Beyond metformin: initiating combination therapy in patients with type 2 diabetes mellitus

The majority of patients with type 2 diabetes mellitus will eventually require combination therapy involving two or more agents to achieve their glycemic target as their disease progresses. This review contrasts current treatment guidelines and recommendations by the American Diabetes Association and the European Association for the Study of Diabetes (referred to as ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (referred to as AACE) for the initiation of combination therapy. Both treatment guidelines emphasize that treatment selection for patients with type 2 diabetes should be guided by the goal of lowering hemoglobin A(1c) (A1C) level and individualizing therapy to each patient based on clinical factors and comorbidities. In addition, combination therapy should include classes of drugs with complementary mechanisms of action that efficiently and effectively target the underlying type 2 diabetes pathophysiology. Both the ADA and AACE recommend metformin as a firstline oral agent; however, the ADA supports early use of sulfonylureas or insulin in patients who do not reach their target A1C goal, whereas the AACE recommends earlier and more frequent use of the newer incretin agents-glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Mechanisms of action, benefits, and risks of traditional and newer agents are discussed to better enable the pharmacist to recommend the best combinations of agents for individual patients.