Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)
- Conditions
- Type 2 Diabetes Mellitus
- Interventions
- Registration Number
- NCT00032487
- Lead Sponsor
- VA Office of Research and Development
- Brief Summary
This study is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 21% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.
- Detailed Description
Primary Hypothesis: Intensive glycemic control reduces major macrovascular morbidity and mortality compared to standard glycemic control in type 2 diabetics who have failed simple therapy.
Secondary Hypotheses: Intensive glycemic control, compared to standard glycemic control, reduces other macrovascular morbidity and total mortality.
Intervention: The intervention is tight glycemic control, aiming at normalization of HbA1c. This will be achieved through stepped care therapy, using all categories of tools available to most diabetologists. These categories include: patient education of diabetes control (e.g. diet, exercise, etc.), oral diabetes medications, and insulin. All drugs to be used are approved. Specific agents will be used within the different classes to promote consistency across sites.
The comparison is standard control, aiming at HbA1c of 8 - 9%. The same agents will be used, but at reduced doses.
The general approach to the stepped care treatment protocol is to treat both groups with the same agents, but at different intensities (doses) (taking into account intolerance/contraindications). The sequence of steps is shown below.
STEP 1: Either Metformin (obese) or Glimepiride (lean)in combination with Rosiglitazone STEP 2: Insulin STEP 3: Increase doses in STEPS 1,2 in the Standard group. Since the Intensive group is already at maximal doses of oral agents, they will intensify insulin and may add Acarbose/Miglitol.
STEP 4: For standard, proceed as in STEP 3 for Intensive; Intensives will use multiple daily injection (MDI) of insulin STEP 5: "Tool Box": Miscellaneous agents, tailored to the individual patient.
Primary Outcomes: Time to one of the following major macrovascular events: myocardial infarction, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, invasive intervention for coronary artery or peripheral vascular disease, inoperable coronary artery disease, or cardiovascular death.
Secondary Outcomes: Angina, transient ischemic attack, intermittent claudication, critical limb ischemia, and total mortality.
Study Abstract: A quarter of the patients treated by the Department of Veterans Affairs (VA) Health Administration have type 2 diabetes mellitus (DM). The costs of care for the treatment of patients with type 2 DM are extremely high, both in treatment expenditures for the metabolic disorder and for the care of end-organ complications. Although patients initially respond to diet and oral agent treatment, most eventually need insulin to near-normalize their glucose level, as the disease is characterized by progressive loss of insulin secretory capacity.
After several clinical trials in both type 1 and type 2 DM, there is a reasonable certainty that about half of the incidence and rate of progression of indicators of microvascular complications (retinopathy, nephropathy, and neuropathy) can be prevented or delayed by achieving and maintaining near-normalization of glycemic levels. Consequently, there has been a uniform trend in recent guidelines to advise a near-normalization of glycemic levels in both type 1 and type 2 DM. Note, however, that the clinical consequences of microvascular deterioration are dependent not only on glycemic levels but also on the duration of the disease. With the early onset of diabetes typical in type 1 patients, there is sufficient time for development of clinical microvascular complications, and prevention of these complications is a goal of treatment in type 1 diabetics. In contrast, the prevalence of hard clinical endpoints indicative of microangiopathy, such as renal failure or blindness, is very low in patients in whom the disease is diagnosed after the 5th decade, the greatest age of prevalence of patients with type 2 DM in this country. Furthermore, microvascular complications can be minimized by the well-established benefits of blood pressure and lipid control, as well as by therapeutic intervention (photocoagulation, cataract extraction). Since the costs and efforts necessary to reach near-normal levels of glycemia are very high, there is a need to determine the cost/benefit ratios of such expenditures in the population subject to type 2 diabetes, namely patients in their 6th to 8th decades of life.
In contrast with the late and relatively infrequent appearance of clinical endpoints of microangiopathy, macrovascular complications (i.e., coronary heart disease and peripheral vascular disease) are responsible for the overwhelming majority of the mortality, morbidity and treatment costs in the American population of type 2 diabetics, even more so in the older VA diabetic population. In the recently concluded United Kingdom Prospective Diabetes Study (UKPDS) on type 2 DM, macrovascular mortality was 70 times higher than that of microvascular mortality. Intervention studies to determine the effect of rigorous glycemic control on these macrovascular events are inconclusive and contradictory. Intensive treatment in patients who are newly diagnosed has failed to demonstrate a beneficial effect of tight control on cardiovascular complications. The few studies conducted in later stages of the disease (i.e., in patients requiring insulin treatment, alone or in combination with oral agents) have been conflicting and indeterminate.
The decision on intensity of treatment is further compromised by current recommendations to attenuate glycemic control goals, especially when usage of insulin is required, both in patients with the common comorbidities of overweight or preexisting cardiovascular disease, and in those in the later decades of life. These concerns are based on fears that intensive insulin treatment might be associated with weight gain, increased cardiovascular risk factors (hypertriglyceridemia, dyslipidemia, hyperinsulinemia, and insulin resistance), and adverse effects of recurrent hypoglycemic events. The prevalent level of glycemic control in insulin-treated type 2 diabetics is relatively poor, likely due to a combination of practical difficulties and the uncertainties of what are the safe and effective glycemic goals. There is no long-term study currently being done in the high-risk population typical of the patient population in the VA. Before the Department of Veterans Affairs devotes considerable resources to a widespread intervention (a quarter of patients) that may be of little value, and might even be counterproductive, a trial to determine the value of the intervention is mandated. It is expected that CSP #465 will provide the scientific data on which the VA can base clinical treatment of Type II diabetes.
CSP #465 is a prospective, 2-arm, randomized controlled trial to determine whether glycemic control, achieved through intensification of treatment, is effective in preventing clinical macrovascular complications in patients with type 2 DM who are no longer responsive to oral agents alone. The study consists of a two-year accrual period and five years of follow-up (7 years total) of 1700 patients across 20 centers. We have powered the study to detect a 25% reduction in the primary event rate. Additional study goals are to determine whether the expenditures, discomfort, and adverse effects associated with intensive intervention are justified in terms of their clinical benefits, considering both macrovascular and microvascular complications.
Main Manuscript:Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N et al., VADT investigators: Glucose Control and Complications in the VA Diabetes Trial (VADT). N Eng J of Med 360:129-139, 2009.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1791
- Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.
- Angina pectoris, Canadian Class I-II,
- congestive heart failure, Class III-IV,
- stroke, incapacitating or in last 6 months,
- Myocardial infarction (MI) or invasive cardiovascular procedure within the past six months,
- ongoing diabetic gangrene,
- BMI > 40,
- hemoglobinopathy that interferes with A1c monitoring,
- serum creatinine > 1.6 mg/dL,
- fasting C-peptide < 0.21 pmol/ml,
- Alanine Amino Transaminase (ALT) > 3 times normal or serum bilirubin > 1.9 mg/dL,
- malignancy or noncardiac life-threatening diseases making life expectancy < 5 years,
- autonomic neuropathy,
- symptomatic pancreatic insufficiency (endocrine or exocrine),
- recurrent seizures within the past year,
- hypopituitarism,
- pregnancy, lactation, or planning a pregnancy,
- active psychosis or substance abuse,
- lack of access to a person who can assist or be called in an emergency,
- underlying conditions that in the site PI's judgment may prevent adherence to protocol,
- current participation in another clinical trial
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intensive glycemic control Insulin Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1 Standard glycemic control Insulin Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs Standard glycemic control Glimepiride Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs Standard glycemic control Rosiglitazone Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs Standard glycemic control Metformin Standard glycemic control to maintain HbA1c between 8.0-9.0%. Metformin 500 mg Rosiglitazone 4 mg Glimepiride 2 mg Insulin 1 unit 9 lbs Intensive glycemic control Metformin Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1 Intensive glycemic control Rosiglitazone Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1 Intensive glycemic control Glimepiride Intensive glycemic control lower HbA1c below 6.0%. Metformin 500 mg (go up to 2000 mg) Rosiglitazone 4 mg bid Glimepiride 8 mg Insulin 1 unit 9 lbs add one injection to Arm 1
- Primary Outcome Measures
Name Time Method Primary Major Macrovascular Events Post baseline time to the first major macrovascular event up to 82 months Myocardial infarction (MI), intervention for coronary artery or Peripheral Vascular Disease (PVD), severe inoperable Coronary Artery Disease (CAD), new or worsening Congestive Heart Failure (CHF), stroke, Cardiovascular (CV) death, or amputation for ischemic gangrene.
- Secondary Outcome Measures
Name Time Method Secondary Endpoint Post baseline time to first event up to 82 months New or worsening angina, new transient ischemic attack (TIA), new intermittent claudication or critical limb ischemia with Doppler evidence or total mortality.
Trial Locations
- Locations (21)
Southern Arizona VA Health Care System, Tucson
🇺🇸Tucson, Arizona, United States
VA Medical Center, Long Beach
🇺🇸Long Beach, California, United States
Edward Hines, Jr. VA Hospital
🇺🇸Hines, Illinois, United States
VA Medical Center, Lexington
🇺🇸Lexington, Kentucky, United States
Ralph H Johnson VA Medical Center, Charleston
🇺🇸Charleston, South Carolina, United States
Hunter Holmes McGuire VA Medical Center
🇺🇸Richmond, Virginia, United States
VA Medical Center, San Juan
🇵🇷San Juan, Puerto Rico
VA Medical Center, Salem VA
🇺🇸Salem, Virginia, United States
VA Medical Center, Omaha
🇺🇸Omaha, Nebraska, United States
VA New Jersey Health Care System, East Orange
🇺🇸East Orange, New Jersey, United States
VA Medical Center
🇺🇸Nashville, Tennessee, United States
VA San Diego Healthcare System, San Diego
🇺🇸San Diego, California, United States
Carl T. Hayden VA Medical Center
🇺🇸Phoenix, Arizona, United States
VA Central California Health Care System, Fresno
🇺🇸Fresno, California, United States
Miami VA Healthcare System, Miami, FL
🇺🇸Miami, Florida, United States
Richard Roudebush VA Medical Center, Indianapolis
🇺🇸Indianapolis, Indiana, United States
VA Medical Center, Minneapolis
🇺🇸Minneapolis, Minnesota, United States
Michael E. DeBakey VA Medical Center (152)
🇺🇸Houston, Texas, United States
VA Pittsburgh Health Care System
🇺🇸Pittsburgh, Pennsylvania, United States
VA South Texas Health Care System, San Antonio
🇺🇸San Antonio, Texas, United States
VA Puget Sound Health Care System, Seattle
🇺🇸Seattle, Washington, United States