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 (7,8) have clearly shown a direct relationship between A1C and CVD, the potential of intensive glycemic control to reduce CVD events has been less clearly defined. In the DCCT, there was a trend toward lower risk of CVD events with intensive control (risk reduction 41% [95% CI 10–68]), but the number of events was small. However, 9-year post-DCCT follow-up of the cohort has shown that participants previously randomized to the intensive arm had a 42% reduction (P = 0.02) in CVD outcomes and a 57% reduction (P = 0.02) in the risk of nonfatal myocardial infarction (MI), stroke, or CVD death compared with those previously in the standard arm (9).
The UKPDS of type 2 diabetes observed a 16% reduction in cardiovascular complications (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm, although this difference was not statistically significant (P = 0.052), and there was no suggestion of benefit on other CVD outcomes such as stroke. However, in an epidemiologic analysis of the study cohort, a continuous association was observed such that for every percentage point of lower median on-study A1C (e.g., 8–7%) there was a statistically significant 18% reduction in CVD events, again with no glycemic threshold.
Because of ongoing uncertainty regarding whether intensive glycemic control can reduce the increased risk of CVD in people with type 2 diabetes, several large long-term trials were launched in the past decade to compare the effects of intensive versus standard glycemic control on CVD outcomes in relatively high-risk participants with established type 2 diabetes. In 2008, two of these trials, Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the Veterans Affairs Diabetes Trial (VADT), were completed and showed no significant reduction in cardiovascular outcomes with intensive glycemic control. A third trial, Action to Control Cardiovascular Risk in Diabetes (ACCORD), terminated its glycemic control study early due to the finding of increased mortality in participants randomized to a strategy of very intensive glycemic control with a target A1C of <6%. The findings of these three major trials led the ADA, with representatives of the American Heart Association (AHA) and the American College of Cardiology (ACC), to reexamine the recommendations for glycemic targets in patients with diabetes, the majority of whom have type 2 diabetes.