Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists

Abstract

Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily and lixisenatide once daily; and longer-acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP-1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these seven GLP-1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short-acting GLP-1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP-1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than liraglutide and dulaglutide. GLP-1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP-1RAs and delivery methods may further expand future treatment options.

Keywords: GLP-1 receptor agonist; albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; taspoglutide; type 2 diabetes.

© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Gastric‐emptying effects of short‐acting versus longer‐acting glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs). (A) Short‐acting GLP‐1RAs suppress gastric emptying, which prolongs the presence of food in the stomach and upper small intestine; the reduced transpyloric flow causes delayed intestinal glucose absorption and diminished postprandial insulin secretion. Short‐acting GLP‐1RAs may also directly suppress glucagon secretion. (B) Longer‐acting GLP‐1RAs do not significantly affect gastric motility, because of tachyphylaxis. Instead, longer‐acting GLP‐1RAs exert more of their effect via the pancreas, increasing insulin secretion, and inhibiting glucagon secretion via paracrine release of somatostatin. By targeting the central nervous system, both shorter‐ (A) and longer (B) ‐acting GLP‐1RAs increase satiety and also may induce nausea. Adapted from Meier 22. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology 2012;8(12):728–42, copyright 2012.

Figure 2

Reductions in glycated haemoglobin (HbA1c) in published phase III (and one phase II) randomized head‐to‐head studies of glucagon‐like peptide‐1 receptor agonists in type 2 diabetes. *Non‐inferiority criteria met. †Non‐inferiority criteria not met. ‡Phase II study. §A 1% change in HbA1c corresponds to a 10.93 mmol/mol change in The International Federation of Clinical Chemistry units.

Figure 3

Mean 24‐h postprandial plasma glucose profiles at baseline and day 28. Data are mean ± standard error of the mean. Adapted from Kapitza et al. 61.

Figure 4

Reductions in weight in published phase III (and one phase II) randomized head‐to‐head studies of glucagon‐like peptide‐1 receptor agonists in type 2 diabetes. *Difference was not significant at week 24, although it was significant at week 20. †Not stated if difference was significant. ‡Data shown at week 24; however, at week 52, weight loss was significantly lower in the taspoglutide 10 mg versus exenatide group (p = 0.01). §Phase II study.