Eight weeks of treatment with long-acting GLP-1 analog taspoglutide improves postprandial insulin secretion and sensitivity in metformin-treated patients with type 2 diabetes.

OBJECTIVE: Loss of pancreatic function is pivotal to the deterioration of fasting and postprandial glycemic control in type 2 diabetes (T2D). We evaluated the effects of a long-acting, human glucagon-like peptide-1 analog, taspoglutide, added to metformin, on pancreatic function and peripheral insulin sensitivity. MATERIALS/METHODS: We studied 80 T2D patients inadequately controlled [glycosylated hemoglobin (HbA1c), 7.0%-9.5%] receiving stable metformin for ≥12weeks. They were a subset of participants to a phase 2 trial that received also a 240-min mixed-meal tolerance test (MTT) at baseline and study end. Patients received once weekly (QW) sc injection of taspoglutide 5, 10, or 20mg (n=21, 19, or 19), or placebo (n=21), plus metformin, for 8weeks. We measured postprandial plasma glucose (PPG) and insulin profiles, insulin secretion rate (ISR), oral glucose insulin sensitivity (OGIS) index; ß-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios, and insulin sensitivity-to-insulin resistance (or disposition) index. RESULTS: After 8 weeks of treatment, taspoglutide 5, 10, and 20mg QW doses vs. placebo improved mean PPG0-240 min (relative change from baseline: -22.1%, -25.9%, and -22.9% vs. -8.1%; P<0.005) and mean postprandial ISR0-240 min (+14%, +18%, and +23% vs. +1%; P<0.005 vs dose). Taspoglutide at 20mg QW dose also resulted in improvements from baseline in OGIS, ß-cell glucose sensitivity, glucagon/glucose and insulin/glucagon ratios and the disposition index during the MTT. CONCLUSION: Taspoglutide QW significantly improved pancreatic function in patients with T2D treated with metformin.

Effects of taspoglutide on glycemic control and body weight in obese patients with type 2 diabetes (T-emerge 7 study).

OBJECTIVE: Therapies that lower blood glucose and provide weight loss may provide meaningful benefits for obese patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy of taspoglutide compared with placebo on glycemic control and weight in obese patients with T2DM inadequately controlled with metformin monotherapy. DESIGN AND METHODS: In a 24-week, randomized, double-blind, placebo-controlled, multicenter trial, obese adults with T2DM were randomized (1:1) to weekly subcutaneous taspoglutide 20 mg (10 mg for first 4 weeks) (n = 154) or placebo (n = 151) for 24 weeks. Efficacy measures included hemoglobin A1c (HbA1c) levels, body weight, percentage of patients achieving HbA1c ≤6.5 and ≤7.0%, and fasting plasma glucose (FPG). Adverse events (AEs) were assessed. RESULTS: Mean baseline HbA1c was 7.55% and mean baseline BMI was 36.7 kg/m(2) . HbA1c reductions from baseline were significantly greater with taspoglutide than placebo (least square mean [LSMean], -0.81% vs. -0.09%; P < 0.0001). Weight loss at week 24 was significantly greater with taspoglutide than placebo (LSMean, -3.16 vs. -1.85 kg; P < 0.01). In the taspoglutide and placebo groups, target HbA1c levels (≤6.5%) were achieved by 49 and 16% of patients, respectively, while 72 and 36% achieved HbA1c levels ≤7%. Decreases in FPG were significantly greater with taspoglutide than placebo (-23.59 vs. 0.09 mg/dl; P < 0.0001). Nausea and vomiting were the most common AEs associated with taspoglutide, but tended to be transient and generally mild or moderate. CONCLUSIONS: In obese patients with T2DM, once-weekly taspoglutide provided the combined benefits of glycemic control and weight loss.

The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial.

OBJECTIVE: Taspoglutide is a long-acting glucagon-like peptide 1 receptor agonist developed for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was compared with twice-daily exenatide. RESEARCH DESIGN AND METHODS: Overweight adults with inadequately controlled type 2 diabetes on metformin ± a thiazolidinedione were randomized to subcutaneous taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 µg twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in HbA(1c) after 24 weeks. RESULTS: Mean baseline HbA(1c) was 8.1%. Both doses of taspoglutide reduced HbA(1c) significantly more than exenatide (taspoglutide 10 mg: -1.24% [SE 0.09], difference -0.26, 95% CI -0.37 to -0.15, P < 0.0001; taspoglutide 20 mg: -1.31% [0.08], difference -0.33, -0.44 to -0.22, P < 0.0001; exenatide: -0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, -1.6 kg; taspoglutide 20 mg, -2.3 kg) as did exenatide (-2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA(1c) and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients. CONCLUSIONS: Once-weekly taspoglutide demonstrated greater glycemic control than twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions.

Efficacy and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-emerge 4 trial).

INTRODUCTION: The efficacy and safety of taspoglutide, a long-acting human glucagon-like peptide-1 analog, were compared with sitagliptin or placebo, as adjunct to metformin, in patients with inadequately controlled type 2 diabetes. METHODS: In this randomized, double-blind, double-dummy, parallel-group trial, patients were randomized to taspoglutide 10 mg once weekly (QW), 20 mg QW, 100 mg sitagliptin once daily (QD), or placebo for 24 weeks, followed by 28-week short-term and 104-week long-term extension periods. The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) after 24 weeks. RESULTS: In this study, 666 patients (baseline HbA(1c), 7.96% [SD, 0.87]; fasting plasma glucose, 9.61 mmol/L [2.56]; body weight, 92.4 kg [19.3]) were randomized to taspoglutide 10 mg QW (n = 190), 20 mg QW (n = 198), 100 mg sitagliptin QD (n = 185), or placebo (n = 93) for 24 weeks. After 24 weeks, least squares mean (SE) HbA(1c) reductions were greater with taspoglutide 10 mg (-1.23% [0.06]) and 20 mg (-1.30% [0.06]) versus sitagliptin (-0.89% [0.06]) or placebo (-0.10% [0.08]). Mean treatment differences with taspoglutide 10 mg and 20 mg were -0.34 (95% confidence intervals [CI]: -0.49, -0.19) and -0.41 (-0.56, -0.26) versus sitagliptin; and -1.13 (-1.31, -0.95) and -1.20 (-1.38, -1.02) versus placebo. Weight loss was greater with taspoglutide 10 mg (-1.8 kg [0.3]) and 20 mg (-2.6 kg [0.3]) than sitagliptin (-0.9 kg [0.3]) or placebo (-0.5 kg [0.4]). Effects on HbA(1c) and weight loss continued through 52 weeks of treatment. No cases of severe hypoglycemia occurred with any active treatment. Gastrointestinal adverse events, and allergic and injection-site reactions were higher in the taspoglutide groups, causing higher discontinuation rates. Anti-taspoglutide antibodies were confirmed in 46% of patients. CONCLUSION: Taspoglutide demonstrated better efficacy on glycemic control and weight loss than sitagliptin, but a high incidence of adverse events led to high discontinuation rates. The safety profile of taspoglutide in this trial was similar to other trials in the clinical program, and led to the discontinuation of dosing.

Efficacy and safety of taspoglutide in patients with type 2 diabetes inadequately controlled with metformin plus pioglitazone over 24 weeks: T-Emerge 3 trial.

OBJECTIVE: This study assessed the efficacy and safety of once-weekly taspoglutide in patients with type 2 diabetes mellitus inadequately controlled with metformin plus pioglitazone compared with placebo. DESIGN: In this randomized, double-blind, parallel-group, placebo-controlled trial (T-emerge 3), 326 patients were randomized to once-weekly sc injections of taspoglutide 10 mg, taspoglutide 20 mg (10 mg for first 4 wk), or placebo. The primary endpoint was change from baseline in glycosylated hemoglobin (HbA1c) at 24 wk. RESULTS: A significant reduction in HbA1c was observed with taspoglutide 10 mg and 20 mg vs. placebo (least square mean -1.35 and -1.40% vs. -0.45%, respectively; P < 0.0001). A greater proportion of taspoglutide-treated patients reached HbA1c target 7% or less (69.8 and 76.1% vs. 35.1%). With taspoglutide 10 mg and 20 mg vs. placebo, significantly greater reductions in fasting plasma glucose [-1.87 mmol/liter (-34 mg/dl) and -2.12 mmol/liter (-38 mg/dl) vs. -0.57 mmol/liter (-10 mg/dl); P < 0.0001], improvements in homeostasis model assessment of ß-cell function score (20.65 and 33.52 vs. -2.03; P < 0.0001), and significant weight loss (-0.64 kg and -1.04 kg vs. 0.59 kg; P < 0.01) were observed. Adverse events were generally mild to moderate; the most frequent adverse events with taspoglutide 10 mg, taspoglutide 20 mg, and placebo were nausea (35, 44, and 10%), vomiting (21, 24, and 2%), and injection site reactions (24, 24, and 5%). CONCLUSIONS: Taspoglutide provided glycemic control with weight loss as add-on therapy to metformin plus pioglitazone for inadequately controlled type 2 diabetes mellitus.

Efficacy and safety of taspoglutide monotherapy in drug-naive type 2 diabetic patients after 24 weeks of treatment: results of a randomized, double-blind, placebo-controlled phase 3 study (T-emerge 1).

OBJECTIVE: To evaluate the efficacy and safety of taspoglutide monotherapy in drug-naive patients with type 2 diabetes inadequately controlled. RESEARCH DESIGN AND METHODS: In this 24-week double-blind, placebo-controlled, multicenter trial, 373 patients with type 2 diabetes naive to antihyperglycemic medication were randomized to weekly subcutaneous taspoglutide 10 or 20 mg or placebo. RESULTS: HbA(1c) reductions from baseline were greater with taspoglutide 10 and 20 mg than placebo (least squares mean [SE] changes: -1.01% [0.07], -1.18% [0.06], and -0.09% [0.07], respectively; both P < 0.0001 vs. placebo). Decreases in bodyweight were greater with taspoglutide 10 mg (-1.45 kg [0.32]) and with 20 mg (-2.25 kg [0.30]) than placebo (-1.23 kg [0.31]; P = 0.61 and P = 0.02 for taspoglutide 10 and 20 mg vs. placebo, respectively). Gastrointestinal adverse events and injection site reactions were more common with taspoglutide than placebo. CONCLUSIONS: In drug-naive patients, once-weekly taspoglutide improved glycemic control, reduced body weight, and was generally well tolerated.

Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study.

CONTEXT: Glucokinase plays a key role in glucose homeostasis. Glucokinase activators can lower glucose levels in both animal and human type 2 diabetes, but their mechanism of action has never been explored in humans. OBJECTIVE: The objective of the study was to investigate the effects of the glucokinase activator piragliatin (RO4389620) on ß-cell function and glucose fluxes in both fasting and fed (oral glucose tolerance test) states in patients with type 2 diabetes. DESIGN: This was a phase Ib randomized, double-blind, placebo-controlled crossover trial of two (25 and 100 mg) doses of piragliatin. SETTING: This study was conducted at a clinical research center. PATIENTS: Patients included 15 volunteer ambulatory patients with mild type 2 diabetes. INTERVENTIONS: Interventions included three 10-h (-300' to +300') studies, with an interval of at least 14 d. Administration of a single dose of placebo or piragliatin 25 mg or piragliatin 100 mg at -120'. Oral glucose tolerance test (at 0') with dual (iv and oral routes) tracer dilution technique was conducted. MAIN OUTCOME MEASURES: The primary measure was plasma glucose concentration. The secondary measure was model assessed ß-cell function and tracer-determined glucose fluxes. RESULTS: Piragliatin caused a dose-dependent reduction of glucose levels in both fasting and fed states (P < 0.01). In the fasting state, piragliatin caused a dose-dependent increase in ß-cell function, a fall in endogenous glucose output, and a rise in glucose use (all P < 0.01). In the fed state, the primary effects of piragliatin were on ß-cell function (P < 0.01). CONCLUSIONS: The glucokinase activator piragliatin has an acute glucose-lowering action in patients with mild type 2 diabetes, mainly mediated through a generalized enhancement of ß-cell function and through fasting restricted changes in glucose turnover.

Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS: Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7-9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline. RESULTS: Significantly greater (P < 0.0001) reductions in A1C from a mean +/- SD baseline of 7.9 +/- 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: -1.0 +/- 0.1% (5 mg once weekly), -1.2 +/- 0.1% (10 mg once weekly), -1.2 +/- 0.1% (20 mg once weekly), -0.9 +/- 0.1% (10 mg Q2W), and -1.0 +/- 0.1% (20 mg Q2W) vs. -0.2 +/- 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (-2.1 +/- 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (-2.8 +/- 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (-1.9 +/- 0.3 kg, P = 0.0083) group than with placebo (-0.8 +/- 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low. CONCLUSIONS: Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.