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  • Perspective
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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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References

  1. Farooqi, I. S. & O’Rahilly, S. Monogenic obesity in humans. Annu. Rev. Med. 56, 443–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Flier, J. S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Friedman, J. M. A war on obesity, not the obese. Science 299, 856–858 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Medina-Gomez, G. & Vidal-Puig, A. Gateway to the metabolic syndrome. Nat. Med. 11, 602–603 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Tobias, D., Pan, A. & Hu, F. B. BMI and mortality among adults with incident type 2 diabetes. N. Engl. J. Med. 370, 1363–1364 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. World Health Organization. Obesity and overweight. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (2021).

  7. World Obese Federation. World Obesity Atlas 2022. https://www.worldobesity.org/resources/resource-library/world-obesity-atlas-2022 (2022).

  8. Maciejewski, M. L. et al. Bariatric surgery and long-term durability of weight loss. JAMA Surg. 151, 1046–1055 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Akalestou, E., Miras, A. D., Rutter, G. A. & le Roux, C. W. Mechanisms of weight loss after obesity surgery. Endocr. Rev. 43, 19–34 (2022).

    Article  PubMed  Google Scholar 

  10. Bennett, B. L., Lawson, J. L., Funaro, M. C. & Ivezaj, V. Examining weight bias before and/or after bariatric surgery: a systematic review. Obes. Rev. 23, e13500 (2022).

    Article  PubMed  Google Scholar 

  11. Albaugh, V. L. et al. Regulation of body weight: lessons learned from bariatric surgery. Mol. Metab. https://doi.org/10.1016/j.molmet.2022.101517 (2022).

  12. Nauck, M. A., Quast, D. R., Wefers, J. & Meier, J. J. GLP-1 receptor agonists in the treatment of type 2 diabetes—state-of-the-art. Mol. Metab. 46, 101102 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Sandoval, D. A. & D’Alessio, D. A. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513–548 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Drucker, D. J. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat. Clin. Pract. Endocrinol. Metab. 1, 22–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Lee, Y. H., Wang, M. Y., Yu, X. X. & Unger, R. H. Glucagon is the key factor in the development of diabetes. Diabetologia 59, 1372–1375 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Sloop, K. W. et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J. Clin. Invest. 113, 1571–1581 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kelly, R. P. et al. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes. Metab. 17, 414–422 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Nair, K. S. Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J. Clin. Endocrinol. Metab. 64, 896–901 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Salem, V. et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes. Metab. 18, 72–81 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Vons, C. et al. Regulation of fatty-acid metabolism by pancreatic hormones in cultured human hepatocytes. Hepatology 13, 1126–1130 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Svendsen, B. et al. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep. 25, 1127–1134 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Brown, J. C. & Dryburgh, J. R. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can. J. Biochem. 49, 867–872 (1971).

    Article  CAS  PubMed  Google Scholar 

  23. Turner, D. S. et al. The effect of the intestinal polypeptides, IRP and GIP, on insulin release and glucose tolerance in the baboon. Clin. Endocrinol. 3, 489–493 (1974).

    Article  CAS  Google Scholar 

  24. Calanna, S. et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care 36, 3346–3352 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Adriaenssens, A. E. et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30, 987–996 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, Q. et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS–GIPR signaling. Cell Metab. 33, 833–844 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Daousi, C. et al. Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes. Clin. Endocrinol. 71, 195–201 (2009).

    Article  CAS  Google Scholar 

  29. Asmar, M. et al. On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans. Am. J. Physiol. Endocrinol. Metab. 298, E614–621 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Miyawaki, K. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738–742 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. McClean, P. L. et al. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am. J. Physiol. Endocrinol. Metab. 293, E1746–1755 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Mroz, P. A. et al. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mol. Metab. 20, 51–62 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Killion, E. A. et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aat3392 (2018).

  34. Kim, S. J. et al. GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS ONE 7, e40156 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Drucker, D. J. & Brubaker, P. L. Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. Proc. Natl Acad. Sci. USA 86, 3953–3957 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Larsen, P. J., Tang-Christensen, M., Holst, J. J. & Orskov, C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77, 257–270 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Campbell, S. A. et al. Human islets contain a subpopulation of glucagon-like peptide-1 secreting alpha cells that is increased in type 2 diabetes. Mol. Metab. 39, 101014 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Muller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Flint, A., Raben, A., Astrup, A. & Holst, J. J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515–520 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Drucker, D. J., Habener, J. F. & Holst, J. J. Discovery, characterization, and clinical development of the glucagon-like peptides. J. Clin. Invest. 127, 4217–4227 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Pi-Sunyer, X. et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015).

    Article  PubMed  Google Scholar 

  42. Davies, M. J. et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 314, 687–699 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Pratley, R. et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 394, 39–50 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Davies, M. et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 397, 971–984 (2021).

    Article  CAS  PubMed  Google Scholar 

  46. Rubino, D. M. et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA 327, 138–150 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pratley, R. E. et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 6, 275–286 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Trujillo, J. M., Nuffer, W. & Smith, B. A. GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 12, 2042018821997320 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Baggio, L. L., Huang, Q., Brown, T. J. & Drucker, D. J. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 127, 546–558 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Cohen, M. A. et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J. Clin. Endocrinol. Metab. 88, 4696–4701 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Wynne, K. et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J. Obes. 30, 1729–1736 (2006).

    Article  CAS  Google Scholar 

  52. Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009). This article describes the beneficial action of a dual agonist in obese animal models.

    Article  CAS  PubMed  Google Scholar 

  53. Pocai, A. et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Simonsen, L. et al. Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: translational difficulties and pitfalls. PLoS ONE 17, e0264974 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Friedrichsen M, et al. Glucagon/GLP-1 receptor co-agonist NNC9204-1177 reduced body weight in adults with overweight or obesity but was associated with safety issues. Preprint at medRxiv https://doi.org/10.1101/2022.06.02.22275920 (2022).

  56. Muller, T. D., Bluher, M., Tschop, M. H. & DiMarchi, R. D. Anti-obesity drug discovery: advances and challenges. Nat. Rev. Drug Discov. 21, 201–223 (2022).

    Article  PubMed  Google Scholar 

  57. Clemmensen, C. et al. Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat. Rev. Endocrinol. 15, 90–104 (2019).

    Article  PubMed  Google Scholar 

  58. Ambery, P. et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 391, 2607–2618 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Asano, M. et al. Pharmacokinetics, safety, tolerability and efficacy of cotadutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, in phase 1 and 2 trials in overweight or obese participants of Asian descent with or without type 2 diabetes. Diabetes Obes. Metab. 23, 1859–1867 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Parker, V. E. R. et al. Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/clinem/dgz047 (2020).

  61. Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44, 1433–1442 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tillner, J. et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes. Metab. 21, 120–128 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Visentin, R. et al. Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes. Diabetes Obes. Metab. 22, 640–647 (2020).

    Article  CAS  PubMed  Google Scholar 

  64. Schiavon, M. et al. Improved postprandial glucose metabolism in type 2 diabetes by the dual glucagon-like peptide-1/glucagon receptor agonist SAR425899 in comparison with liraglutide. Diabetes Obes. Metab. 23, 1795–1805 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013). This was the first study testing the effects of an unimolecular dual incretin in humans.

    Article  PubMed  Google Scholar 

  66. Portron, A., Jadidi, S., Sarkar, N., DiMarchi, R. & Schmitt, C. Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects. Diabetes Obes. Metab. 19, 1446–1453 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Frias, J. P. et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 26, 343–352 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Coskun, T. et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol. Metab. 18, 3–14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Frias, J. P. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392, 2180–2193 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Nauck, M. A. & D’Alessio, D. A. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol. 21, 169 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rosenstock, J. et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 398, 143–155 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Frias, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021). This phase 3 trial shows the efficacy of tirzepatide managing type 2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  73. Ludvik, B. et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 398, 583–598 (2021).

    Article  CAS  PubMed  Google Scholar 

  74. Del Prato, S. et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 398, 1811–1824 (2021).

    Article  PubMed  Google Scholar 

  75. Dahl, D. et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 327, 534–545 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. https://doi.org/10.1016/S2213-8587(22)00243-1 (2022).

    Article  PubMed  Google Scholar 

  77. Gastaldelli, A. et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 10, 393–406 (2022).

    Article  CAS  PubMed  Google Scholar 

  78. Frias, J. P. et al. Efficacy and safety of an expanded dulaglutide dose range: a phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin. Diabetes Obes. Metab. 21, 2048–2057 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Inagaki, N., Takeuchi, M., Oura, T., Imaoka, T. & Seino, Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 623–633 (2022).

    Article  CAS  PubMed  Google Scholar 

  80. Kadowaki, T., Chin, R., Ozeki, A., Imaoka, T. & Ogawa, Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 10, 634–644 (2022).

    Article  CAS  PubMed  Google Scholar 

  81. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022). This phase 3 trial shows the efficacy of tirzepatide inducing weight loss.

    Article  CAS  PubMed  Google Scholar 

  82. Sorli, C. et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 5, 251–260 (2017). This work designed and described the action of triagonists in animal models of obesity.

    Article  CAS  PubMed  Google Scholar 

  83. Schlogl, H. et al. Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care 36, 1933–1940 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Jall, S. et al. Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice. Mol. Metab. 6, 440–446 (2017). This study tested a triple agonist in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Knerr, P. J. et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol. Metab. 63, 101533 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bossart, M. et al. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell Metab. 34, 59–74 (2022).

    Article  CAS  PubMed  Google Scholar 

  88. Zhao, S. et al. A GLP-1/glucagon (GCG)/CCK2 receptors triagonist provides new therapy for obesity and diabetes. Br. J. Pharmacol. 179, 4360–4377 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 34, 1234–1247 (2022).

    Article  CAS  PubMed  Google Scholar 

  90. Urva, S. et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet 400, 1869–1881 (2022).

    Article  CAS  PubMed  Google Scholar 

  91. Kim, J. A. et al. Neuroprotective effects of HM15211, a novel long-acting GLP-1/glucagon/GIP triple agonist in the MPTP Parkinson’s disease mouse model. American Diabetes Association’s 77th Scientific Sessions (2017).

  92. Choi, I. Y. et al. Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP-1/glucagon/GIP triple-agonist (HM15211). American Diabetes Association’s 77th Scientific Sessions (2017).

  93. Choi, J. D. et al. A double-blinded, placebo controlled, single ascending dose study for safety, tolerability, pharmacokinetics and pharmacodynamics after subcutaneous administration of novel long-acting GLP-1/GIP/glucagon triple agonist (HM15211) in healthy obese subjects. Diabetes 68, 982-P (2019).

  94. Wilson, J. M. et al. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: a post hoc analysis. Diabetes Obes. Metab. 24, 148–153 (2022).

    Article  CAS  PubMed  Google Scholar 

  95. Hartman, M. L. et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of non-alcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care 43, 1352–1355 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kelly, A. S. et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N. Engl. J. Med. 382, 2117–2128 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Weghuber, D. et al. Once-weekly semaglutide in adolescents with obesity. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2208601 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Tamborlane, W. V. et al. Liraglutide in children and adolescents with type 2 diabetes. N. Engl. J. Med. 381, 637–646 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Arslanian, S. A. et al. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes. N. Engl. J. Med. 387, 433–443 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Lingvay, I. et al. A 26-week randomized controlled trial of semaglutide once daily versus liraglutide and placebo in patients with type 2 diabetes suboptimally controlled on diet and exercise with or without metformin. Diabetes Care 41, 1926–1937 (2018).

    Article  CAS  PubMed  Google Scholar 

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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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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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