The results of three recent trials, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease (ADVANCE) trial, and the Veterans Affairs Diabetes Trial (VADT), indicate that lower blood glucose levels are not always better. The major aim of all three randomized controlled trials was to determine whether lowering the blood glucose (hemoglobin A [A1C]) to normal or near-normal would _1c reduce the occurrence of cardiovascular events. In the ACCORD trial, unexpected deaths in the intensive therapy (IT) group, over and above the number of deaths in the conventional therapy (CT) group, resulted in the early discontinuation of the trial.¹ There were no findings of increased mortality related to IT in the ADVANCE trial; however, preliminary analyses have found no reduction in rates of macrovascular events in the IT group.² The VADT also found no difference in macrovascular event rates between IT and CT groups.³ Taken together, data from all three of these trials suggest there is no benefit of aggressive glycemic control on macrovascular complications in diabetic patients.

These outcomes leave many of us questioning what we thought we knew. Glycemic control as close to the normal range as possible purportedly simulates the nondiabetic state. It is well established that tight glycemic control reduces rates of microvascular complications in diabetic patients; why wouldn't the same hold true for macrovascular events and cardiovascular mortality? A closer look at these important clinical trials may clarify some points but may also leave us with further questions.

All three trials shared the aim of determining the relationship between glycemic control and macrovascular events (myocardial infarction and stroke); however, the study designs, populations, and outcomes were somewhat different. ACCORD randomized 10,251 patients with type 2 diabetes (mean age 62 years) and a baseline median …