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Biological Variation in A1c on Mortality, Cardiovascular Events, Hypoglycemia

A1c 的生物变异对死亡率、心血管事件、低血糖的影响

基本信息

批准号：
8336905
负责人：
VIVIAN A FONSECA
金额：
$ 23.78万
依托单位：
CHILDREN'S HOSPITAL (NEW ORLEANS)
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8336905
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

项目摘要

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

总结雅阁研究验证了强化葡萄糖管理可以减少心血管疾病的假设， 2型糖尿病患者的心血管疾病的危险因素。虽然强化治疗靶向研究证明，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死亡率增加是高风险患者强化降糖治疗的一个先前未被认识到的危害， 2型糖尿病患者强化血糖控制和血脂异常的联合治疗减少糖尿病性视网膜病变的进展速度和延迟蛋白尿的发生。但这些强化管理的微血管获益并未明显超过伴随的风险增加，严重低血糖或总体或心血管疾病相关死亡率。症状性重度低血糖在强化治疗组和标准治疗组中，解释了强化治疗组中观察到的较高死亡率。本提案将评价雅阁研究的数据，以确定血红蛋白A1c的生物学变异与2型糖尿病强化血糖控制的临床结局相关。一些个人家庭和种族群体的A1c水平始终高于平均水平，与血液的影响无关。葡萄糖浓度血红蛋白糖化指数（HGI）测量血红蛋白A1c控制血液葡萄糖，是微血管并发症风险的生物标志物，其影响超过血液葡萄糖浓度HGI与糖尿病并发症之间的潜在关联，微血管尚未研究。高HGI的特点是持续高于平均A1c水平与血糖浓度无关。值得注意的是，雅阁研究报告称，较高的A1c水平与强化治疗组的死亡风险更高相关。我们假设HGI反映了对代谢的遗传影响，导致血红蛋白糖化和大血管和微血管并发症由于高HGI患者的血糖水平低于低HGI患者，对于A1c相似的患者，我们推测，高HGI患者的强化治疗可以降低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与1）死亡率和心血管事件，2）微血管疾病，和3）低血糖。结果可以帮助解释雅阁中的过度死亡率强化治疗组。这些结果也可以验证HGI在评估 2型糖尿病并发症的风险。高HGI患者更易发生低血糖的证据建议临床使用HGI来识别高风险个体，这将使医生能够个性化治疗，以达到个性化的低A1c目标，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