Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials.

BACKGROUND AND AIM: Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population. MATERIALS AND METHODS: The intent-to-treat (ITT) population contained 1379 patients (baseline mean ± standard deviation glycated hemoglobin [HbA1c] levels of 8.4% ± 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with ≥ 22 weeks of exposure) were evaluated. RESULTS: The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (-1.4% [-1.5% to -1.4%]), fasting blood glucose levels (-36 mg/dL [-38.4 mg/dL to -33.8 mg/dL]), and body weight (-2.5 kg [-2.8 kg to -2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, -2.8 mm Hg [-3.5 mm Hg to -2.1 mm Hg]; diastolic blood pressure, -0.8 mm Hg [-1.2 mm Hg to -0.4 mm Hg]), and fasting lipid levels (total cholesterol, -6.5 mg/dL [-8.2 mg/dL to -4.7 mg/dL]; low-density lipoprotein cholesterol, -3.9 mg/dL [5.3 mg/dL to -2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], -6% [-8% to -4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment-emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea. CONCLUSION: This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated. TRIAL REGISTRATION: www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects.

AIMS: Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc ) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc . METHODS: Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. RESULTS: Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml(-1) , 399 ± 11.9 pg ml(-1) and 627 ± 21.2 pg ml(-1) ). QTc P, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTc P (ΔΔQTc P) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml(-1) (ΔΔQTc P(avg) ) was -1.13 [-2.11, -0.15). No correlation was observed between ΔΔQTc P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. CONCLUSIONS: These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes.

CONTEXT: We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes. OBJECTIVE: The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety. DESIGN: This was a 24-wk, randomized, open-label, comparator-controlled study. SETTING: The study was conducted at 43 sites in the United States. PATIENTS: The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications. INTERVENTIONS: Interventions included ExQW 2 mg for 24 wk or ExBID 5 µg for 4 wk followed by ExBID 10 µg for 20 wk. MAIN OUTCOME MEASURE: The change in HbA1c from baseline to wk 24 was measured. RESULTS: At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred. CONCLUSIONS: Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.