The PubMed literature search was repeated on October 11, 2007 with search limits “humans, clinical trial, meta-analysis, randomized controlled trial, English language” and yielded 13 records, of which eight were included, the remainder being pharmacokinetic or pharmacodynamics studies. Abstracts from the 2006 and 2007 annual meetings of the ADA and European Association for the Study of Diabetes (EASD) were also searched and 12 were included after removal of duplicates, subanalyses, and out-of-scope records. Finally, four full papers were identified from a meta analysis (Amori et al. 2007) that were not present in the PubMed search. Disease overview The increasing prevalence of type 2 diabetes It is estimated that there are currently approximately 194 million people with diabetes worldwide and the prevalence is projected to exceed 333 million by 2025 (IDF 2005a). Over 90% of those affected have type 2 diabetes. Furthermore, due to its asymptomatic nature, a substantial proportion of individuals with type 2 diabetes are unaware that they have the disease (WHO 2003). Global estimates of the number of individuals with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) (often referred to as prediabetes) are unavailable. However, the World Health Organization (WHO) has suggested that it is likely to be even greater than the number with diabetes (WHO 2003). Type 2 diabetes usually occurs in adults over the age of 40 years and is associated with a number of factors, including obesity, family history of diabetes, physical inactivity, and race/ethnicity. However, over the last two decades the increasing prevalence of type 2 diabetes in children and adolescents has been recognized as a global health problem (CDC 2005a; Pinhas-Hamiel & Zeitler 2005). Diabetes is one of the most common chronic diseases among children in the US with approximately 150 000 young people under the age of 18 years having the condition. It is estimated that 8–43% of those affected have type 2 diabetes (CDC 2005a). To examine the prevalence of diabetes among children and adolescents in the US, a 5-year study, SEARCH for Diabetes in Youth, has been initiated by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health. Type 2 diabetes is most commonly observed in American Indian, African American, Asian, and Hispanic/Latino youths. However, the obesity epidemic and a sedentary lifestyle are thought to be contributing factors. Generally, children and adolescents diagnosed with type 2 diabetes are between 10 and 19 years old, obese, and have insulin resistance and a strong family history of type 2 diabetes (Bloomgarden 2004; CDC 2005b). Medical and socioeconomic burden of type 2 diabetes Type 2 diabetes is associated with significant morbidity and mortality because of the resulting complications. Diabetes is the leading cause of end-stage renal disease, accounting for 44% of new cases and is the leading cause of blindness in the Western world (CDC 2003). People with diabetes are also likely to have a clustering of cardiovascular risk factors such as obesity, hypertension, and dyslipidemia, which is often referred to as the Core Evidence 2008;3(1) Vildagliptin | place in therapy review “metabolic syndrome” (Kahn et al. 2005). Individuals with diabetes are two to four times more likely to develop cardiovascular disease and have a greater risk of heart attack or stroke than individuals without diabetes (IDF 2005a). Indeed, a recent meta analysis of prospective cohort studies in patients with diabetes showed that hyperglycemia is associated with an increased risk of cardiovascular disease (Selvin et al. 2004). There is also increasing evidence that cardiovascular risk factors are more prevalent in individuals with IFG or IGT compared with those with normal glucose levels, and that these individuals have an increased risk of cardiovascular disease and death (Coutinho et al. 1999; DECODE Study Group 2001; Saydah et al. 2001). Recent data have shown that abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction (Bartnik et al 2004). In addition, the presence of cardiovascular disease risk factors explains the relationship between prediabetes and the development of chronic kidney disease (Fox et al. 2005). These complications place a huge burden on healthcare services. It is estimated that the total direct and indirect expenditure for diabetes in the US alone in 2002 was $US132 billion (Hogan et al. 2003). The European Cost of Diabetes in Europe – type 2 (CODE-2) study estimated that three times the healthcare resources are spent on treating the complications of type 2 diabetes than those spent on controlling the disease before the onset of complications (Jonsson 2002). Hospitalization accounted for over 50% of the total cost. In contrast, management of glucose control with oral drugs and insulin accounted for only 7% of healthcare costs. It is evident that preventing the development of type 2 diabetes complications could have a beneficial effect on the huge economic and healthcare burden of type 2 diabetes. The UK Prospective Diabetes Study (UKPDS) 41 compared the cost effectiveness of intensive blood glucose control (sulfonylurea or insulin) with conventional glucose control (primarily diet) in patients with type 2 diabetes (Gray et al. 2000). This study showed that although intensive blood glucose control significantly increased treatment costs, it substantially reduced the cost of complications and increased the time free of complications. The role of incretin hormones in the pathophysiology of type 2 diabetes Type 2 diabetes is a complex metabolic disease that has a multifactorial pathogenesis (Stumvoll et al. 2005). Factors involved in the development and progression of type 2 diabetes include insulin resistance, reduced pancreatic beta-cell response, and inappropriately elevated glucagon levels. These in turn can be affected by secondary factors such as overeating, lack of exercise, liver damage, hyperlipidemia, and impaired secretion of incretin hormones. Beta-cell dysfunction is a major factor in the pathogenesis of type 2 diabetes. Insulin from the pancreas normally reduces glucose output by the liver, enhances glucose uptake by skeletal muscle, and suppresses fatty acid release from fat tissue. Individuals develop insulin resistance in peripheral tissues and to maintain normal glucose levels pancreatic beta cells increase the amount of insulin they produce. However, over time there is a progressive 15