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OBJECTIVE: To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267). RESULTS: Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by -1.1 +/- 0.1% (P < 0.001) and -1.3 +/- 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference

Objective: To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin.Research Design and Methods: We conducted a randomized, multicenter, double-masked, 2-year study of 428 drug-naïve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured.Results: In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively.Conclusions: Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy. [ABSTRACT FROM AUTHOR]

Objective: ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3-6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA 1c >10% [86 mmol/mol])., Research Design and Methods: This 39-week, open-label, phase 3 trial enrolled patients aged 18-80 years with HbA 1c >10% to ≤12% (86-108 mmol/mol) and BMI 25-45 kg/m 2 . Patients received ITCA 650 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. The primary end point was change in HbA 1c at week 39., Results: Sixty patients were enrolled. At baseline, mean HbA 1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA 1c of -2.8% (-30.3 mmol/mol; P < 0.001 vs. baseline) and in body weight of -1.2 kg ( P = 0.105), and 25% of patients achieved HbA 1c <7% (53 mmol/mol). A reduction in HbA 1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events., Conclusions: Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA 1c >10%., (© 2018 by the American Diabetes Association.)

Objective: ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes., Research Design and Methods: This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA 1c ) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA 1c at 39 weeks., Results: Least squares (LS) mean change from baseline HbA 1c was -1.1% [-12.2 mmol/mol] and -1.2% [-13.2 mmol/mol] for ITCA 650 40 and 60 μg/day, respectively ( P < 0.001 vs. placebo -0.1% [-1.3 mmol/mol]). In a prespecified analysis, greater HbA 1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% [-18.6 and -13.1 mmol/mol]). At week 39, HbA 1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively ( P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 μg/day, respectively ( P ≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient., Conclusions: ITCA 650 significantly reduced HbA 1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications., (© 2017 by the American Diabetes Association.)

Objective: To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes., Research Design and Methods: We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5 → 10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24., Results: HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering., Conclusions: ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 μg/day regimen was considered the best dose for further examination in phase 3.

Objective: This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT)., Research Design and Methods: A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Delta) area under the curve (AUC)(0-2 h) for these analytes were assessed by ANCOVA; glucose AUC(0-2 h) was the primary outcome variable., Results: Relative to placebo, vildagliptin increased GLP-1 (DeltaAUC, +6.0 +/- 1.2 pmol x l(-1) x h(-1), P < 0.001) and GIP (DeltaAUC, +46.8 +/- 5.4 pmol . l(-1) x h(-1), P < 0.001) and decreased glucagon (DeltaAUC, -3.0 +/- 1.0 pmol x l(-1) x h(-1), P = 0.003). Although postprandial insulin levels were unaffected (DeltaAUC, +20.8 +/- 35.7 pmol x l(-1) x h(-1), P = 0.561), prandial glucose excursions were reduced (DeltaAUC, -1.0 +/- 0.3 mmol x l(-1) x h(-1), P < 0.001), representing an approximately 30% decrease relative to placebo. Beta-cell function as assessed by the ISR AUC(0-2 h)/glucose AUC(0-2 h) was significantly increased (+6.4 +/- 2.0 pmol x min(-1) x m(-2) x mmol x l(-1), P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported., Conclusions: The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.