Vildagliptin | place in therapy review Table 5 | Effects of vildagliptin on plasma insulin, glucagon, and GLP-1 levels (all level 2 evidence). Design Treatment and dose Outcome Reference Mean change from Mean change from baseline in baseline in 30 min 4 h-postprandial plasma postprandial glucagon insulin (pmol/L) (ng/mL) Mean change from baseline in 30 min postprandial GLP-1 (pmol/L) NR Ristic et al. 2005 Double-blind, placebo- controlled, multicenter RCT, 12 weeks Double-blind, placebo- controlled, multicenter RCT, 12 weeks Optional extension for further 40 weeks Double-blind, placebo- controlled, multicenter RCT, 4 weeks Double-blind, placebo- controlled RCT, 4 weeks Double-blind, placebo- controlled, single center RCT, 4 weeks Placebo (n=58) V 25 mg bid (n=51) V 25 mg qd (n=54) V 50 mg qd (n=53) V 100 mg qd (n=63) 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 Placebo (n=19) V 100 mg qd (n=18) Placebo (n=20) V 100 mg qd (n=20) Placebo (n=11) V 100 mg bid (n=9) Placebo –30.1 V 25 mg bid +3.0 V 25 mg qd –48.2 V 50 mg qd +2.8 V 100 mg qd +19.7 (P=0.022 vs placebo) All other doses NSD vs placebo NSD between groups at 12 weeks Greater increase with V than placebo at 52 weeks (P=0.015) Insulin response to meal ingestion NSD between groups Insulin response to meal ingestion NSD between groups NR NR NR bid, twice daily; NR, not reported; NSD, not statistically significantly different; qd, once daily; RCT, randomized controlled trial; V, vildagliptin. FPG than rosiglitazone (Table 4), suggesting a more sustained effect throughout the day (Rosenstock et al. 2007b). Effects on glucagon, insulin, and GLP-1 As expected from its mechanism of action, evidence consistently shows that vildagliptin increases postprandial GLP-1 levels relative to placebo (Table 5). Vildagliptin also consistently lowers plasma glucagon relative to placebo, but most of the evidence appears to show little effect on plasma insulin levels (Table 5). However, it has been argued that plasma insulin levels are not necessarily a direct measure of plasma insulin secretion, and that beta-cell function can be improved without appreciable changes in plasma insulin (Mari et al. 2005). Moreover, this observation probably reflects improved insulin secretion and sensitivity, shown by the same insulin level in response to lower glucose levels. Inhibition of DPP-4 might not be expected to have a significant effect on fasting GLP-1 or GIP because incretin release depends on nutrient intake. However, there is some evidence from a small study that a high dose of vildagliptin, 100 mg twice daily, significantly increased GLP-1 and GIP in patients with type 1 (n=11) or type 2 (n=9) diabetes after 4 weeks (Kelley et al. 2006). Core Evidence 2008;3(1) Effects on beta-cell function Evidence suggests that vildagliptin can increase the secretion of insulin in response to glucose, indicating an improvement in beta-cell function (Table 6). The dose-ranging study found that only the highest dose of vildagliptin (100 mg/day) was significantly superior to placebo, whereas other studies have shown statistically significant differences from placebo at lower doses (Table 6). However, this may reflect the variety of measures used to assess beta-cell function, which makes it difficult to compare results across different studies. In patients inadequately controlled with metformin ≥1.5 g/day, the insulin secretory response increased by 5.2 and 5.7 pmol/min/m2 with vildagliptin 50 and 100 mg/day, respectively, compared with placebo (Bosi et al. 2007). Adding vildagliptin to pioglitazone also improved beta- cell function (Rosenstock et al. 2007a; Table 6). Effects on insulin sensitivity Evidence from one randomized controlled trial (Ahrén et al. 2005b) indicates that long-term vildagliptin treatment can increase insulin sensitivity during oral glucose intake (Table 7). The same study also found that vildagliptin increased the adaptation index 23 NR Ahrén et al. 2004a Significant reduction in V group (P=0.005) No significant change in placebo group Placebo +2 V 12 (P<0.01) 3.5 h mean glucagon: lower with V than placebo but NSD Significant increase in V group (P<0.001) Placebo NR Placebo +0.9 V +4.7 (P<0.001) Greater increase with V than placebo in 13.5 h mean GLP-1 (P<0.001) Ahrén et al. 2004b Ahrén et al. 2003 Mari et al. 2005