Biological Variation in A1c on Mortality, Cardiovascular Events, Hypoglycemia

摘要 ACCORD研究验证了强化血糖管理将减少心血管疾病的假设 具有已知心血管危险因素的2型糖尿病患者的疾病。尽管强化治疗靶向 研究表明，接近正常的血红蛋白A1c水平(6%)并不能减少主要的心血管事件 在高危人群中，强化降糖治疗的死亡率增加是一种以前未被认识到的危害 2型糖尿病患者。强化血糖控制和联合治疗降低血脂异常 糖尿病视网膜病变的进展速度和延缓蛋白尿的发病。然而，这些 集约化管理的微血管益处并没有明显超过随之而来的风险增加。 严重低血糖或总的或心血管疾病相关的死亡。症状性重度低血糖 在强化治疗组和标准治疗组中都与死亡风险增加有关，但没有 解释强化治疗组中观察到的更高的死亡率。 这项提案将评估ACCORD研究的数据，以确定血红蛋白A1c的生物变异 与2型糖尿病强化血糖控制的临床结果有关。一些个人、家庭 种族群体的A1c水平一直高于平均水平，与血液的影响无关 葡萄糖浓度。血红蛋白糖化指数(HGI)衡量控制在血液中的血红蛋白A1c 血糖是微血管并发症的生物标志物，其作用超出血液的影响。 葡萄糖浓度。HGI与其他糖尿病并发症的潜在联系 目前还没有对微血管进行研究。高血糖指数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，ACCORD研究报告称，较高的A1c水平 在强化治疗组中与更大的死亡风险相关。我们假设HGI反映了 遗传性对代谢的影响，有助于血红蛋白糖化和大血管和 微血管并发症。因为与低血糖指数相比，高血糖指数患者的血糖水平较低 有相似A1c的患者，我们推测高HGI患者的强化治疗将达到低A1c的目标 可能会不经意间产生低于预期的血糖水平。我们的具体目标是确定 高HGI与1)死亡率和心血管事件、2)进展的风险更大相关 微血管疾病；3)低血糖。这一结果可能有助于解释协议中的超额死亡率 强化治疗组。这一结果也可能验证HGI在临床上用于评估 2型糖尿病的并发症风险。高血糖指数患者更容易发生低血糖的证据 建议在临床上使用HGI来识别高危个体，这将使医生能够 针对个性化的低A1c目标进行个性化治疗，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

Summary 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