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GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus

Nature Reviews Endocrinology volume 8, pages 728–742 (2012)Cite this article

Subjects

Abstract

In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ∼2–3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.

Key Points

  • Native human GLP-1 normalizes hyperglycaemia in patients with type 2 diabetes mellitus, but the short in vivo half-life of this hormone limits its therapeutic application

  • A number of synthetic GLP-1 receptor agonists, with half-lives between 2–3 h and several days, have been developed for the long-term treatment of type 2 diabetes mellitus

  • Short-acting GLP-1 receptor agonists (such as exenatide and lixisenatide) predominantly lower postprandial glucose levels and insulin concentrations via retardation of gastric emptying

  • Long-acting GLP-1 receptor agonists (such as albiglutide, dulaglutide, exenatide long-acting release and liraglutide) predominantly lower blood glucose levels through stimulation of insulin secretion and reduction of glucagon levels

  • Adverse effects of GLP-1 receptor agonists include nausea, vomiting and diarrhoea, injection-site reactions, antibody formation and increased heart rate

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Figure 1: Reported pleiotropic effects of GLP-1 or GLP-1 receptor agonists on various tissues and organs under experimental conditions.
Figure 2: GLP-1 has differential dose-dependent effects on glucose and insulin levels in the postprandial and fasting states.
Figure 3: Gastric emptying is inhibited in a dose-dependent manner by GLP-1 administration.
Figure 4: Strategies employed to develop GLP-1 receptor agonists with prolonged in vivo half-lives.
Figure 5: Physiological role of GLP-1 and proposed working models for the actions of short-acting and long-acting GLP-1 receptor agonists in the postprandial state.

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  1. Division of Diabetology, St Josef-Hospital, Ruhr-University Bochum, Gudrunstraße 56, Bochum, 44791, Germany

    Juris J. Meier

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The author declares associations with the following companies: Astra-Zeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme, NovoNordisk and Sanofi-Aventis (advisory board membership; speakers bureau); Berlin-Chemie and Roche (speakers bureau); Boehringer-Ingelheim (advisory board membership); Eli Lilly and Novartis (speakers bureau; research support).

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Meier, J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 8, 728–742 (2012). https://doi.org/10.1038/nrendo.2012.140

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