The diabetes epidemic continues to grow worldwide, with the number of patients increasing each year due to risk factors of obesity and sedentary lifestyle.1 In addition, patients with type 2 diabetes have a 2-4 fold increased risk of cardiovascular disease, including heart disease and stroke, resulting in a higher incidence of morbidity and mortality, compared to those individuals without diabetes.2 A higher incidence of microvascular complications, which includes renal disease, retinal disease and neuropathic disease, have also been reported; with diabetes being the leading cause of end-stage renal disease and blindness, and a chief cause of lower extremity amputation.2

Type 2 diabetes is a disease of progressive β-cell dysfunction in presence of insulin resistance, leading to gradual loss of glycemic control. An initial loss of first phase insulin response contributes to elevated postprandial plasma glucose concentrations.3 The pathological loss of β-cell function may be the result of a number of factors including β-cell secretory defects, glucotoxicity due to hyperglycemia, lipotoxicity due to dislipidemia, and possibly abnormalities in secretion of, or response to, incretin hormones. The characteristic β-cell dysfunction, seen in patients with type 2 diabetes, most likely develops years before the manifestation of overt hyperglycemia, and it has been suggested that at the time of diagnosis of disease β-cell mass and secretory function may have declined by as much as 50%.4,5

Before the availability of incretin mimetic agent(s), the approach to treat patients with type 2 diabetes was to start with lifestyle changes (diet and exercise), followed by single and combination oral drug therapy, focused on either compensation for relative insulin deficiency or insulin resistance. If lifestyle changes fail to provide adequate management, treatment of diabetes was initialized in a systematic step-wise fashion with either insulin secretogogues (sulfonylureas, nateglinide, repaglinide), or with agents that suppressed abnormally elevated hepatic glucose production (metformin), or utilized a treatment to reduce glucose absorption (with an α-glucosidase inhibitor), and/or increased insulin sensitivity with the use of insulin sensitizers (thiazolidinediones [TZDs]). If lifestyle changes, and/or subsequent pharmacological treatment did not provide adequate management of diabetes, exogenous insulin treatment was initiated.6-8

Many of these agents either induce weight gain or edema (sufonylurea, insulin, TZDs), or have no significant effect of body weight (metformin, α-glucosidase inhibitor), but are associated with some treatment-limiting side effects such as hypoglycaemia (e.g. sulfonylurea, insulin), or poorly tolerated gastrointestinal side effects (e.g. metformin, α-glucosidase inhibitor).6-9 Furthermore, the focus of each of these pharmacologic interventions has been to target either insulin resistance or the relative insulin deficiency, but not the dysfunction of other hormones (such as glucagon) involved in maintaining glycemic control. Due to the limitations of existing therapies, there is a continued interest in the development of agents that offer better glycemic control. Incretin mimetics and DPP-IV inhibitors, leverage the effects of known gut hormones. Clinical data with these newer agents (incretin mimetics and DPP-IV inhibitors) have shown fewer treatment limiting side effects, with either no effect on body weight while improving glycemic control (DPP-IV inhibitors), or decreasing body weight with improved glycemic control, as is the case with incretin mimetics (liraglutide and exenatide).