Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials

Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C <6.05%, mean achieved A1C ∼7%) and the standard group (A1C ∼9%) over an average of 6.5 years. The relationship between glucose control (as reflected by the mean on-study A1C value) and risk of complications was log-linear and extended down to the normal A1C range (<6%) with no threshold noted. In the UK Prospective Diabetes Study (UKPDS), participants newly diagnosed with type 2 diabetes were followed for 10 years, and intensive control (median A1C 7.0%) was found to reduce the overall microvascular complication rate by 25% compared with conventional treatment (median A1C 7.9%). Here, too, secondary analyses showed a continuous relationship between the risk of microvascular complications and glycemia extending into the normal range of A1C, with no glycemic threshold. On the basis of these two large controlled trials, along with smaller studies and numerous epidemiologic reports, the consistent findings related to microvascular risk reduction with intensive glycemic control have led the American Diabetes Association (ADA) to recommend an A1C goal of <7% for most adults with diabetes (6), recognizing that more or less stringent goals may be appropriate for certain patients. Whereas many epidemiologic studies and meta-analyses …