Changing the Treatment Paradigm for Type 2 Diabetes

Based on the results of the U.K. Prospective Diabetes Study (UKPDS), “… treatment of type 2 diabetes [should] include aggressive efforts to lower blood glucose levels as close to normal as possible. …” This was the recommendation the American Diabetes Association promulgated based on the results of the UKPDS when published (1). The suggestion was soon adopted by official guidelines in every region of the world (2). They are generally consistent in recommending an A1C goal of <7.0%. However, the results of the UKPDS remained inconclusive with respect to cardiovascular (CV) complications because of a risk reduction that was only close to statistical significance (−16%, P = 0.052). In support of the UKPDS results, however, a recent meta-analysis of randomized trials in type 2 diabetes (3) calculated a 19% reduction in the incidence of any type of macrovascular event associated with improved long-term glycemic control. Moreover, a strong association between glycemic control and micro- and macrovascular disease has been highlighted in type 1 diabetic patients (4,5).

Nevertheless, these results have been challenged by recent large-scale intervention trials. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial randomized >10,000 subjects with type 2 diabetes and vascular disease, or multiple CV risk factors, to an intensive treatment program targeting normal blood glucose values and A1C <6%, or a standard treatment program aiming at A1C between 7 and 7.9%. The intensive blood glucose arm was prematurely stopped because of excess mortality (hazard ratio [HR] 1.22, 95% CI 1.01–1.46; P = 0.04) and lack of significant reduction of primary outcome, i.e., a composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV causes (HR 0.90, 0.78–1.04; P = 0.16) (6). After a median 5-year follow-up, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), …