Piragliatin, an allosteric activator of glucokinase, greatly enhances glucose-induced pancreatic islet respiration and insulin release.

| 209 followed by add-on therapy. The efficacy and safety of initial therapy with the fixed-dose combination tablet of sitagliptin and metformin (SITA/MET) compared with metformin alone (MET) was assessed over 44 weeks in patients with type 2 diabetes mellitus and inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5%) on diet and exercise. Methods and Materials: The double-blind treatment period included an 18-week, Phase A and a 26-week Phase B. During Phase A, 1250 patients (mean baseline HbA1c 9.9%) were randomized 1:1 to SITA/ MET 50/500 mg BID or MET 500 mg BID, each uptitrated over 4 weeks to SITA/MET 50/1000 mg BID or MET 1000 mg BID, respectively. In Phase A, additional antihyperglycemic agents (AHA) were allowed for patients not meeting progressively stricter glycemic criteria. In Phase B, patients continued their double-blind study medication but, unlike in Phase A, investigators received unmasked HbA1c and FPG results and were to add AHAs as appropriate to achieve glycemic goal per clinical practice. results: In this study, AHAs were initiated by the investigator half as often in the SITA/MET group compared with the MET group (8.8% vs. 16.7% of patients, respectively). Over the 44-week treatment period, HbA1c reductions from baseline were -2.3% (95% CI: -2.4, -2.1) for SITA/MET administered as initial therapy and -1.8% (95% CI: -1.9, -1.6) for MET alone administered as initial therapy. The betweengroup difference of -0.5% favored the SITA/MET group. Fifty percent more patients who initiated treatment with SITA/MET reached the HbA1c goal of <7.0% compared with patients initiating MET alone (46% vs. 30%; p<0.001). Reductions in FPG were also greater in the group initially treated with SITA/MET (-65.0 mg/dL) compared with the MET group (-53.4 mg/dL) (p<0.001). Similar reductions in body weight from baseline were observed in both treatment groups (-1.1 kg SITA/MET; -1.2 kg MET). The incidence of hypoglycemia was low and similar across treatment groups. However, the incidence of abdominal pain and diarrhea was significantly (p <0.05) lower in the SITA/MET group compared with the MET group. conclusions: After 44 weeks, a treatment strategy implementing early, aggressive initial combination therapy with SITA/MET in drugnaive patients provided superior glycemic improvement and a greater proportion of patients achieving HbA1c-goal with similar weight loss, and lower incidences of abdominal pain and diarrhea versus a strategy implementing initial therapy with MET monotherapy. Oral glucose-lowering therapies; Conflict of interest Stock ownership: T. Seck, D. Williams-Herman, E. Luo, M. Chen, L. Reigle, Y. Ling, W. Taggart, K. Kaufman, B. J. Goldstein Employee: T. Seck, D. Williams-Herman, E. Luo, M. Chen, L. Reigle, Y. Ling, W. Taggart, K. Kaufman, B. J. Goldstein Commercially-sponsored research: L. Olansky, C.A. Reasner