Exenatide once weekly improved 24-hour glucose control and reduced glycaemic variability in metformin-treated participants with type 2 diabetes: a randomized, placebo-controlled trial

Abstract

Aim: To assess the effects of once-weekly exenatide on 24-hour glucose control and variability.

Materials and methods: This double-blind, placebo-controlled trial randomized metformin-treated adults with type 2 diabetes to once-weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM-measured 24-hour mean glucose level.

Results: In the once-weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention-to-treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once-weekly exenatide significantly (p < 0.001) reduced 24-hour mean glucose level versus placebo (week 4, -1.44 vs -0.29 mmol/L; week 10, -1.71 vs -0.17 mmol/L), with consistent control throughout the week. Once-weekly exenatide significantly reduced FPG and 2-hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, -1.65 vs -0.11 mmol/L; PPG, -1.79 vs -0.11 mmol/L) and week 10 (FPG, -2.32 vs -0.28 mmol/L; PPG, -2.46 vs -0.33 mmol/L). At week 10, once-weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; -0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (-0.35 vs 0.04 mmol/L). By week 10, once-weekly exenatide-treated participants spent more time in euglycaemia (once-weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection-site nodule (once-weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%).

Conclusions: In metformin-treated participants with type 2 diabetes, once-weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24-hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

Keywords: 24-hour glucose profile; continuous glucose monitoring; exenatide once weekly; glycaemic variability; type 2 diabetes.

Conflict of interest statement

J. P. F. is an investigator and a consultant for AstraZeneca. J. A. R. and S. Z. are employees of AstraZeneca. E. K. is a speaker for AstraZeneca and Janssen, and an investigator for Antares, Asahi Kasei, AstraZeneca, Bristol‐Myers Squibb, Catabasis, and Novo Nordisk. R. Z. is an employee of Medpace. P. S. is a consultant for AstraZeneca. S.N. has nothing to disclose.

© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

A, Least‐squares (LS) mean ± s.e. change from baseline in 24‐hour mean glucose at week 4 and week 10. Modified intention‐to‐treat population [once‐weekly exenatide + metformin (MET), n = 60; placebo + MET, n = 56]. B, Comparison of change from baseline in the mean 24‐hour glucose profile at week 10, as shown by MADz. Fourier coefficients for individual participant continuous glucose monitoring data from each 24‐hour period were derived using 24 hours as the longest cycle and aggregated for each protocol period.14 The data were then aggregated across the whole treatment group for that period, resulting in a defined group function for each period by treatment from which changes from baseline and treatment difference functions were derived. To control for multiplicity, a bootstrap was performed to define the 95% confidence bounds of the MADz by time point. Solid blue line = once‐weekly exenatide + MET; solid green line = placebo + MET; solid black line = treatment difference (once‐weekly exenatide – placebo) of the change from baseline at each time point; a significant difference between treatments is designated when this black line is outside the range of the 95% confidence interval (red lines). *p < 0.001, treatment difference (once‐weekly exenatide – placebo) in LS mean changes.

Figure 2

A, Least‐squares (LS) mean ± s.e. change from baseline in fasting plasma glucose (FPG). B, Mean ± s.e. Postprandial glucose (PPG) concentrations after the standardized breakfast meal. Black squares = once‐weekly exenatide + metformin (MET); white circles = placebo + MET. C, LS mean ± s.e. change from baseline in 2‐hour mean PPG. D, LS mean ± s.e. change from baseline in mean amplitude of glucose excursions (MAGE). E, Mean proportions of time spent in glycaemic ranges. Modified intention‐to‐treat population (once‐weekly exenatide + MET, n = 60; placebo + MET, n = 56). *p < 0.001, treatment difference (once‐weekly exenatide – placebo) in LS mean changes.