Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

GLP-1-based therapies for diabetes, obesity and beyond

Nature Reviews Drug Discovery volume 24, pages 631–650 (2025)Cite this article

Subjects

An Author Correction to this article was published on 28 May 2025

This article has been updated

Abstract

Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics. 

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline for GLP-1-based therapeutics.
Fig. 2: New classes of GLP-1-related therapies in clinical development.
Fig. 3: Actions and indications for GLP-1-based therapies.
Fig. 4: Direct and indirect mechanisms mediating the benefits of GLP-1-based therapies.

Similar content being viewed by others

Change history

References

  1. Drucker, D. J., Philippe, J., Mojsov, S., Chick, W. L. & Habener, J. F. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc. Natl Acad. Sci. USA 84, 3434–3438 (1987).

    Article  CAS  Google Scholar 

  2. Mojsov, S., Weir, G. C. & Habener, J. F. Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest. 79, 616–619 (1987).

    Article  CAS  Google Scholar 

  3. Holst, J. J., Orskov, C., Nielsen, O. V. & Schwartz, T. W. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 211, 169–174 (1987).

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Turton, M. D. et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72 (1996).

    Article  CAS  Google Scholar 

  6. Tang-Christensen, M. et al. Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am. J. Physiol. 271, R848–R856 (1996).

    CAS  Google Scholar 

  7. Scrocchi, L. A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996).

    Article  CAS  Google Scholar 

  8. Zander, M., Madsbad, S., Madsen, J. L. & Holst, J. J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824–830 (2002).

    Article  CAS  Google Scholar 

  9. Hammoud, R. & Drucker, D. J. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023).

    Article  CAS  Google Scholar 

  10. Drucker, D. J. et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372, 1240–1250 (2008).

    Article  CAS  Google Scholar 

  11. Fineman, M. S. et al. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes. Metab. 14, 546–554 (2012).

    Article  CAS  Google Scholar 

  12. Knudsen, L. B. Inventing liraglutide, a glucagon-like peptide-1 analogue, for the treatment of diabetes and obesity. ACS Pharmacol. Transl. Sci. 2, 468–484 (2019).

    Article  CAS  Google Scholar 

  13. Drucker, D. J. GLP-1 physiology informs the pharmacotherapy of obesity. Mol. Metab. 57, 101351 (2022).

    Article  CAS  Google Scholar 

  14. Drucker, D. J. Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity. Diabetes Care 47, 1873–1888 (2024).

    Article  CAS  Google Scholar 

  15. Drucker, D. J. The GLP-1 journey: from discovery science to therapeutic impact. J. Clin. Invest. 134, e175634 (2024).

    Article  CAS  Google Scholar 

  16. Drucker, D. J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).

    Article  CAS  Google Scholar 

  17. Jalleh, R. J., Jones, K. L., Nauck, M. & Horowitz, M. Accurate measurements of gastric emptying and gastrointestinal symptoms in the evaluation of glucagon-like peptide-1 receptor agonists. Ann. Intern. Med. 176, 1542–1543 (2023).

    Article  Google Scholar 

  18. Patel, H. et al. Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials. Diabetes Obes. Metab. 26, 473–481 (2024).

    Article  CAS  Google Scholar 

  19. Wharton, S. et al. Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes. Metab. 24, 94–105 (2022).

    Article  CAS  Google Scholar 

  20. Blundell, J. et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes. Metab. 19, 1242–1251 (2017).

    Article  CAS  Google Scholar 

  21. Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).

    Article  CAS  Google Scholar 

  22. Rosenstock, J. et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 36, 2945–2951 (2013).

    Article  CAS  Google Scholar 

  23. Buse, J. B. et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 381, 117–124 (2013).

    Article  CAS  Google Scholar 

  24. Sanford, M. Dulaglutide: first global approval. Drugs 74, 2097–2103 (2014).

    Article  CAS  Google Scholar 

  25. Dungan, K. M. et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 384, 1349–1357 (2014).

    Article  CAS  Google Scholar 

  26. Buse, J. B. et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 33, 1255–1261 (2010).

    Article  CAS  Google Scholar 

  27. Willard, F. S. et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI insight 5, e140532 (2020).

    Article  Google Scholar 

  28. 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  Google Scholar 

  29. Frias, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).

    Article  CAS  Google Scholar 

  30. Aroda, V. R. et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 5, 355–366 (2017).

    Article  CAS  Google Scholar 

  31. Frias, J. P. et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 9, 563–574 (2021).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. 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  Google Scholar 

  34. El, K. et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat. Metab. 5, 945–954 (2023).

    Article  CAS  Google Scholar 

  35. Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013).

    Article  Google Scholar 

  36. 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.e2 (2017).

    Article  CAS  Google Scholar 

  37. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).

    Article  CAS  Google Scholar 

  38. Garvey, W. T. et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 402, 613–626 (2023).

    Article  CAS  Google Scholar 

  39. Aronne, L. J. et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 331, 38–48 (2024).

    Article  CAS  Google Scholar 

  40. Wadden, T. A. et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat. Med. 29, 2909–2918 (2023).

    Article  CAS  Google Scholar 

  41. Wilding, J. P. H. et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes. Metab. 24, 1553–1564 (2022).

    Article  CAS  Google Scholar 

  42. German, J. et al. Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery. Nat. Med. https://doi.org/10.1038/s41591-025-03645-3 (2025).

  43. Kinzig, K. P., D’Alessio, D. A. & Seeley, R. J. The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J. Neurosci. 22, 10470–10476 (2002).

    Article  CAS  Google Scholar 

  44. Huang, K. P. et al. Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature 632, 585–593 (2024).

    Article  Google Scholar 

  45. Borner, T. et al. GIP receptor agonism attenuates GLP-1 receptor agonist-induced nausea and emesis in preclinical models. Diabetes 70, 2545–2553 (2021).

    Article  CAS  Google Scholar 

  46. Knop, F. K. et al. A long-acting glucose-dependent insulinotropic polypeptide receptor agonist improves the gastrointestinal tolerability of glucagon-like peptide-1 receptor agonist therapy. Diabetes Obes. Metab. 26, 5474–5478 (2024).

    Article  CAS  Google Scholar 

  47. Overgaard, R. V., Hertz, C. L., Ingwersen, S. H., Navarria, A. & Drucker, D. J. Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes. Cell Rep. Med. 2, 100387 (2021).

    Article  CAS  Google Scholar 

  48. He, L. et al. Association of glucagon-like peptide-1 receptor agonist use with risk of gallbladder and biliary diseases: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern. Med. 182, 513–519 (2022).

    Article  CAS  Google Scholar 

  49. Thompson, C. A. & Sturmer, T. Putting GLP-1 RAs and thyroid cancer in context: additional evidence and remaining doubts. Diabetes Care 46, 249–251 (2023).

    Article  CAS  Google Scholar 

  50. Drucker, D. J. Advances in oral peptide therapeutics. Nat. Rev. Drug. Discov. 19, 277–289 (2020).

    Article  CAS  Google Scholar 

  51. Haggag, A. Z. et al. Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist. Diabetes, Obes. Metab. https://doi.org/10.1111/dom.16047 (2024).

  52. Griffith, D. A. et al. A small-molecule oral agonist of the human glucagon-like peptide-1 receptor. J. Med. Chem. 65, 8208–8226 (2022).

    Article  CAS  Google Scholar 

  53. Sloop, K. W. et al. The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron. Sci. Transl. Med. 16, eadp5765 (2024).

    Article  CAS  Google Scholar 

  54. Saxena, A. R. et al. Efficacy and safety of oral small molecule glucagon-like peptide 1 receptor agonist danuglipron for glycemic control among patients with type 2 diabetes: a randomized clinical trial. JAMA Netw. Open. 6, e2314493 (2023).

    Article  Google Scholar 

  55. Saxena, A. R. et al. Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: a 12-week, randomized, placebo-controlled, phase 2 study comparing different dose-escalation schemes. Diabetes Obes. Metab. 25, 2805–2814 (2023).

    Article  CAS  Google Scholar 

  56. Fediuk, D. J. et al. Effect of renal impairment on the pharmacokinetics of a single oral dose of danuglipron in participants with type 2 diabetes. J. Clin. Pharmacol. 64, 449–460 (2024).

    Article  CAS  Google Scholar 

  57. Kawai, T. et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc. Natl Acad. Sci. USA 117, 29959–29967 (2020).

    Article  CAS  Google Scholar 

  58. Frias, J. P. et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet 402, 472–483 (2023).

    Article  CAS  Google Scholar 

  59. Wharton, S. et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2302392 (2023).

  60. Ma, X. et al. Effect of food consumption on the pharmacokinetics, safety, and tolerability of once-daily orally administered orforglipron (LY3502970), a non-peptide GLP-1 receptor agonist. Diabetes Ther. 15, 819–832 (2024).

    Article  CAS  Google Scholar 

  61. Guo, W. et al. Discovery of ecnoglutide—a novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog. Mol. Metab. 75, 101762 (2023).

    Article  CAS  Google Scholar 

  62. Zhu, D. et al. Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial. Nat. Commun. 15, 8408 (2024).

    Article  CAS  Google Scholar 

  63. Zhang, M. et al. GZR18, a novel long-acting GLP-1 analog, demonstrated positive in vitro and in vivo pharmacokinetic and pharmacodynamic characteristics in animal models. Eur. J. Pharmacol. 928, 175107 (2022).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  65. 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.e5 (2021).

    Article  CAS  Google Scholar 

  66. 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. 10, eaat3392 (2018).

    Article  CAS  Google Scholar 

  67. 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  Google Scholar 

  68. Sattar, N. et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat. Med. 28, 591–598 (2022).

    Article  CAS  Google Scholar 

  69. 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  Google Scholar 

  70. Garvey, W. T. et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat. Med. 28, 2083–2091 (2022).

    Article  CAS  Google Scholar 

  71. Gewitz, A. et al. Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): results from a first-in-human phase I study. Clin. Transl. Sci. 17, e13762 (2024).

    Article  CAS  Google Scholar 

  72. Styrkarsdottir, U. et al. Obesity variants in the GIPR gene are not associated with risk of fracture or bone mineral density. J. Clin. Endocrinol. Metab. 109, e1608–e1615 (2024).

    Article  CAS  Google Scholar 

  73. Yuan, J. et al. Molecular dynamics-guided optimization of BGM0504 enhances dual-target agonism for combating diabetes and obesity. Sci. Rep. 14, 16680 (2024).

    Article  CAS  Google Scholar 

  74. Fan, Y. et al. The safety, tolerability, pharmacokinetics and pharmacodynamics of an optimized dual GLP-1/GIP receptor agonist (BGM0504) in healthy volunteers: a dose-escalation phase I study. Diabetes Obes. Metab. 27, 2110–2119 (2025).

    Article  CAS  Google Scholar 

  75. Baggio, L. L. & Drucker, D. J. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol. Metab. 46, 101090 (2021).

    Article  CAS  Google Scholar 

  76. Campbell, J. E. et al. GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. Cell Metab. 35, 1519–1529 (2023).

    Article  CAS  Google Scholar 

  77. Kizilkaya, H. S. et al. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. Nat. Metab. 6, 1268–1281 (2024).

    Article  CAS  Google Scholar 

  78. Killion, E. A. et al. Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism. Nat. Commun. 11, 4981 (2020).

    Article  CAS  Google Scholar 

  79. Veniant, M. M. et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat. Metab. 6, 290–303 (2024).

    Article  CAS  Google Scholar 

  80. Jensen, M. H. et al. AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys. Mol. Metab. 88, 102006 (2024).

    Article  CAS  Google Scholar 

  81. Riddle, M. C. & Drucker, D. J. Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes care 29, 435–449 (2006).

    Article  CAS  Google Scholar 

  82. Ravussin, E. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity 17, 1736–1743 (2009).

    Article  CAS  Google Scholar 

  83. Kruse, T. et al. Development of cagrilintide, a long-acting amylin analogue. J. Med. Chem. 64, 11183–11194 (2021).

    Article  CAS  Google Scholar 

  84. Cao, J. et al. A structural basis for amylin receptor phenotype. Science 375, eabm9609 (2022).

    Article  CAS  Google Scholar 

  85. Lau, D. C. W. et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet 398, 2160–2172 (2021).

    Article  CAS  Google Scholar 

  86. Frias, J. P. et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 402, 720–730 (2023).

    Article  CAS  Google Scholar 

  87. Boland, M. L. et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2, 413–431 (2020).

    Article  CAS  Google Scholar 

  88. Romero-Gomez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).

    Article  CAS  Google Scholar 

  89. le Roux, C. W. et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 12, 162–173 (2024).

    Article  Google Scholar 

  90. Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).

    Article  CAS  Google Scholar 

  91. Rosenstock, J. et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet 402, 529–544 (2023).

    Article  CAS  Google Scholar 

  92. Friedrichsen, M. H. et al. Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: effects on weight loss and safety in adults with overweight or obesity. Mol. Metab. 78, 101801 (2023).

    Article  CAS  Google Scholar 

  93. Nestor, J. J., Parkes, D., Feigh, M., Suschak, J. J. & Harris, M. S. Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis. Sci. Rep. 12, 6666 (2022).

    Article  CAS  Google Scholar 

  94. Jiang, H. et al. A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes. Nat. Commun. 13, 3613 (2022).

    Article  CAS  Google Scholar 

  95. Ji, L. et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat. Commun. 14, 8289 (2023).

    Article  CAS  Google Scholar 

  96. Zimmermann, T. et al. BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Mol. Metab. 66, 101633 (2022).

    Article  CAS  Google Scholar 

  97. 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.e9 (2022).

    Article  CAS  Google Scholar 

  98. Finan, B. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).

    Article  CAS  Google Scholar 

  99. Quarta, C. et al. Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity. Cell Metab. 26, 620–632.e6 (2017).

    Article  CAS  Google Scholar 

  100. Petersen, J. et al. GLP-1-directed NMDA receptor antagonism for obesity treatment. Nature 629, 1133–1141 (2024).

    Article  CAS  Google Scholar 

  101. Drucker, D. J. Prevention of cardiorenal complications in people with type 2 diabetes and obesity. Cell Metab. 36, 338–353 (2024).

    Article  CAS  Google Scholar 

  102. Drucker, D. J. The benefits of GLP-1 drugs beyond obesity. Science 385, 258–260 (2024).

    Article  CAS  Google Scholar 

  103. Sattar, N. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 9, 653–662 (2021).

    Article  CAS  Google Scholar 

  104. Ussher, J. R. & Drucker, D. J. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat. Rev. Cardiol. 20, 463–474 (2023).

    Article  CAS  Google Scholar 

  105. Husain, M. et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 381, 841–851 (2019).

    Article  CAS  Google Scholar 

  106. Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).

    Article  CAS  Google Scholar 

  107. McGuire, D. K. et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2501006 (2025).

  108. Lincoff, A. M. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N. Engl. J. Med. 389, 2221–2232 (2023).

    Article  CAS  Google Scholar 

  109. Ryan, D. H. et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat. Med. 30, 2049–2057 (2024).

    Article  CAS  Google Scholar 

  110. Verma, S. et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT): outcomes by sex. J. Am. Coll. Cardiol. 84, 1678–1682 (2024).

    Article  CAS  Google Scholar 

  111. Kosiborod, M. N. et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. 389, 1069–1084 (2023).

    Article  CAS  Google Scholar 

  112. Kosiborod, M. N. et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N. Engl. J. Med. 390, 1394–1407 (2024).

    Article  CAS  Google Scholar 

  113. Kosiborod, M. N. et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet 404, 949–961 (2024).

    Article  CAS  Google Scholar 

  114. Nicholls, S. J. et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am. Heart J. 267, 1–11 (2024).

    Article  CAS  Google Scholar 

  115. Bonaca, M. P. et al. Design and baseline characteristics of the STRIDE trial: evaluating semaglutide in people with symptomatic peripheral artery disease and type 2 diabetes. Eur. Heart J. Cardiovasc. Pharmacother. 10, 728–737 (2025).

    Article  Google Scholar 

  116. Bonaca, M. P. et al. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled trial. Lancet https://doi.org/10.1016/S0140-6736(25)00509-4 (2025).

  117. Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).

    Article  CAS  Google Scholar 

  118. Gragnano, F., De Sio, V. & Calabro, P. FLOW trial stopped early due to evidence of renal protection with semaglutide. Eur. Heart J. Cardiovasc. Pharmacother. 10, 7–9 (2024).

    Article  Google Scholar 

  119. Mann, J. F. E. et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat. Med. 30, 2849–2856 (2024).

    Article  CAS  Google Scholar 

  120. Colhoun, H. M. et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat. Med. 30, 2058–2066 (2024).

    Article  CAS  Google Scholar 

  121. Bliddal, H. et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N. Engl. J. Med. 391, 1573–1583 (2024).

    Article  CAS  Google Scholar 

  122. Malhotra, A. et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N. Engl. J. Med. 391, 1193–1205 (2024).

    Article  CAS  Google Scholar 

  123. Harrison, S. A. et al. Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: a randomized, double-blind, placebo-controlled study. J. Hepatol. 82, 7–17 (2025).

    Article  CAS  Google Scholar 

  124. Loomba, R. et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med. 391, 299–310 (2024).

    Article  CAS  Google Scholar 

  125. Sanyal, A. J. et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N. Engl. J. Med. 391, 311–319 (2024).

    Article  CAS  Google Scholar 

  126. Newsome, P. N. et al. Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial. Aliment. Pharmacol. Ther. 60, 1525–1533 (2024).

    Article  CAS  Google Scholar 

  127. Sanyal, A. J. et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat. Med. 30, 2037–2048 (2024).

    Article  CAS  Google Scholar 

  128. Bruns Vi, N., Tressler, E. H., Vendruscolo, L. F., Leggio, L. & Farokhnia, M. IUPHAR review—glucagon-like peptide-1 (GLP-1) and substance use disorders: an emerging pharmacotherapeutic target. Pharmacol. Res. 207, 107312 (2024).

    Article  CAS  Google Scholar 

  129. Luthi, H. et al. Effect of dulaglutide in promoting abstinence during smoking cessation: 12-month follow-up of a single-centre, randomised, double-blind, placebo-controlled, parallel group trial. EClinicalMedicine 68, 102429 (2024).

    Article  Google Scholar 

  130. Klausen, M. K. et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight 7, e159863 (2022).

    Article  Google Scholar 

  131. Hendershot, C. S. et al. Once-weekly semaglutide in adults with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry 82, 395–405 (2025).

    Article  Google Scholar 

  132. Lahteenvuo, M. et al. Repurposing semaglutide and liraglutide for alcohol use disorder. JAMA Psychiatry 82, 94–98 (2025).

    Article  Google Scholar 

  133. Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat. Med. https://doi.org/10.1038/s41591-024-03412-w (2025).

  134. Gerstein, H. C. et al. The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol. 8, 106–114 (2020).

    Article  CAS  Google Scholar 

  135. Strain, W. D. et al. Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomized SUSTAIN 6 and PIONEER 6. Stroke 53, 2749–2757 (2022).

    Article  CAS  Google Scholar 

  136. Aviles-Olmos, I. et al. Exenatide and the treatment of patients with Parkinson’s disease. J. Clin. Invest. 123, 2730–2736 (2013).

    Article  CAS  Google Scholar 

  137. Athauda, D. et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 390, 1664–1675 (2017).

    Article  CAS  Google Scholar 

  138. Meissner, W. G. et al. Trial of lixisenatide in early Parkinson’s disease. N. Engl. J. Med. 390, 1176–1185 (2024).

    Article  CAS  Google Scholar 

  139. McGarry, A. et al. Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 23, 37–45 (2024).

    Article  CAS  Google Scholar 

  140. Vijiaratnam, N. et al. Exenatide once a week versus placebo as a potential disease-modifying treatment for people with Parkinson’s disease in the UK: a phase 3, multicentre, double-blind, parallel-group, randomised, placebo-controlled trial. Lancet 405, 627–636 (2025).

    Article  CAS  Google Scholar 

  141. Cukierman-Yaffe, T. et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 19, 582–590 (2020).

    Article  CAS  Google Scholar 

  142. Norgaard, C. H. et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement. (N. Y.) 8, e12268 (2022).

    Article  Google Scholar 

  143. Wang, W. et al. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 20, 8661–8672 (2024).

    Article  CAS  Google Scholar 

  144. Cummings, J. L. et al. EVOKE and EVOKE+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alzheimers Res. Ther. 17, 14 (2025).

    Article  CAS  Google Scholar 

  145. Lachin, J. M., Nathan, D. M. & Group, D. E. R. Understanding metabolic memory: the prolonged influence of glycemia during the Diabetes Control and Complications Trial (DCCT) on future risks of complications during the study of the epidemiology of diabetes interventions and complications (EDIC). Diabetes care 44, 2216–2224 (2021).

    Article  CAS  Google Scholar 

  146. Lund, P. K., Goodman, R. H., Dee, P. C. & Habener, J. F. Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem. Proc. Natl Acad. Sci. USA 79, 345–349 (1982).

    Article  CAS  Google Scholar 

  147. Bell, G. I., Sanchez-Pescador, R., Laybourn, P. J. & Najarian, R. C. Exon duplication and divergence in the human preproglucagon gene. Nature 304, 368–371 (1983).

    Article  CAS  Google Scholar 

  148. Bell, G. I., Santerre, R. F. & Mullenbach, G. T. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302, 716–718 (1983).

    Article  CAS  Google Scholar 

  149. Eng, J., Kleinman, W. A., Singh, L., Singh, G. & Raufman, J. P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267, 7402–7405 (1992).

    Article  CAS  Google Scholar 

  150. Davidson, M. B., Bate, G. & Kirkpatrick, P. Exenatide. Nat. Rev. Drug Discov. 4, 713–714 (2005).

    Article  CAS  Google Scholar 

  151. Drucker, D., Easley, C. & Kirkpatrick, P. Sitagliptin. Nat. Rev. Drug Discov. 6, 109–110 (2007).

    Article  CAS  Google Scholar 

  152. 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  Google Scholar 

  153. Valentine, V., Goldman, J. & Shubrook, J. H. Rationale for, initiation and titration of the basal insulin/GLP-1RA fixed-ratio combination products, IDegLira and IGlarLixi, for the management of type 2 diabetes. Diabetes Ther. 8, 739–752 (2017).

    Article  CAS  Google Scholar 

  154. Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).

    Article  CAS  Google Scholar 

  155. Syed, Y. Y. Tirzepatide: first approval. Drugs 82, 1213–1220 (2022).

    Article  CAS  Google Scholar 

  156. Abbasi, J. FDA green-lights tirzepatide, marketed as Zepbound, for chronic weight management. JAMA 330, 2143–2144 (2023).

    Article  Google Scholar 

  157. Packer, M. et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. 392, 427–437 (2025).

    Article  CAS  Google Scholar 

  158. McLean, B. A. et al. Revisiting the complexity of GLP-1 action from sites of synthesis to receptor activation. Endocr. Rev. 42, 101–132 (2021).

    Article  Google Scholar 

  159. Lv, D. et al. Neuroprotective effects of GLP-1 class drugs in Parkinson’s disease. Front. Neurol. 15, 1462240 (2024).

    Article  Google Scholar 

  160. Park, B. et al. GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage. Am. J. Physiol. Heart Circ. Physiol. 326, H1159–H1176 (2024).

    Article  CAS  Google Scholar 

  161. Wong, C. K. et al. Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell Metab. 34, 1514–1531.e7 (2022).

    Article  CAS  Google Scholar 

  162. Wong, C. K. et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab. 36, 130–143.e5 (2024).

    Article  CAS  Google Scholar 

  163. Benz, E. et al. Sarcopenia and sarcopenic obesity and mortality among older people. JAMA Netw. Open. 7, e243604 (2024).

    Article  Google Scholar 

  164. Tinsley, G. M. & Heymsfield, S. B. Fundamental body composition principles provide context for fat-free and skeletal muscle loss with GLP-1 RA treatments. J. Endocr. Soc. 8, bvae164 (2024).

    Article  CAS  Google Scholar 

  165. Conte, C., Hall, K. D. & Klein, S. Is weight loss-induced muscle mass loss clinically relevant? Jama 332, 9–10 (2024).

    Article  Google Scholar 

  166. Jensen, S. B. K. et al. Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial. EClinicalMedicine 69, 102475 (2024).

    Article  Google Scholar 

  167. Trivedi, A. et al. Evaluation of the pharmacokinetics and safety of AMG 986 tablet and capsule formulations in healthy adult subjects: a phase I, open-label, randomized study. Drugs R. D. 22, 147–154 (2022).

    Article  CAS  Google Scholar 

  168. Rodriguez, P. J. et al. Discontinuation and reinitiation of dual-labeled GLP-1 receptor agonists among us adults with overweight or obesity. JAMA Netw. Open. 8, e2457349 (2025).

    Article  Google Scholar 

  169. Locatelli, J. C. et al. Incretin-based weight loss pharmacotherapy: can resistance exercise optimize changes in body composition? Diabetes Care 47, 1718–1730 (2024).

    Article  CAS  Google Scholar 

  170. Linge, J., Birkenfeld, A .L. & Neeland, I. J. Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss? Circulation 150, 1216–1218 (2024).

    Article  Google Scholar 

  171. Halberg, I. B. et al. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol. 7, 179–188 (2019).

    Article  Google Scholar 

  172. Aroda, V. R. et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet 402, 693–704 (2023).

    Article  CAS  Google Scholar 

  173. Knop, F. K. et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 402, 705–719 (2023).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

D.J.D. is supported, in part, by a Banting and Best Diabetes Centre–Novo Nordisk Chair in Incretin Biology, a Sinai Health–Novo Nordisk Foundation Fund in Regulatory Peptides, CIHR grants 154321 and 19204 and Diabetes Canada-Canadian Cancer Society grant (OG-3- 24-5819-DD).

Author information

Authors and Affiliations

  1. Department of Medicine and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Daniel J. Drucker

Authors
  1. Daniel J. Drucker
    View author publications

    Search author on:PubMed Google Scholar

Contributions

D.J.D. conceptualized, researched, wrote and edited the manuscript.

Corresponding author

Correspondence to Daniel J. Drucker.

Ethics declarations

Competing interests

D.J.D. has received consulting fees from Amgen, AstraZeneca Inc., Insulet, Kallyope and Pfizer Inc. and speaking fees from Boehringer Ingelheim and Novo Nordisk Inc. Mount Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc., Novo Nordisk, Pfizer and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker laboratory.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks Timo Müller and the other anonymous reviewer/s for their contribution to the peer review of this manuscript.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ACCG-2671: https://ir.structuretx.com/static-files/ca239943-dfac-45e0-8ec8-6e4f3ba06e42

Amycretin: https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/cmd/2024/P5-Obesity-Care.pdf and https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=915251 and https://www.novonordisk.com/investors/capital-markets-day-2024.html

ASC30: https://www.ascletis.com/news_detail/192/id/1146.html

AZD5004: https://www.astrazeneca.com/content/dam/az/Investor_Relations/events/Weight-Management-Virtual-Event-IR-presentation.pdf

AZD6234: https://www.astrazeneca.com/content/dam/az/Investor_Relations/events/Weight-Management-Virtual-Event-IR-presentation.pdf

Bioglutide: https://www.biomedind.com/news-NA-931-world-obesity.html

Bofanglutide: https://onlinelibrary.wiley.com/doi/full/10.1002/oby.24194 and https://www.ganlee.com/detail/765.html

CT-868: https://assets.roche.com/f/176343/x/f513f69de2/pharma_day_20240930_final_online_v02.pdf

CT-996: https://assets.roche.com/f/176343/x/f513f69de2/pharma_day_20240930_final_online_v02.pdf and https://www.roche.com/media/releases/med-cor-2024-07-17

Danuglipron: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-advances-development-once-daily-formulation-oral-glp and https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist

GSBR-1290: https://ir.structuretx.com/static-files/775ca535-9bd3-455e-a41a-44dea273c90d

KAI-7535: https://www.kailera.com/wp-content/uploads/2024/09/95-LB_2023_ADA_2023_7535_LBA_poster_final.pdf

KAI-9531: https://www.kailera.com/wp-content/uploads/2024/09/LBA66_Hong-Chen_HRS9531-in-T2DM_HRS9531-202_EASD2024.pdf and https://www.kailera.com/wp-content/uploads/2024/09/HRS9531-201_ADA2024_Poster.pdf and https://www.kailera.com/press-release/jiangsu-hengrui-pharmaceuticals-and-kailera-therapeutics-report-positive-topline-data-from-8-mg-dose-of-phase-2-obesity-trial-of-glp-1-gip-receptor-dual-agonist-hrs9531/

LY3537021: https://diabetesjournals.org/diabetes/article/72/Supplement_1/56-OR/150974/56-OR-A-Long-Acting-Glucose-Dependent

MariTide: https://www.amgen.com/newsroom/press-releases/2024/11/amgen-announces-robust-weight-loss-with-maritide-in-people-living-with-obesity-or-overweight-at-52-weeks-in-a-phase-2-study

Mazdutide: https://www.prnewswire.com/news-releases/innovent-presents-the-results-of-the-first-phase-3-study-of-mazdutide-for-weight-management-at-the-adas-84th-scientific-sessions-302180995.html

MET-097: https://www.businesswire.com/news/home/20240924023447/en/Metsera-Reports-Highly-Competitive-Results-from-Ongoing-Trial-of-Novel-Potential-Once-Monthly-Injectable-GLP-1-Receptor-Agonist-MET-097 and https://investors.metsera.com/news-releases/news-release-details/metsera-announces-positive-topline-phase-2a-clinical-data-its

NPM-115: https://investors.vivani.com/investors/news-events/press-releases/detail/184/vivani-medical-announces-initiation-of-first-in-human

Oral VK2735: https://ir.vikingtherapeutics.com/2024-03-26-Viking-Therapeutics-Announces-Results-from-Phase-1-Clinical-Trial-of-Oral-Tablet-Formulation-of-Dual-GLP-1-GIP-Receptor-Agonist-VK2735

Orforglipron: https://investor.lilly.com/static-files/cdedba2e-c4a7-4047-9e61-4ac3b1e2cd73 and https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically

Pemvidutide: https://ir.altimmune.com/news-releases/news-release-details/altimmune-presents-data-phase-2-momentum-trial-pemvidutide and https://ir.altimmune.com/news-releases/news-release-details/altimmune-announces-successful-completion-end-phase-2-meeting

Petrelintide: https://www.zealandpharma.com/pipeline/petrelintide/

REDEFINE trials Cagri-Sema: https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/cmd/2024/P5-Obesity-Care.pdf and https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=915082 and https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/newsdetails.html?id=915294

Retatrutide: https://investor.lilly.com/static-files/cdedba2e-c4a7-4047-9e61-4ac3b1e2cd73

RGT-075: https://www.prnewswire.com/news-releases/regor-releases-phase-2a-topline-results-for-rgt-075-an-oral-once-daily-small-molecule-glp-1r-agonist-and-begins-phase-2b-study-in-the-us-for-the-treatment-of-obesity-302348153.html

SURMOUNT-5 trial: https://investor.lilly.com/news-releases/news-release-details/lillys-zepboundr-tirzepatide-superior-wegovyr-semaglutide-head

TERN-601: https://ir.ternspharma.com/news-releases/news-release-details/terns-pharmaceuticals-announces-positive-phase-1-clinical-trial

The ESSENCE trial: https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=171971

The SOUL Trial: https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=171480

VK2735: https://vikingtherapeutics.com/pipeline/metabolic-disease-program/vk2735/

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Drucker, D.J. GLP-1-based therapies for diabetes, obesity and beyond. Nat Rev Drug Discov 24, 631–650 (2025). https://doi.org/10.1038/s41573-025-01183-8

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41573-025-01183-8

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research