The Diabetes Control and Complications Trial (DCCT)³ and the United Kingdom Prospective Diabetes Study (UKPDS)^4,5 demonstrated the benefits of improving glycemic control in both type 1 and type 2 diabetes respectively. Both studies showed that improved glycemic control is associated with sustained decreased rates of microvascular and neuropathic complications. Current guidelines issued by the American Association of Clinical Endocrinologists (AACE) recommend that glycated hemoglobin (HbA_1c) be adopted as the primary method of assessment of glycemic control, with an HbA_1c target of ²6.5%,⁶ while the American Diabetes Association (ADA) recommends a target HbA_1c of <7%.⁷ Improving glycemic control in individuals with type 2 diabetes has not been shown to be directly associated with macrovascular benefits in large-scale clinical intervention studies;^8,9 indeed, there was a suggestion of harm associated with tight glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. While the current HbA_1c targets provide a generalized goal, it should be noted that the guidelines also stress that HbA_1c targets should be individualized, taking into account factors such as the patient’s age, life expectancy, comorbid conditions, and preferences.^8,9

The most recent consensus guidelines for the management of hyperglycemia in type 2 diabetes from the ADA and the European Association for the Study of Diabetes (EASD) recommend that initial management should always include lifestyle modifications.¹⁰ Due to the progressive chronic nature of type 2 diabetes, the initiation of pharmacotherapy is often necessary to reach or maintain the target HbA_1c, with the biguanide metformin recommended as the initial drug. However, the majority of patients will require additional medications during the course of the disease, either to maintain or to intensify treatment. Several therapeutic options are now available for the treatment of type 2 diabetes, including metformin, alpha glucosidase inhibitors, thiazolidinediones, meglitinides, and insulin. More recently approved agents include dipeptidyl peptidase-4 (DPP-4) inhibitors, amylin analogs, and incretin mimetics. With the availability of multiple agents with differing pharmacological targets, the question then arises, in the absence of head-tohead clinical trials, of how best to compare the relative effectiveness of these newer treatments, especially against established agents, which have accumulated long-term efficacy and safety data.