Vildagliptin | place in therapy review Table 7 | Effects of vildagliptin on insulin sensitivity (level 2 evidence) Design Treatment and dose Outcome Reference Double-blind, placebo- controlled, multicenter RCT, 12 weeks Optional extension for further 40 weeks Placebo (n=51, of whom 29 completed extension) V 50 mg qd (n=56, of whom 42 completed extension All patients were also taking stable doses of metformin 1.5–3 g/day qd, once daily; RCT, randomized controlled trial; V, vildagliptin. (Table 7), which is considered by the authors to be a measure of the ability of beta cells to adapt insulin secretion to the prevailing insulin sensitivity (Ahrén et al. 2005b). Effects on bodyweight Excess bodyweight is a major risk factor in type 2 diabetes (see Disease overview section). Thus, it is important that medications for the treatment of diabetes should not cause an increase in bodyweight. Vildagliptin is not associated with significantly more weight gain than placebo according to level 1 evidence from a meta analysis; there was a small increase of 0.42 kg [95% confidence interval (CI): 0.12, 0.72] (Amori et al. 2007). Weight reduction was greater with vildagliptin compared with pioglitazone or rosiglitazone (mean 1.7 kg difference), but less than that with metformin (mean 2.2 kg difference). The effects of vildagliptin on bodyweight are shown in Table 8. Combination with other agents Some evidence from animal models suggested that pioglitazone and vildagliptin could have synergistic effects on glucose clearance after an oral glucose load (Burkey et al. 2002). The combination has subsequently been studied in humans. One study investigated the combination in 12 patients with type 2 diabetes (Serra et al. 2005). Patients received pioglitazone 45 mg once daily for 8 weeks, and were then randomized to receive add-on placebo or vildagliptin 100 mg once daily for 28 days, followed by vildagliptin alone for 7 days. Coadministration did not alter the pharmacokinetic behavior of either compound, but the combination reduced postprandial glucose significantly (P<0.05) more than pioglitazone alone (Serra et al. 2005). A crossover study in 15 patients with type 2 diabetes found that coadministration of glyburide 10 mg once daily and vildagliptin 100 mg twice daily did not modify the peak plasma concentration, area-under-the-curve, or half-life of either agent. Two hypoglycemic events occurred in patients receiving glyburide alone, but none in patients receiving the combination (Barilla et al. 2004). A study in 16 healthy volunteers reported that vildagliptin significantly enhanced glibenclamide-stimulated insulin secretion, Core Evidence 2008;3(1) Oral glucose insulin sensitivity (mL/min/m2) Adaptation index (insulin secretion x insulin sensitivity) Greater with V than placebo at Greater with V than placebo at Ahrén et al. 2005b 24 and 52 weeks (P<0.05) 12, 24 (P<0.05), and 52 weeks (P<0.01) but did not increase the risk of reactive hypoglycemia (El-Ouaghlidi et al. 2003, 2004). These early studies have been verified in larger, randomized placebo-controlled trials. The combination of vildagliptin 50 mg once or twice daily plus metformin caused a significant decrease of HbA1c compared with metformin alone, and a significantly greater proportion of patients achieved levels <7.0% (Dejager et al. 2007b; Table 3). Similarly, there was a significantly greater reduction in HbA1c when vildagliptin 50 mg or 100 mg daily was added to pioglitazone 15, 30, or 45 mg daily compared with pioglitazone 30 or 45 mg alone (Garber et al. 2007b; Rosenstock et al. 2007a; Table 3). Effects in prediabetes There is some preliminary evidence that vildagliptin is effective in people with prediabetes. In a 12-week randomized trial, vildagliptin 50 mg once daily (n=90) significantly (P<0.001) increased GLP-1 and GIP compared with placebo (n=89), and improved beta- cell function (Rosenstock et al. 2007c). Furthermore, vildagliptin reduced prandial glucose excursions by 22% compared with baseline, and by 32% compared with placebo. Vildagliptin 100 mg once daily also improved insulin sensitivity and beta-cell function in 22 patients with prediabetes after 6 weeks (Utzschneider et al. 2007). Safety and tolerability Level 1 evidence from a meta analysis of 12 randomized controlled trials comparing vildagliptin with placebo (Ristic et al. 2005; Mimori et al. 2006; Pratley et al. 2006; Pi-Sunyer et al. 2007; Dejager et al. 2007), metformin with or without placebo (Ahrén et al. 2004a; Bosi et al. 2007; Schweitzer et al. 2007), pioglitazone with or without placebo (Garber et al. 2007b; Rosenstock et al. 2007a), rosiglitazone (Rosenstock et al. 2007b), or insulin (Fonseca et al. 2007) revealed that vildagliptin was well tolerated with few adverse effects (Amori et al. 2007). There was no risk of gastrointestinal adverse effects compared with placebo; urinary tract infection and headache were more frequent with vildagliptin versus comparator (3.6% versus 1.3%, and 6.3% versus 4.4%, respectively). Nasopharyngitis occurred in 7.3% of vildagliptin recipients and upper respiratory tract 25