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

描述（由申请人提供）：ACCORD研究验证了强化葡萄糖管理可以减少已知心血管危险因素的2型糖尿病患者心血管疾病的假设。虽然以接近正常血红蛋白A1c水平（6%）为目标的强化治疗并没有减少主要心血管事件，但研究表明，在高危2型糖尿病患者中，强化降糖治疗增加了死亡率，这是以前未认识到的危害。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益处并没有明显超过伴随的严重低血糖或总死亡率或心血管疾病相关死亡率的增加。在强化治疗组和标准治疗组中，症状性严重低血糖与死亡风险增加相关，但不能解释强化治疗组观察到的更高死亡率。该提案将评估ACCORD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果相关。一些个人、家庭和种族的糖化血红蛋白水平持续高于平均水平，与血糖浓度无关。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。除微血管外，HGI与糖尿病并发症之间的潜在联系尚未研究。高HGI的特征是与血糖浓度无关的A1c水平持续高于平均水平。值得注意的是，ACCORD研究报告称，在强化治疗组中，较高的A1c水平与更高的死亡风险相关。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。由于与A1c相似的低HGI患者相比，高HGI患者的血糖水平较低，我们推测，对高HGI患者进行强化管理以达到低A1c目标可能会无意中产生低于预期的血糖水平。我们的具体目的是确定高HGI是否与以下风险增加有关：1)死亡率和心血管事件；2)微血管疾病进展；3)低血糖。结果可以帮助解释ACCORD强化治疗组的高死亡率。该结果也可能验证HGI在评估2型糖尿病并发症风险方面的临床应用。有证据表明，高HGI患者更容易发生低血糖，因此推荐临床使用HGI来识别高危人群，这将使医生能够针对个性化的低A1c目标进行个性化治疗，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

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.