This Physician’s Weekly feature on interpreting new data on glucose control was completed in cooperation with the experts at the American Diabetes Association.

Glycemic control is fundamental to the management of type 2 diabetes, and studies have demonstrated that intensive therapy can result in significant reductions in microvascular and neuropathic complications associated with the disease. “Over the years, epidemiological studies have suggested that higher glucose levels result in higher rates of cardiovascular disease (CVD) events, and lower glucose values result in lower rates of CVD,” says David M. Kendall, MD. “Only recently have researchers explored the impact of getting patients with type 2 diabetes to go from high or moderate levels of glucose control to even lower A1C values with intensive or very intensive interventions and its role in CVD.”

“Glucose control remains essential for reducing the risk
of the microvascular complications of diabetes.”

Three Important Investigations

Several large long-term trials have been launched to compare the effects of intensive versus standard glycemic control on CVD outcomes in relatively high-risk patients with established type 2 diabetes. In particular, three trials from 2008—the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, and the Veterans Affairs Diabetes Trial (VADT)—have shed some light on the subject, but have also further fueled the debate regarding the role of intensive glucose therapy. “A common link between ACCORD, ADVANCE, and VADT is that they explored the potential impact of intensive glucose control strategies on the rates of CVD in patients with type 2 diabetes,” Dr. Kendall says (Table). “However, interpreting this data may be challenging for some physicians because each study had key differences to consider.”


Data from the ACCORD study demonstrated that using a strategy of intensively treating patients to achieve an A1C value of less than 6% had no impact on the rates of major CVD events when compared with patients randomized to achieve A1C levels between 7.0% and 7.9%. “ACCORD was unique in that it was interrupted because of an unanticipated finding of higher mortality in patients who were treated with an intensive strategy,” says Dr. Kendall. “To date, however, this is the only study in which this observation has been made. At this point, we have limited understanding as to the origins of this observed increase in mortality.”

Dr. Kendall adds that “physicians should recognize that although normalizing A1C in all patients with type 2 diabetes is probably not advisable, achieving reasonable glucose control is still quite effective  and has been shown to improve outcomes in these individuals.”


The ADVANCE study, according to Dr. Kendall, implemented an intensive glycemic control strategy in patients with lesser degrees of antecedent hyperglycemia. “These patients presented at baseline with lower A1C levels (7.2%) than participants in the ACCORD study (8.1%), suggesting less glucose exposure over the years prior,” he says. “They also had slightly shorter durations of diabetes and were using less medication at baseline to treat their diabetes.”

In ADVANCE, the goal was to reduce A1C to 6.5% in one cohort of patients and use local A1C guidelines for the other cohort. Findings demonstrated a significant reduction in the cumulative primary endpoint of microvascular and macrovascular outcomes. “However,” Dr. Kendall says, “there was no specific reduction in the rate of CVD events in the intensive glucose control group. Most of the advantages derived in ADVANCE resulted from decreased rates of microvascular complications, a finding that is consistent with other published literature.”


The study population in VADT had longer-standing diabetes and entered the trial with much higher A1C values (median A1C, 9.4%). Patients were older and had failed to achieve glycemic control with usual non-insulin therapies. “The ADVANCE patient population was earlier in the disease course and, theoretically, a relatively simpler group to treat,” explains Dr. Kendall. “Conversely, the VADT patient group was likely to require more complex treatment regimens and medications. In VADT, the intensive glucose lowering intervention was effective, achieving an average A1C of 6.9%. Again, however, it failed to show an effect on reducing the rate of future CVD events.”

Translating the Data

Findings from ACCORD, ADVANCE, and VADT suggest that intensive glucose control interventions appear to have a limited impact on future CVD events when other risk factors (eg, blood pressure and cholesterol) are well controlled in patients with longer duration type 2 diabetes. “It should be noted, however, that these studies do provide helpful information for practitioners,” Dr. Kendall says. “For example, an important finding consistent within all three studies was a reduction in the risk of early evidence of renal disease for patients receiving the more intensive glycemic strategy. ACCORD, ADVANCE, and, to a lesser degree, VADT also confirmed that glucose control—albeit not more intensive glucose control—may still play a small role in CVD risk reduction. They all support the concept that glucose control remains essential for reducing the risk of the microvascular complications of diabetes.”