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

A1c 生物变异对死亡率、心血管事件和 Hy 的影响

• 批准号: 8201735
• 负责人: VIVIAN A FONSECA
• 金额: $ 30.56万
• 依托单位: CHILDREN'S HOSPITAL (NEW ORLEANS)
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201735
• 关键词: Acute; Affect; Albuminuria; Biological; Biological Markers; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Clinical; Complications of Diabetes Mellitus; Data; Databases; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Dyslipidemias; Equation; Ethnic group; Event; Excess Mortality; Family; Glucose; Glycosylated hemoglobin A; Hemoglobin; Hypoglycemia; Individual; Inherited; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Linear Regressions; Measures; Metabolic Control; Metabolism; National Health and Nutrition Examination Survey; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Patients; Physicians; Population; Predictive Value; Reporting; Retinal Diseases; Risk; Testing; Time; Variant; base; cardiovascular risk factor; diabetes control; diabetes management; fasting plasma glucose; glycation; glycemic control; high risk; indexing; macrovascular disease; mortality; novel; type I and type II diabetes

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.

描述（由申请人提供）：ACCORD 研究测试了这样的假设：强化血糖管理可以减少具有已知心血管危险因素的 2 型糖尿病患者的心血管疾病。尽管以接近正常血红蛋白 A1c 水平 (6%) 为目标的强化治疗并不能减少主要心血管事件，但该研究记录了 2 型糖尿病高危患者的死亡率增加，这是强化降糖治疗之前未被认识到的危害。强化血糖控制和血脂异常联合治疗可降低糖尿病视网膜病变的进展速度并延缓蛋白尿的发生。然而，强化管理的这些微血管益处并没有明显超过随之而来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风险。在强化治疗组和标准治疗组中，有症状的严重低血糖均与死亡风险增加相关，但并不能解释强化治疗组中观察到的较高死亡率。该提案将评估 ACCORD 研究的数据，以确定糖化血红蛋白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，是微血管并发症风险的生物标志物，其影响超出了血糖浓度的影响。尚未研究 HGI 与微血管以外的糖尿病并发症之间的潜在关联。高 HGI 的特点是 A1c 水平持续高于平均水平，与血糖浓度无关。值得注意的是，ACCORD 研究报告称，在强化治疗组中，较高的 A1c 水平与较高的死亡风险相关。我们假设 HGI 反映了对代谢的遗传影响，这些影响导致血红蛋白糖化以及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，因此我们推测，针对低 A1c 目标对高 HGI 患者进行强化管理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) 低血糖的更大风险相关。结果可能有助于解释 ACCORD 强化治疗组死亡率过高的原因。该结果还可能验证 HGI 评估 2 型糖尿病并发症风险的临床应用。有证据表明高 HGI 患者更容易发生低血糖，建议临床使用 HGI 来识别高危个体，这将使医生能够针对个体化的低 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 公共健康相关性：该提案将评估 ACCORD 研究的数据，以确定糖化血红蛋白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。我们将使用一种新型血红蛋白糖化指数 (HGI) 来评估由平均血糖以外的因素引起的 A1c 变化，并确定 HGI 是否与个体死亡、心血管事件、微血管疾病或低血糖风险相关。结果可以帮助解释 ACCORD 强化治疗组的过高死亡率，也可以验证 HGI 评估 2 型糖尿病急性和慢性并发症风险的临床应用。