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GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management

Nature Metabolism (2024)Cite this article

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Abstract

The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15–25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy.

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Fig. 1: The structure of proglucagon and its processing in the pancreas and in the gut and brain.
Fig. 2: Structures of the currently approved GLP-1RAs.
Fig. 3: Secretion, degradation and neural transmission of the actions of endogenous GLP-1.

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  1. Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Jens Juul Holst

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Throughout the development of GLP-1RAs, J.J.H. has had numerous contacts with the pharmaceutical industry and has been a member of advisory boards and given paid lectures. Most contacts have been with Merck and Novo Nordisk. Currently, J.J.H. is a member of advisory boards for Novo Nordisk and gives occasional paid lectures for this and other companies. J.J.H. is a cofounder and a member of the board of Antag Therapeutics. J.J.H. does not have any economical engagements with any other company.

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Holst, J.J. GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab (2024). https://doi.org/10.1038/s42255-024-01113-9

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