Clinical practice in type 2 diabetes: After metformin and lifestyle, then what?

According to the most recent data from the Centers for Disease Control, nearly 24 million Americans have type 2 diabetes mellitus (T2DM); of these, 6 million individuals with T2DM remain undiagnosed. At least 57 million more American adults are at high risk for developing T2DM by virtue of having impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both, which constitute prediabetes. Treating T2DM remains challenging, despite the availability of effective therapies. Recent data indicate that slightly more than half of the patients (~56%) with T2DM are achieving the American Diabetes Association (ADA) glycosylated hemoglobin (HbA1C) goal of <7%. A major contributing factor to the inability to maintain glycemic control in patients with T2DM is its progressive nature. There is a continuum from normoglycemia to IGT/IFG (prediabetes) to diabetes, and from uncomplicated diabetes to more difficult-to-control diabetes and diabetes with complications. This continuum has implications for treatment strategies and for the need to continually modify these strategies as the disease progresses. Understanding where the patient is on the continuum of disease may help identify mechanisms of action that can be targeted and aid in therapeutic decision-making. For example, early in the disease process, T2DM is characterized by insulin resistance and hyperinsulinemia. As such, agents that target insulin sensitivity and insulin resistance may be especially useful early in the disease process. Although the 2 main defects of T2DM are insulin resistance and pancreatic beta-cell dysfunction/failure, other aspects of its pathophysiology may be targeted to specific metabolic pathways and effects.