Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: Veterans Affairs Diabetes Trial
Introduction
In patients with diabetes mellitus (DM) type 1, glycemic control reduces the development and progression of microvascular complications (The Diabetes Control and Complication Trial Research Group, 1993). Glycemic control trials in patients with type 2 DM confirm an improvement in markers of microangiopathy Levin et al., 2000, Shichiri et al., 2000, UKPDS Group, 1998a. The main clinical benefit is a reduction in retinal photocoagulation (3/1000 patients/year in the UK Prospective Diabetes Study [UKPDS]) but no effect was shown on visual acuity and renal failure (UKPDS Group, 1998a). These findings are consistent with the relatively low prevalence of vision loss and end-stage renal disease in older patients with type 2 DM as compared with type 1 DM (Vijan, Hofer, & Hayward, 1997). The prevalence of serious microvascular endpoints in older patients with hemoglobin A1c (HbA1c) <9.5% is quite low and, therefore, benefits of glycemic control would be difficult to demonstrate (Vijan et al., 1997). There is a shorter lifetime exposure to hyperglycemia in this population than in patients with type 1 DM, and the clinical benefit of intensive glucose control is reduced as the population ages (Vijan et al., 1997). Furthermore, type 2 DM patients are susceptible to coexisting conditions such as hypertension (UKPDS Group, 1998b) and eye changes unrelated to diabetic retinopathy, which are the main cause of vision loss in older patients with diabetes (Klein & Klein, 1995). Correction of hypertension significantly reduces clinical microangiopathic endpoints (UKPDS Group, 1998b). Periodic eye examinations and intervention alone may prevent 90% of the vision loss in patients with diabetes (Ferris, 1993).
Nonetheless, type 2 DM is currently responsible for the majority of the photocoagulation and dialysis in patients with diabetes. The reasons are the overwhelming predominance of type 2 DM, poor blood pressure, lipid and glycemic control in such patients, and, in many cases, irregular or no adherence to periodic ophthalmic examinations.
The main toll, by far, of type 2 DM is cardiovascular (CV) mortality and morbidity. CV mortality is increased two- to fourfold (Geiss, Herman, & Smith, 1995) and is 40- to 70-fold higher than mortality due to microvascular lesions, almost entirely renal, in type 2 DM (Turner, Cull, & Holman, 1996). Approximately two-thirds of all patients with type 2 DM die of CV disease. Some epidemiological studies have shown a correlation of glycemia with CV disease, while others have not Barrett-Connor, 1997, Laakso, 1999, Meigs et al., 1997. No intensive glycemic control trial has yet improved or prevented CV events. By contrast, even modest blood pressure reduction has protective effects on CV events and mortality (UKPDS Group, 1998b). Several drug treatment trials for dyslipidemia have shown benefits in CV endpoints in the diabetic participants, even exceeding those shown in the nondiabetic patients Pyorala et al., 1997, Sacks et al., 1996. However, excess morbidity and mortality persists in patients with type 2 DM if those risk factors are excluded.
Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, very common patients in the United States (Camacho, Pitale, & Abraira, 2000). In the VA system, the average age of patients treated for diabetes is 66 years (Zhang et al., 2000). The earlier 3-year U.S. feasibility study on 153 insulin-requiring, older, obese men with high prevalence of CV complications (VA-CSDM) is the only study in this population that maintained a separation of 2.1% in HbA1c between standard and intensive glycemic control treatment arms, without deterioration of HbA1c in either arm during the trial (Abraira et al., 1997). In spite of this, there were more CV events in the intensive arm than in the standard arm, correlating with lower attained HbA1c (P=.05). Consequently, the VA-CSDM group recommended that glycemic control goals be set at a level not much lower than 8% until targeting HbA1c levels to normal is demonstrated to be beneficial for CV disease in this population. The present Veterans Affairs Diabetes Trial (VADT) is designed to clarify this question.
Section snippets
Objectives
The primary objective of the trial is to determine whether a reduction in major CV events—myocardial infarction (MI), stroke, new or worsening congestive heart failure (CHF), amputation for ischemic diabetic gangrene, invasive intervention for coronary artery disease (CAD) or peripheral vascular disease (PVD), and CV death—can be observed in the intensive glycemic control group compared to a standard care group. The secondary objectives are to assess differences between treatment groups in
Design
Male and female veterans, ≥41 years old, who are nonresponsive to a maximum dose of at least one oral agent and/or daily insulin injections, are eligible for screening for the study. Nonresponsiveness is defined as having centrally measured HbA1c level >4 standard deviations above the normal mean, that is, ≥7.5%, or else local HbA1c ≥8.3%.
Patients are excluded if they have conditions that would preclude them from receiving intensive treatment or completing the trial. The exclusion criteria are
Measured outcomes
The primary endpoint for the study is the occurrence of any major CV event (see Objectives). Primary and secondary CV endpoints (see Objectives) are determined by the independent Endpoints Committee, masked to treatment assignment, by evaluation of supporting documentation. Changes in visual acuity, laser treatment, or cataract extraction are other clinical endpoints. Retinopathy is documented primarily by seven field stereo photographs at entry and 5 years later; these are read centrally at
Risk factor intervention
Basic tenets in type 2 DM are instructed and enforced in both treatment arms for education, diet, blood pressure, and lipid control.
Goals
As near to normal glycemia as possible is to be achieved in each patient, aiming for HbA1c at or below 6%. A priority is to avoid hypoglycemia, even if asymptomatic.
Treatment
Self-blood glucose monitoring (SBGM) is done at least twice per day and once or more weekly at 3 a.m. HbA1c is centrally measured every 3 months. The pharmacologic step therapy is similar to that of the standard arm. For obese patients (BMI ≥27 kg/m2) entering on oral agents alone, the following should be followed: (1) metformin
Goals
The goals are good medical care and well-being, avoidance of deterioration of HbA1c, keeping levels at 8–9% and preventing symptoms of glycosuria, hypoglycemia, and ketonuria. The treatment outline is not rigid. Oral agent substitutions or changes in regimen are possible if there is a given drug intolerance or a patient's conditions or preference so require it.
Treatment regimen
All patients are instructed in SBGM for documentation of symptomatic hyperglycemia or hypoglycemia. HbA1c is centrally measured every 3
Sample size
Calculations are based on the assumption that in the standard treatment arm, the rate of major CV events will be 40% over an average of 6 years of follow-up. This estimate is based on the rate in the standard arm of the feasibility study, VA-CSDM (Abraira et al., 1997). Simply extrapolating that 2-year rate to 6 years yields a rate of 44%. This event rate compares to those of other populations ETDRS Investigators, 1992, Kannel et al., 1990, Pyorala et al., 1997, UKPDS Group, 1998a. The present
Central laboratories
Six laboratories analyze samples and data. Samples are shipped to the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC Lab, Boston, MA) for forwarding and storage. The central Biochemistry Lab at Tufts University measures plasma cholesterol, TG, HDL-C, HbA1c (Chang, Hoke, Ettinger, & Penerian, 1998), plasma fibrinogen Swaim & Feders, 1967, von Clauss, 1957, and PAI-1 (DeClerk et al., 1988) and urine for microalbumin and creatinine. The C-Peptide Laboratory is located
Administration and organization
Directly responsible for the conduct of this trial are the Co-Chairmen's Offices in Miami, FL, and Phoenix, AZ. Both offices work with a central coordinating facility, the Hines VA Cooperative Studies Program Coordinating Center in Hines, IL. All three centers report to Cooperative Studies Program VA Central Office in Washington, DC.
The central pharmacy is the Cooperative Studies Program Clinical Research Pharmacy Coordinating Center in Albuquerque, NM. Overseeing the ethical and scientific
Discussion
The VA Diabetes Trial evolved from the VA Feasibility Trial, which was conducted between 1990 and 1993 Abraira et al., 1995, Abraira et al., 1997. Although the long-term trial was subsequently approved, its costs exceeded the existing resources of the Cooperative Studies Program at that time (Abraira et al., 1998) and remained without funding. In 1997, a Request for Proposals from the VA Cooperative Studies Program resulted in the 1998 approval for planning for the current VADT, Cooperative
Conclusion
The VADT is expected to determine the risk/benefit ratio of intensive glycemic control on CV morbidity and mortality, over that of meticulous control of dyslipidemia, arterial pressure, and lifestyle, equally enforced in both treatment arms. The treatment of risk factors for retinopathy and nephropathy, especially hypertension and periodic eye examination and intervention, permits the evaluation of additional benefits of the intensification of glycemic control beyond levels generally considered
Acknowledgements
This study is supported by the Cooperative Studies Program of the Department of Veterans Affairs Research and Development Service and also by the American Diabetes Association, National Eye Institute, GlaxoSmithKline Pharmaceuticals, Novo Nordisk Pharmaceuticals, Aventis Pharmaceuticals, Roche Diagnostic Pharmaceuticals, and KOS Pharmaceuticals.
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The VADT Planning Committee also included Stephen Davis, Rodney Hayward, Robert Henry, Nancy Morgan, Clark Sawin, Franklin Zieve, Morris Weinberger, John Colwell, Ronald Klein, Charles Clark, and Steven Goldman. The ad hoc members are Peter Savage (NHLBI, NIH) and Judith Fradkin (NIDDK, NIH). A complete listing of the VADT participants appears in Appendix C.