While long-term glycemic control is clearly important, if vildagliptin (and other DPP-4 inhibitors) is shown to have disease-modifying effects by protecting against the prolonged decline in beta-cell function that continues with other drugs, this could be of greater potential benefit in people with diabetes. Inhibiting disease progression and hence reducing or delaying the development of diabetic complications could provide substantial economic benefits. Evidence is also needed to compare vildagliptin with injected insulin in type 2 diabetes. An oral glucose-lowering drug that could reduce HbA1c as effectively as insulin, without weight gain or hypoglycemia, would have a considerable advantage over injected insulin in terms of patient convenience. However, direct evidence will be necessary to assess the likely impact of vildagliptin on resource utilization. Patient group/population Vildagliptin acts by prolonging the life of GLP-1 and thereby enhancing its effect on beta cells, so vildagliptin relies on the patient having an intact GLP-1 response to food and at least some beta-cell function. Vildagliptin would therefore not be expected to work in people with diabetes with little or no beta-cell function, such as those with type 1 diabetes, and these patients have been excluded from the trial populations. It is possible that vildagliptin may work better in patients with less advanced type 2 diabetes, and there is some evidence that it is effective in patients with prediabetes (Rosenstock et al. 2007c). Patients with significant diabetic or cardiovascular complications were excluded from the published studies, so there is no evidence relating to the use of vildagliptin in this population with more severe disease. Vildagliptin has been investigated in patients not previously treated for diabetes, and as an add-on to metformin in patients with an inadequate response to metformin therapy. All studies of vildagliptin were conducted in adults (aged ≥18 years). Pooled analyses indicate that the drug is effective in different ethnicities (Rosenstock et al. 2007d) and in elderly patients (Pratley et al. 2007b), and has a tolerability profile similar to that of metformin, pioglitazone, and rosiglitazone in patients with moderate renal insufficiency [glomerular filtration rate (GFR) 30 to <60 mL/min/1.73 m2), but better than metformin in those with mild dysfunction (GFR 60 to <90 mL/min/1.73 m2) (Thuren et al. 2007). Thus, the majority of the present evidence base relates to the use of vildagliptin in adult patients with type 2 diabetes but without diabetic or cardiovascular complications and who may be either drug-naïve or who have not responded adequately to metformin therapy. Further results may extend this population to patients with prediabetes. Dosage, administration, and formulations Vildagliptin (Galvus) can be prescribed to patients with type 2 diabetes at a dosage of 50 mg once daily in combination Core Evidence 2008;3(1) Vildagliptin | place in therapy review with a sulfonylurea, or 50 mg twice daily with metformin or a thiazolidinedione such as pioglitazone. A 100 mg formulation of vildagliptin is available in Brazil and Mexico. A fixed dose combination of vildagliptin 50 mg plus metformin 850 mg or vildagliptin 50 mg plus metformin 1000 mg (Eucreas®) has also been approved for twice-daily use in patients inadequately controlled with metformin alone or who are already receiving each drug separately. Liver function tests should be conducted before beginning treatment with vildagliptin, every 3 months in the first year of treatment, and periodically thereafter. Vildagliptin should not be used in patients with liver impairment, those with type 1 diabetes, patients with moderate to severe renal impairment, or those with congestive heart failure. Place in therapy Metformin is currently first line treatment for people with type 2 diabetes, with sulfonylureas established as second line, until newer agents such as DPP-4 inhibitors and PPAR agonists can demonstrate a clear advantage in terms of efficacy, safety, disease progression, or cost. There is clear evidence of improved glycemic control (measured by HbA1c, blood glucose or numbers of patients achieving HbA1c <7.0%) with vildagliptin compared with placebo, either as monotherapy or in combination with metformin, the thiazolidinediones pioglitazone and rosiglitazone, or the sulfonylurea glimepride. Since most patients with type 2 diabetes ultimately require more than one drug for effective glycemic control, this evidence indicates a valuable place for vildagliptin in combination therapy. The drug is effective in drug-naïve patients, those poorly controlled with current treatment, in the elderly, and in different ethnicities. There is also evidence of improved beta-cell function and improved insulin sensitivity compared with placebo. Vildagliptin was not associated with significantly more weight gain than placebo, and is not associated with a higher rate of hypoglycemia (Amori et al. 2007). The drug is well tolerated with few adverse effects. The incidence of liver enzyme elevations with vildagliptin 50 mg once daily in clinical trials is comparable to that seen with metformin, a thiazolidinedione, or a sulfonylurea; the incidence with 50 mg twice daily is less than that with placebo. The present evidence base supports the use of vildagliptin in adults with type 2 diabetes and no significant diabetic or cardiovascular complications. It can be inferred from the drug’s mechanism of action that it may be of most benefit in patients in the early stages of type 2 diabetes. As some authorities advocate earlier use of insulin in people with diabetes at this stage, studies comparing vildagliptin with early insulin would be valuable. There is evidence that vildagliptin is effective in patients with prediabetes. The main area where further evidence is required is on the effect of vildagliptin on important patient-oriented outcomes such as disease progression, impact on cardiovascular risk, long- term complications, health-related quality of life, and adherence 27