• The primary outcome is the occurrence of any one of the following: myocardial infarction, surgery for atherosclerotic disease, stroke, congestive heart failure, or amputation for ischemic gangrene. [ Time Frame: Time to first primary event (survival analysis). ] [ Designated as safety issue: No ]
  

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 MDI 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: