Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study

Abstract

Aims: The study objective was to investigate the safety and tolerability of up-titration to high doses of taspoglutide, a once-weekly human glucagon-like peptide-1 analogue, in subjects with Type 2 diabetes inadequately controlled on metformin alone.

Methods: In this double-blind phase II trial, subjects were randomized to placebo or taspoglutide (20 mg; three separate groups) administered once weekly by subcutaneous injection for 4 weeks. This was followed by dose maintenance at 20 mg, or titration to 30 mg (20/30) or 40 mg (20/40) once weekly with matched placebo for an additional 4 weeks. Subjects were monitored for adverse events (AEs) throughout the study and 4-week follow-up.

Results: One hundred and twenty-nine subjects were randomized and treated [mean age 57 years, mean baseline glycated haemoglobin (HbA(1c)), 7.9%]. The most frequently reported AEs were nausea and vomiting. The number of patients reporting gastrointestinal AEs did not increase following titration to higher doses of taspoglutide or when continuing the initial 20 mg regimen. Three subjects were withdrawn from the study as a result of gastrointestinal AEs (one before and two after titration to higher doses). Although not designed to investigate efficacy, improvement in glycaemic control was observed in all active arms of the study. The proportion of subjects achieving HbA(1c) < 7.0% after 8 weeks of treatment was 72, 53 and 70% in the 20/20-, 20/30- and 20/40-mg arms, respectively, vs. 19% for placebo.

Conclusions: Taspoglutide was safe, well tolerated at high doses and efficacious for lowering HbA(1c). Up-titration of dose was not associated with a worsening AE profile.

Trial registration: ClinicalTrials.gov NCT00460941.

Figures

FIGURE 1

Study design.

FIGURE 2

The number of subjects with nausea; mild/moderate (white) or severe (black) over the 8-week study period in the: A, placebo; B, 20/20 mg; C, 20/30 mg; and D, 20/40 mg once-weekly taspoglutide arms (safety population).

FIGURE 3

Plasma concentration (mean ± standard error) of taspoglutide in groups receiving subcutaneous administration of 20/20 mg once weekly (white circles), 20/30 mg once weekly (black circles) or 20/40 mg once weekly (black squares). All groups received 20 mg once weekly until week 3. The first doses of 30 or 40 mg once weekly were administered at week 4. Pre-dose (trough) concentrations are shown for weeks 0–7; the insets show post-dose concentrations for the first 10 h after treatment at weeks 0, 4, and 7.

FIGURE 5

Fasting plasma glucose (FPG) concentrations change from baseline (last observation carried forward) over time. Placebo (white triangles); 20/20 mg taspoglutide (black squares); 20/30 mg taspoglutide (white circles); 20/40 mg taspoglutide (black circles). Intent-to-treat population; least squares mean ± standard error.

FIGURE 4

Glycated haemoglobin (HbA1c) (%) (last observation carried forward) over time. Placebo (white); 20/20 mg taspoglutide (diagonal shade); 20/30 mg taspoglutide (checkered); 20/40 mg taspoglutide (black). Intent-to-treat population; least squares mean + standard error.