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Gut hormone co-agonists for the treatment of obesity: from bench to bedside

Nature Metabolism volume 5, pages 933–944 (2023)Cite this article

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Abstract

The discovery and development of so-called gut hormone co-agonists as a new class of drugs for the treatment of diabetes and obesity is considered a transformative breakthrough in the field. Combining action profiles of multiple gastrointestinal hormones within a single molecule, these novel therapeutics achieve synergistic metabolic benefits. The first such compound, reported in 2009, was based on balanced co-agonism at glucagon and glucagon-like peptide-1 (GLP-1) receptors. Today, several classes of gut hormone co-agonists are in development and advancing through clinical trials, including dual GLP-1–glucose-dependent insulinotropic polypeptide (GIP) co-agonists (first described in 2013), and triple GIP–GLP-1–glucagon co-agonists (initially designed in 2015). The GLP-1–GIP co-agonist tirzepatide was approved in 2022 by the US Food and Drug Administration for the treatment of type 2 diabetes, providing superior HbA1c reductions compared to basal insulin or selective GLP-1 receptor agonists. Tirzepatide also achieved unprecedented weight loss of up to 22.5%—similar to results achieved with some types of bariatric surgery—in non-diabetic individuals with obesity. In this Perspective, we summarize the discovery, development, mechanisms of action and clinical efficacy of the different types of gut hormone co-agonists, and discuss potential challenges, limitations and future developments.

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Fig. 1: Summary of the main actions and target tissues of glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and glucagon.
Fig. 2: Main actions and target tissues for gut hormone co-agonists.

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Authors and Affiliations

  1. CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain

    Ruben Nogueiras

  2. Galicia Agency of Innovation, Xunta de Galicia, Santiago de Compostela, Spain

    Ruben Nogueiras

  3. Diabetes, Endocrinology and Metabolism Section, Medical Department I, St. Josef-Hospital, Katholisches Klinikum Bochum, Ruhr University of Bochum, Bochum, Germany

    Michael A. Nauck

  4. Helmholtz Zentrum München, Neuherberg, Germany

    Matthias H. Tschöp

  5. Division of Metabolic Diseases, Department of Medicine, Technische Universität München, München, Germany

    Matthias H. Tschöp

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  1. Ruben Nogueiras
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  2. Michael A. Nauck
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  3. Matthias H. Tschöp
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Conceptualization, writing, editing and revising were a joint effort by R.N., M.A.N. and M.H.T.

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Correspondence to Matthias H. Tschöp.

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R.N. declares no competing interests. M.A.N. has been a member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma and Structure Therapeutics (ShouTi, Gasherbrum). M.A.N. has received grant support from Merck, Sharp & Dohme. M.A.N. has also served on the speakers’ bureau of Eli Lilly & Co., Menarini/Berlin Chemie, Merck, Sharp & Dohme, Medscape, Medical Learning Institute and NovoNordisk. M.H.T. is a member of the scientific advisory board of ERX Pharmaceuticals. M.H.T. was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019. M.H.T. attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. M.H.T. received funding for his research projects from Novo Nordisk (2016–2020) and Sanofi-Aventis (2012–2019). M.H.T. was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S. p.A. (2016) and Bayer Pharma AG Berlin (2016). As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018), and since 2018, as CEO of Helmholtz Zentrum München, M.H.T. has been responsible for collaborations with a multitude of companies and institutions worldwide. In this capacity, M.H.T. discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industries and academia worldwide, including, but not limited to, pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen and others. In this role, M.H.T. was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes-related patent portfolios of Helmholtz Zentrum München as, for example, WO/2016/188,932 A2 or WO/2017/194,499 A1.

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Nature Metabolism thanks Karen Jones and the other, anonymous, reviewer for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

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Nogueiras, R., Nauck, M.A. & Tschöp, M.H. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab 5, 933–944 (2023). https://doi.org/10.1038/s42255-023-00812-z

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