GLYCEMIC CONTROL AND COMPLICATIONS IN DIABETES MELLITUS TYPE 2

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：2型糖尿病是一种常见的代谢性疾病，影响约1500万美国人，并与相当大的发病率和死亡率有关。最近的几项研究，包括英国的前瞻性糖尿病研究，都表明用胰岛素、磺脲类药物或二甲双胍强化血糖控制都能减少微血管并发症；在本研究中，只有二甲双胍才能减少微血管并发症。然而，糖尿病患者是新诊断的，控制良好(HbA1c~7.0%)，在入院时没有并发症。目前，还没有干预性研究考察胰岛素强化血糖控制对控制不良的2型糖尿病高危人群和口服降糖药的影响。这项研究测试了这样一种假设，即改善2型糖尿病患者的血糖控制将减少大血管并发症的发生率--具体地说，它将推迟冠状动脉和外周血管疾病的发生和发展。 研究计划和方法：本研究是一项为期7年的前瞻性、随机性、多中心、对照试验，旨在确定强化血糖控制在预防不再仅对口服药物有效的2型糖尿病患者大血管并发症方面是否有效。这项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。 受试者被随机分为强化治疗和标准治疗两组中的一组。随机分组按医院、当前使用的胰岛素和既往的微血管疾病进行分层。血糖控制的目标是：标准治疗组的血红蛋白A1c水平为8.0-9.0%，强化治疗组的Hb A1c水平为6.0%。治疗步骤由方案确定，旨在使两组患者接触相同的药物，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)治疗。如果没有达到手臂的血红蛋白A1c或血糖目标，就会补充胰岛素(标准手臂早上服用，强化手臂晚上服用)。进一步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一次。参加这两个项目的受试者都会接受营养咨询、运动建议和糖尿病教育。两组糖尿病并发症的辅助治疗是相同的，并遵循退伍军人管理局和美国糖尿病协会的临床指南。两组的高血压和高脂血症的管理都是标准化的。两组均给予戒烟建议。所有受试者将被要求每天服用325毫克阿司匹林。我们的目标是在研究的两个方面有主要的区别，主要是血糖控制水平。 在后续访问中，将对两个研究组的受试者进行以下评估： 1.将在每次后续访问中评估副作用、风险因素和治疗依从性。具体包括：高血糖、糖尿或低血糖发作的症状；胰岛素或口服药物的剂量和时机；坚持不吸烟；体重；评估饮食治疗方案的依从性和血糖控制的自我监测；血压和脉搏；以及腿部检查(皮肤、脉搏、溃疡)。 2.神经学检查--每12个月一次。 3.眼科检查--每12个月一次。 4.血液和尿液化学-每次检查血糖-每年进行其他检查 5.心电图--每6个月做一次 6.对并发疾病、感染和新事件的评估--每次就诊 7.生活质量和活动评估--每12个月一次。 8.完成体检--每12个月。 9.伴随的药物评估(包括叶酸、维生素B6、维生素C和维生素E的使用)--每3个月。 10.饮食评估--每次就诊。 主要终点是以下任何一种情况发生的时间：心肌梗死、新的或恶化的充血性心力衰竭、中风、侵入性血运重建、因缺血而截肢、心血管死亡。次要终点还包括新的或恶化的心绞痛、新的短暂性脑缺血发作、新的间歇性跛行、新的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.