Clinical evidence with vildagliptin In-vitro studies have shown that vildagliptin is a potent, reversible, competitive inhibitor of human and rat DPP-4, with high selectivity for DPP-4 over other peptidase enzymes (Hughes et al. 2002; Villhauer et al. 2003; Brandt et al. 2005). In vivo, vildagliptin has been shown to inhibit plasma DPP-4 activity in rats (Villhauer et al. 2003) and in cynomolgus monkeys for up to 10 hours (Hughes et al. 2002). In obese, insulin-resistant cynomolgus monkeys, vildagliptin treatment for 10 weeks significantly (P<0.05) reduced HbA1c and fasting plasma insulin (Dardik et al. 2003a). Plasma fibrinogen and plasminogen activator inhibitor-1 (PAI-1), two thrombogenic risk factors, were also significantly (P<0.05) reduced during vildagliptin treatment (Dardik et al. 2003a). Acute administration of vildagliptin significantly (P<0.05) delayed gastric emptying (Dardik et al. 2003b), although this was unaffected in 14 patients with type 2 diabetes given vildagliptin 50 mg twice daily for 10 days (Vella et al. 2007). A study in obese Zucker rats suggests that pioglitazone and vildagliptin may have synergistic effects. When coadministered, pioglitazone and vildagliptin increased the glucose clearance rate after an oral glucose tolerance test, but neither drug alone had this effect (Burkey et al. 2002). Oral administration of vildagliptin improved glucose tolerance in various animal models of diabetes, including obese Zucker rats (Villhauer et al. 2003), obese, insulin-resistant cynomolgus monkeys (Dardik et al. 2003b), and ob/ob mice (Mika et al. 2003). Chronic dosing in obese Zucker rats produced similar effects to those of acute dosing, and vildagliptin had no effect on the animals’ bodyweight (Burkey et al. 2005). There is some evidence from animal studies that vildagliptin may have beneficial effects on beta-cell function. A study in mice showed that the improvement in glucose tolerance was paralleled by an increase in glucose-stimulated insulin secretion from isolated islet cells, and was lost in transgenic mice with a defect in the islet beta-cell response to glucose (Ahrén et al. 2005a). Vildagliptin has also been shown to increase beta- cell mass in newborn rats, apparently by stimulating beta-cell genesis and inhibiting beta-cell apoptosis (Duttaroy et al. 2005a). A separate study in mice showed that vildagliptin improved glucose tolerance in mice subjected to streptozocin-induced beta-cell damage, but in this case there was no effect on apoptosis and the effect appeared to be mediated via enhanced differentiation of pancreatic progenitor cells (Duttaroy et al. 2005b). However, vildagliptin was unable to prevent progression of diabetes in the ZDF rat, a model of rapidly-developing diabetes (Rolin et al. 2004). Vildagliptin’s major antidiabetic mechanism of action appears to be an enhancement of glucose-stimulated insulin release, mediated via an increase in GLP-1 levels (Burkey et al. 2005; Holst & Deacon 2005). It has also been argued that increased GLP-1 may not be the only mediator of the clinical effects of DPP-4 inhibitors, and that other neuropeptides may be implicated (Nauck & El-Ouaghlidi 2005). Recently, however, it has Core Evidence 2008;3(1) Vildagliptin | place in therapy review been shown that insulin secretion stimulated by the neuropeptide pituitary adenylate cyclase-activating peptide was unaffected by vildagliptin, which appears to act by prolonging the half life of L- and K-cell derived incretin hormones (Hjøllund et al. 2007). The clinical evidence on vildagliptin published to date is mainly concerned with disease-oriented outcomes (such as HbA1c, blood glucose, and insulin levels), and patient-oriented evidence on weight gain and adverse events. Effects on glycated HbA1c HbA1c is an established measure of glycemic control. Evidence shows that treatment for up to 52 weeks with vildagliptin at doses of 50 or 100 mg/day is effective in reducing HbA1c (Tables 3 and 4). The mean reduction in HbA1c with vildagliptin was typically up to 1 percentage point (Table 3). As discussed earlier (Unmet needs section), most of the commonly used oral glucose-lowering drugs are also able to reduce HbA1c by approximately 1 percentage point. One early study showed that addition of vildagliptin 50 mg/day to metformin treatment resulted in improved glycemic control at 12 weeks compared with metformin alone (Ahrén et al. 2004a; Table 4). An optional 40-week extension to this study provided limited evidence that adding vildagliptin 50 mg/day to metformin treatment may help to maintain long-term glycemic control. There was a slight increase in HbA1c during the extension phase, but this was less in the patients receiving vildagliptin plus metformin than in the patients receiving metformin alone, and was not statistically significantly different from zero (Ahrén et al. 2004a; Table 4). More robust evidence has substantiated the beneficial effects of adding vildagliptin to patients whose diabetes is poorly controlled by metformin alone. After 24 weeks, HbA1c was significantly improved by vildagliptin 50 or 100 mg/ day compared with placebo in patients receiving metformin ≥1.5 g/day (Bosi et al. 2007; Dejager et al. 2007b; Table 4). Vildagliptin 50 mg once or twice daily also caused a further reduction in HbA1c of 0.7% compared with placebo in patients taking glimepride 4 mg once daily (Garber et al. 2007a; Table 4). Similarly, adding vildagliptin 50 mg twice daily reduced HbA1c compared with placebo in patients poorly controlled on insulin therapy after 24 weeks (Fonseca et al. 2007; Table 4). Patients receiving placebo were switched to vildagliptin 50 mg once daily and after a further 28 week extension HbA1c decreased significantly by 0.4% (Fonseca et al. 2006). The percentage of patients reaching a target of <7.0% HbA1c was consistently in the range 40–47% with vildagliptin at 50 or 100 mg/day, compared with only up to 23% with placebo (Tables 3 and 4). It appears that 25 mg/day is little more effective than placebo, and that 50 mg/day and 100 mg/day have approximately similar effectiveness (Tables 3 and 4). However, in patients with a higher baseline HbA1c (>8.0%) the effect of vildagliptin 100 mg given either as a single dose or as 50 mg twice daily was greater than that of vildagliptin 50 mg once daily (Dejager et al. 2007a; Pi-Sunyer et al. 2007). Similarly, the reduction in HbA1c was greater in patients with higher (mean 8.5%) versus lower (mean 7.5% baseline HbA1c with vildagliptin 25 mg twice daily (Pratley et al. 2006). Nearly four times as many patients achieved HbA1c <7.0% when vildagliptin was added to metformin, and nearly half as 19