Vildagliptin | place in therapy review deterioration of pancreatic beta-cell function and these cells are unable to meet the demand for further increases in insulin levels, resulting in elevated glucose levels and subsequently type 2 diabetes (Stumvoll et al. 2005). It has been suggested that there is approximately a 50% loss of beta-cell function in patients with newly diagnosed type 2 diabetes (Turner et al. 1999). Furthermore, it has been shown that beta-cell response continues to decline (by as much as 4% per year) despite the use of insulin or oral glucose-lowering drugs (Holman 1998). Glucagon is a hormone that stimulates the release of glucose from the liver during fasting to maintain normal glucose homeostasis. During periods of hyperglycemia glucagon secretion is suppressed. In patients with type 2 diabetes, glucagon concentrations are elevated resulting in increased hepatic glucose output and postprandial glucose spikes (excursions). The role of the incretins, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), in the regulation of postprandial insulin secretion have recently been elucidated (Holst & Gromada 2004). GLP-1 is an incretin hormone secreted into the bloodstream from endocrine cells located in the intestinal mucosa in response to a meal. It mediates its insulintropic activity via GLP-1 receptors on pancreatic beta cells and other tissues. The biological activities of GLP-1 include mediating glucose-dependent insulin secretion; suppression of postprandial glucagon secretion; regulation of gastric emptying; and suppression of appetite leading to reduction of food intake (Nauck et al. 1996; Zaunder et al. 2002). In individuals with type 2 diabetes or IGT, the release of GLP-1 in response to a meal is defective, resulting in reduced circulating concentrations of postprandial GLP-1 and a blunted insulin secretory response to food intake (Nauck et al. 1986). The action of GLP-1 is inactivated by the enzyme DPP-4. Current therapy options Initially, patients with type 2 diabetes may be able to control their blood glucose levels with diet and exercise alone. However, many people with diabetes progress to require antidiabetic medications. Currently, there are five classes of oral glucose- lowering drugs available that may be used as a monotherapy or in combination. The mechanism of action and the risks and benefits of each of these therapy classes are indicated in Fig. 1 and Table 2, respectively. The choice of antidiabetic medication is a complex decision that requires several factors to be taken into consideration, therefore a decision is often made on a case by case basis. Metformin is widely regarded as the drug of choice for patients with type 2 diabetes (IDF 2005b), especially for people who are overweight or obese. Indeed, the UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend metformin as a first-line therapy option for the treatment of type 2 diabetes (NICE 2002) (Table 2). In comparison, the European Diabetes Policy Group (EDPG) guidelines, The American Association of Clinical Endocrinologists (AACE) guidelines, and the ADA guidelines do not specify their recommendation for first-line therapy with oral glucose-lowering drugs (EDPG 1999; AACE 2002; ADA 2005). With 16 Fig.1 | Mechanism of action of current oral glucose-lowering drugs (reprinted from Stumvoll et al. 2005, with permission from Elsevier). DPP-lV, dipephidyl peptidase lV; GLP-1 glucagon-like peptide 1; NEFA, nonesterified fatty acid. the continuous deterioration of glucose control over time, the use of combination therapy is recommended and many combination preparations are available. After the failure of multiple oral agents, people with diabetes additionally require insulin therapy. The aims of treatment with currently available antidiabetic agents are to control hyperglycemia and to reduce cardiovascular risk and prevent the development of complications. Recent European, UK, and US guidelines for type 2 diabetes recommend glycemic targets, with a glycated hemoglobin A1c (HbA1c) target range below 6.5–7.5% (EDPG 1999; AACE 2002; NICE 2002; ADA 2005). However, the recently completed Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in patients with type 2 diabetes revealed increased mortality with treatment to get HbA1c levels below 6% (ACCORD Study Group 2008). The AACE have published a series of road maps that suggest treatment algorithms to achieve AACE glycemic goals for patients with type 2 diabetes (HbA1c ≤6.5%) naïve to therapy or those previously treated with monotherapy or combination therapy (AACE 2005; Jellinger et al. 2007). Unmet needs Long-term glycemic control The AACE has reported that 67% of individuals with type 2 diabetes do not have adequately controlled blood glucose (AACE 2005). Furthermore, the National Health and Nutrition Examination Survey (NHANES III) has reported that from 1998 to 2000 the frequency of poor glycemic control increased among US adults with type 2 diabetes (Koro et al. 2004). In general, for every 1.0% unit reduction in HbA1c, the risk of developing microvascular diabetic complications is reduced by 40% (CDC 2003). The UKPDS demonstrated that the risk of © 2008 Core Medical Publishing Limited