GLYCEMIC CONTROL AND COMPLICATIONS IN DIABETES MELLITUS TYPE 2

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 目的：2型糖尿病是一种常见的代谢紊乱，影响约1500万美国人，并与相当大的发病率和死亡率相关。 最近的几项研究，包括英国前瞻性糖尿病研究，表明胰岛素、磺脲类药物或二甲双胍强化血糖控制均可降低微血管并发症;在本研究中，仅二甲双胍可降低微血管并发症。 然而，糖尿病患者是新诊断的，控制良好（HbA 1c ~ 7.0%），入组时无并发症。 目前，没有干预研究已经检查了胰岛素强化血糖控制在控制不佳和口服降糖药的2型糖尿病患者的高危人群中的效果。 本研究验证了一个假设，即改善2型糖尿病患者的血糖控制将降低大血管并发症的发生率-特别是它将延迟冠状动脉和外周血管疾病的发病率和进展。 研究方法：本研究是一项为期7年的前瞻性、随机、多中心、对照试验，旨在确定强化血糖控制是否能有效预防2型糖尿病患者的大血管并发症，这些患者不再对单独口服药物有反应。 该研究将在退伍军人管理局医疗保健系统内的20个中心进行。 受试者被随机分配到强化治疗与标准治疗的两个组中的一个。 随机化按医院、当前胰岛素使用和既往微血管疾病分层。 血糖控制的目标是：标准治疗组的血红蛋白A1 c水平为8.0 - 9.0%，强化治疗组的血红蛋白A1 c水平为6.0%。治疗步骤由方案确定，设计为使两组患者暴露于相同的药物，但剂量不同。 两组均接受罗格列酮和格列美脲（瘦）或二甲双胍（肥胖）。 如果未达到该组的血红蛋白A1 c或血糖目标，则添加胰岛素（标准组早晨，强化组晚上）。 进一步的措施增加剂量或添加其他口服药物，以使患者保持在目标范围内。 患者每1.5个月就诊一次，重症患者至少每两周就诊一次。 两组受试者均接受营养咨询、锻炼建议和糖尿病教育。 两组糖尿病并发症的辅助治疗相同，并遵循VA和美国糖尿病协会临床指南。 两组高血压和高脂血症的管理标准化。 戒烟建议是给这两个群体。 要求所有受试者每日服用325 mg阿司匹林。 目标是使研究的两组之间的主要差异主要是血糖控制水平。 在随访访视时，将评估两个研究组中的受试者： 1. 将在每次随访访视时评估副作用、风险因素和治疗依从性。 具体而言，高血糖、糖尿或低血糖发作的症状;胰岛素或口服药物剂量和时间;不吸烟依从性;体重;对饮食治疗方案依从性的估计和血糖控制的自我监测;血压和脉搏;以及下肢检查（皮肤、脉搏、溃疡）。 2. 神经系统检查-每12个月。 3. 眼科检查-每12个月。 4. 血液和尿液化学-每次访视时的葡萄糖-每年进行其他检查 5. 心电图-每6个月 6. 评估并发疾病、感染和新发事件-每次访视 7. 生活质量和活动评估-每12个月。 8. 全面体检-每12个月一次。 9. 伴随用药评估（包括使用叶酸、维生素B6、维生素C和E）-每3个月一次。 10.饮食评估-每次访问。 主要终点是至发生以下任何事件的时间：心肌梗死、新发或恶化的充血性心力衰竭、卒中、侵入性血运重建、缺血性截肢、心血管死亡。 此外，次要终点还包括新发或恶化的心绞痛、新发短暂性脑缺血发作、新发间歇性跛行、新发严重肢体缺血和全因死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Type 2 diabetes mellitus is a common metabolic disorder that affects approximately 15 million Americans and is associated with considerable morbidity and mortality. Several recent studies, including the United Kingdom Prospective Diabetes Study, have shown that intensive glycemic control with insulin, sulfonylureas, or metformin all decreased microvascular complications; only metformin decreased microvascular complications in this study. However, the diabetic patients were newly diagnosed, reasonably well controlled (HbA1c ~ 7.0%), and free of complications at the time of entry. Currently, no intervention study has examined the effect of intensive glycemic control with insulin in a high risk population of type 2 diabetic patients who are poorly controlled and on oral hypoglycemic agents. This study tests the hypothesis that improved glycemic control in persons with established type 2 diabetes will reduce the incidence of macrovascular complications -- specifically it will delay the onset and progression of incidence of coronary artery and peripheral vascular disease. RESEARCH PLAN AND METHODS: The present study is a 7 year prospective, randomized, multicenter, controlled trial to determine whether intensified glycemic control is effective in preventing macrovascular complications in type 2 diabetic patients who no longer are responsive to oral agents alone. The study will be performed at 20 centers within the Veterans Administration Health Care System. Subjects are randomized into one of two arms of intensive treatment vs. standard treatment. The randomization is stratified by hospital, current insulin use, and prior microvascular disease. The goals of glycemic control are: Hemoglobin A1c levels of 8.0 - 9.0% in the standard therapy arm and hemoglobin A1c levels 6.0% in the intensive treatment arm. The treatment steps are determined by the protocol and are designed to expose both groups of patients to the same agents, but at different dosages. Both groups receive Rosiglitazone and either Glimepiride (lean) or Metformin (obese). If the hemoglobin A1c or blood glucose goals for the arm are not met, insulin is added (morning in the standard arm, evening in the intensive arm). Further steps increase dose or add other oral agents to keep patients within goals. Patients are seen every 1.5 months, and intensive patients are called at least every two weeks. Subjects enrolled in both arms receive nutritional counseling, advice about exercise, and diabetes education. Ancillary treatment for diabetic complications is the same for both groups and follows VA and American Diabetes Association Clinical Guidelines. Management of hypertension and hyperlipidemia is standardized for both groups. Smoking cessation advice is given to both groups. All subjects will be asked to take 325 mg of Aspirin daily. The goal is to have the primary difference between the two arms of the study primarily be level of glycemic control. At follow-up visits, subjects in both study arms will be assessed for: 1. Assessments of side effects, risk factors, and treatment adherence will be assessed at each follow-up visit. Specifically, symptoms of hyperglycemia, glyucosuria, or episodes of hypoglycemia; insulin or oral agent dosage and timing; non-smoking adherence; body weight; estimations of compliance with dietary treatment regimen and self-monitoring of glycemic control; blood pressure and pulse; and examination of lower extremities (skin, pulses, ulcers). 2. Neurological examination - every 12 months. 3. Ophthalmological examination - every 12 months. 4. Blood and urine chemistries - glucose each visit - other tests yearly 5. Electrocardiogram - every 6 months 6. Assessments of intercurrent illnesses, infections, and new events - each visit 7. Quality of Life and Activity Assessment - every 12 months. 8. Complete physical examination - every 12 months. 9. Concomitant medication assessment (including use of folate, vitamin B6, vitamins C and E) - every 3 months. 10. Dietary Assessment - every visit. The primary endpoint is time to occurrence of any of the following: myocardial infarction, new or worsening congestive heart failure, stroke, invasive revascularization, amputation for ischemia, cardiovascular death. The secondary endpoints include, in addition, new or worsening angina, new transient ischemic attack, new intermittent claudication, new critical limb ischemia, and all-cause mortality.