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 Ϫ1.35 and Ϫ1.40% vs. Ϫ0.45%, respectively; P Ͻ 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 [Ϫ1.87 mmol/liter (Ϫ34 mg/dl) and Ϫ2.12 mmol/liter (Ϫ38 mg/dl) vs. Ϫ0.57 mmol/ liter (Ϫ10 mg/dl); P Ͻ 0.0001], improvements in homeostasis model assessment of ␤-cell function score (20.65 and 33.52 vs. Ϫ2.03; P Ͻ 0.0001), and significant weight loss (Ϫ0.64 kg and Ϫ1.04 kg vs. 0.59 kg; P Ͻ 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. (J Clin Endocrinol Metab 97: 2370 -2379, 2012)

To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double-blind, placebo-controlled, randomized two-period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 1/3 days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0-infinity, Cmax, tmax, and t 1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one-quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t 1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.

To investigate the influence of orlistat on the pharmacokinetics of selected concomitant medications (amitriptyline, atorvastatin, cyclosporine, losartan, metformin, phentermine, and sibutramine) at or within two-fold of therapeutic doses, open-label, multiple-dose (for 6 or 7 days), randomized, two-period (except for cyclosporine, for which a three-way crossover design was used) crossover studies were performed in healthy volunteers ages 18 to 65 years, with a body mass index between 18 and 30 kg/m2. At steady state, blood samples were taken for measuring plasma concentrations of interacting drugs and/or active metabolites. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. Treatments were compared for AUC0-24, Cmax, tmax, and t1/2 of selected concomitant medications (parent drugs and/or active metabolites). ANOVA was performed to assess the significance of the carry-over effect and provide the variance estimate for the 90% confidence intervals (CIs). With the exception of cyclosporine, whose absorption was reduced by approximately one-third, the results of the statistical analysis demonstrated equivalencefor the two primary parameters for all drugs studied: ratios of the log-transformed means for both AUC and Cmax were close to 1.00, with 90% CIs contained entirely within the bioequivalence region of 0.80 to 1.25; there were no clinically significant differences in t1/2 and tmax. There was a higher incidence of adverse events under treatment B (selective concomitant medications and orlistat) than under treatment A (selective concomitant medications alone); most of this difference was due to expected gastrointestinal adverse events known to occur with orlistat. Other adverse events were sporadic and unremarkable. All adverse events were either mild or moderate in intensity. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for cyclosporine, there was no effect of orlistat on the pharmacokinetics of selective concomitant medications when these drugs were taken concomitantly with orlistat.

Administration of orlistat had no significant effect on the balance of six selected minerals in adolescent obese patients.

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 ¼ 154) or placebo (n ¼ 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], À0.81% vs. À0.09%; P < 0.0001). Weight loss at week 24 was significantly greater with taspoglutide than placebo (LSMean, À3.16 vs. À1.85 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 (À23.59 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.