化血糖控制的临床结局相关。我们将使用一种新的血红蛋白糖化指数（HGI）来评估平均血糖以外的因素引起的A1c变化，并确定HGI是否与死亡、心血管事件、微血管疾病或低血糖的个体风险相关。这些结果可以帮助解释雅阁强化治疗组的死亡率过高，也可以验证HGI在评估2型糖尿病急性和慢性并发症风险方面的临床应用。

DESCRIPTION (provided by applicant): The ACCORD study tested the hypothesis that intensive glucose management would reduce cardiovascular disease in type 2 diabetes patients with known cardiovascular risk factors. Although intensive therapy targeting near normal hemoglobin A1c levels (6%) did not reduce major cardiovascular events, the study documented increased mortality as a previously unrecognized harm of intensive glucose lowering therapy in high-risk patients with type 2 diabetes. Intensive glycemic control and combination treatment of dyslipidemia reduced the rate of progression of diabetic retinopathy and delayed the onset of albuminuria. However, these microvascular benefits of intensive management did not clearly outweigh the concomitant increased risk for severe hypoglycemia or total or cardiovascular disease-related mortality. Symptomatic severe hypoglycemia was associated with increased risk of death in both the intensive and standard therapy groups but did not explain the greater mortality observed in the intensive therapy group. This proposal will evaluate data from the ACCORD study to determine if biological variation in hemoglobin A1c is associated with clinical outcomes of intensive glycemic control in type 2 diabetes. Some individuals, families and ethnic groups have consistently higher than average A1c levels independent of the effects of blood glucose concentration. The hemoglobin glycation index (HGI) measures hemoglobin A1c controlled for blood glucose and is a biomarker of risk for microvascular complications above and beyond the effects of blood glucose concentration. Potential associations between HGI and diabetes complications other than microvascular have not been studied. High HGI is characterized by persistently higher than average A1c levels independent of blood glucose concentration. Significantly, the ACCORD study reported that higher A1c levels were associated with greater risk of mortality in the intensively treated group. We hypothesize that HGI reflects hereditary influences on metabolism that contribute to hemoglobin glycation and risk for macrovascular and microvascular complications. Since high HGI patients have lower blood glucose levels compared to low HGI patients with a similar A1c, we speculate that intensive management of high HGI patients to a low A1c target could inadvertently produce lower than expected blood glucose levels. Our specific aims are to determine if high HGI is associated with greater risk for 1) mortality and cardiovascular events, 2) progression of microvascular disease, and 3) hypoglycemia. The results could help explain excess mortality in the ACCORD intensive treatment group. The results may also validate the clinical use of HGI for assessment of complications risk in type 2 diabetes. Evidence that high HGI patients are more susceptible to hypoglycemia would recommend the clinical use of HGI for identifying high-risk individuals which would allow physicians to personalize treatment to an individualized low A1c target that would minimize both acute (hypoglycemia) and chronic (macrovascular and microvascular) diabetes complications. 1 PUBLIC HEALTH RELEVANCE: This proposal will evaluate data from the ACCORD study to determine if biological variation in hemoglobin A1c is associated with clinical outcomes of intensive glycemic control in type 2 diabetes. We will use a novel hemoglobin glycation index (HGI) to assess variation in A1c caused by factors other than mean blood glucose and determine if HGI is associated with individual risk for mortality, cardiovascular events, microvascular disease or hypoglycemia. The results could help explain excess mortality in the ACCORD intensive treatment group and may also validate the clinical use of HGI for assessment of both acute and chronic complications risk in type 2 diabetes.