This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 yearly5. Electrocardiogram - every 6 months6. Assessments of intercurrent illnesses, infections, and new events - each visit7. 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.
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