OBJECTIVE -We sought to evaluate the efficacy and safety of vildagliptin, a new dipeptidyl peptidase-4 inhibitor, added to metformin during 24 weeks of treatment in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -This was a double-blind, randomized, multicenter, parallel group study of a 24-week treatment with 50 mg vildagliptin daily (n ϭ 177), 100 mg vildagliptin daily (n ϭ 185), or placebo (n ϭ 182) in patients continuing a stable metformin dose regimen (Ն1,500 mg/day) but achieving inadequate glycemic control (A1C 7.5-11%).RESULTS -The between-treatment difference (vildagliptin Ϫ placebo) in adjusted mean change (AM⌬) Ϯ SE in A1C from baseline to end point was Ϫ0.7 Ϯ 0.1% (P Ͻ 0.001) and Ϫ1.1 Ϯ 0.1% (P Ͻ 0.001) in patients receiving 50 or 100 mg vildagliptin daily, respectively. The between-treatment difference in the AM⌬ fasting plasma glucose (FPG) was Ϫ0.8 Ϯ 0.3 mmol/l (P ϭ 0.003) and Ϫ1.7 Ϯ 0.3 mmol/l (P Ͻ 0.001) in patients receiving 50 or 100 mg vildagliptin daily, respectively. Adverse events (AEs) were reported by 63.3, 65.0, and 63.5% of patients receiving 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo, respectively. Gastrointestinal AEs were reported by 9.6 (P ϭ 0.022 vs. placebo), 14.8, and 18.2% of patients receiving 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo, respectively. One patient in each treatment group experienced one mild hypoglycemic event.CONCLUSIONS -Vildagliptin is well tolerated and produces clinically meaningful, doserelated decreases in A1C and FPG as add-on therapy in patients with type 2 diabetes inadequately controlled by metformin. Diabetes Care 30:890 -895, 2007

Aim: The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/ pioglitazone to component monotherapy. Methods: This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA 1c in patients receiving initial combination therapy compared with pioglitazone monotherapy. Results: After 24-week treatment, adjusted mean changes in HbA 1c from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were ÿ1.4 AE 0.1%, ÿ1.7 AE 0.1%, ÿ1.9 AE 0.1% and ÿ1.1 AE 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p ¼ 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were ÿ1.9 AE 0.2, ÿ2.4 AE 0.2, ÿ2.8 AE 0.2 and ÿ1.3 AE 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p ¼ 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy. Conclusions: First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy.

Abstract. Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150ϩV80) in 12 mildly sodium-depleted normotensive individuals. In this doubleblind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150ϩV80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150ϩV80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 ϩV80 combination had a synergistic effect on renin release. The A150ϩV80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.Numerous experimental and clinical studies have demonstrated that the combination of currently available angiotensin I-converting enzyme (ACE) inhibitors and AT1 receptor (AT1R) antagonists provides additive or synergistic effects on BP lowering (1) and on the prevention of cardiovascular (2) and renal lesions (3). These observations have previously been explained by AT1R blockers inhibiting the effects of non-ACE-dependent angiotensin II (Ang II) production (4,5) or by the bradykinin-NO-related effects of ACE inhibition (6). However, the additive effects of low doses of two different renin angiotensin system (RAS) inhibitors may be better explained by inhibition of the biologic effects of the reactive renin release that is triggered by single-site RAS blockade. The amount of compensatory renin release is proportional to the extent of decrease in the amount of Ang II generated or bound to the AT1R of the renal juxtaglomerular cells. This counterregulation may be overcome by using higher-than-usual or repeated doses of single-site RAS blockers (7,8) or by neutralizing the biologic effects of the counterbalancing rise in active renin by using a combined RAS blockade.Direct demonstration of the importance of renin in this counterregulatory mechanism has not previously been possible in humans because of the absence of convenient orally available renin inhi...

In patients with T2DM inadequately controlled with prior SU monotherapy, addition of vildagliptin (50 or 100 mg daily) to glimepiride (4 mg once daily) improves glycaemic control and is well tolerated. Addition of vildagliptin 50 mg daily to SU monotherapy may be a particularly attractive therapy in elderly patients.

Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.