Incretin-based therapies: advancements, challenges, and future directions in type 2 diabetes management

References

1. Labarre, JF. Sur les possibilites d’un traitement du diabete par I’incretine. 1932. Available from: https://api.semanticscholar.org/CorpusID:87922449.Search in Google Scholar

2. Moore, B, Edie, ES, Abram, JH. On the treatment of Diabetus mellitus by acid extract of duodenal mucous membrane. Biochem J [Internet] 1906;1:28–38. https://doi.org/10.1042/bj0010028.Search in Google Scholar PubMed PubMed Central

3. Bayliss, WM, Starling, EH. The mechanism of pancreatic secretion. J Physiol [Internet] 1902;28:325–53. https://doi.org/10.1113/jphysiol.1902.sp000920. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1113/jphysiol.1902.sp000920.Search in Google Scholar PubMed PubMed Central

4. D’Alessio, DA, Marks, V. Glucagon as the first incretin: objects (in the rearview mirror) are closer than they appear. Diabetes [Internet] 2023;72:1739–40. https://doi.org/10.2337/dbi26-0026. Available from: https://diabetesjournals.org/diabetes/article-pdf/72/12/1739/738520/dbi260026.pdf.Search in Google Scholar PubMed

5. Hofmeister, F. About the science of the effects of salts: about the water withdrawing effect of the salts. Arch Exp Pathol Pharmacol [Internet] 1888;24:247–60. Available from https://cir.nii.ac.jp/crid/1573950400557907840.10.1007/BF01918191Search in Google Scholar

6. Elrick, H, Stimmler, L, Hlad, JRCJ, Arai, Y. Plasma insulin response to oral and intravenous glucose Administration1. J Clin Endocrinol Metab [Internet] 1964;24:1076–82. https://doi.org/10.1210/jcem-24-10-1076.Search in Google Scholar PubMed

7. Mcintyre, N, Holdsworth, CD, Turner, DS. New interpretation of oral glucose tolerance. The Lancet [Internet] 1964;284:20–1. https://doi.org/10.1016/s0140-6736(64)90011-x. Available from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(64)90011-X/fulltext.Search in Google Scholar PubMed

8. Unger, RH, Ketterer, H, Eisentraut, AM. Distribution of immunoassayable glucagon in gastrointestinal tissues. Metabolism [Internet] 1966;15:865–7. https://doi.org/10.1016/0026-0495(66)90156-9. Available from: https://www.metabolismjournal.com/article/0026-0495(66)90156-9/abstract.Search in Google Scholar PubMed

9. Brown, JC, Dryburgh, JR. A gastric inhibitory polypeptide II: the complete amino acid sequence. Can J Biochem [Internet] 1971;49:867–72. https://doi.org/10.1139/o71-122. Available from: https://cdnsciencepub.com/doi/10.1139/o71-122.Search in Google Scholar PubMed

10. Brown, JC, Mutt, V, Pederson, RA. Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol [Internet] 1970;209:57–64. https://doi.org/10.1113/jphysiol.1970.sp009155. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1113/jphysiol.1970.sp009155.Search in Google Scholar PubMed PubMed Central

11. Dupre, J, Ross, SA, Watson, D, Brown, JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in Man.1. J Clin Endocrinol Metab [Internet] 1973;37:826–8. https://doi.org/10.1210/jcem-37-5-826. Available from: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem-37-5-826.Search in Google Scholar PubMed

12. Bell, GI, Santerre, RF, Mullenbach, GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature [Internet] 1983;302:716–8. https://doi.org/10.1038/302716a0. Available from https://www.nature.com/articles/302716a0.Search in Google Scholar PubMed

13. Luo, J, Feldman, R, Callaway Kim, K, Rothenberger, S, Korytkowski, M, Hernandez, I, et al.. Evaluation of out-of-pocket costs and treatment intensification with an SGLT2 inhibitor or GLP-1 RA in patients with type 2 diabetes and cardiovascular disease. JAMA Netw Open [Internet] 2023;6:e2317886. https://doi.org/10.1001/jamanetworkopen.2023.17886. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805937.Search in Google Scholar PubMed PubMed Central

14. Imarhia, FI, Malveaux, JN. Evaluation of glycemic control and cost savings associated with liraglutide dose reduction at a veterans affairs hospital. Fed Pract [Internet] 2020;37:447–51. Available from: https://cdn.mdedge.com/files/s3fs-public/issues/articles/fdp03710447.pdf.10.12788/fp.0057Search in Google Scholar PubMed PubMed Central

15. Docimo, S, Shah, J, Warren, G, Ganam, S, Sujka, J, DuCoin, C. A cost comparison of GLP-1 receptor agonists and bariatric surgery: what is the break even point? Surg Endosc 2024;38:6560–5. https://doi.org/10.1007/s00464-024-11191-1.Search in Google Scholar PubMed

16. GLP-1 RAs Storage & Stability. Scientific exchange [internet]. [cited 2025 Jan 19]. Available from: https://www.scientific-exchange.com/product-information/storage-and-stability/glp-1-ras.html.Search in Google Scholar

17. Polonsky, WH, Arora, R, Faurby, M, Fernandes, J, Liebl, A. Higher rates of persistence and adherence in patients with type 2 diabetes initiating once-weekly vs daily injectable glucagon-like peptide-1 receptor agonists in US clinical practice (STAY study). Diabetes Ther [Internet] 2022;13:175–87. Available from: https://doi.org/10.1007/s13300-021-01189-6.Search in Google Scholar PubMed PubMed Central

18. Horii, T, Masudo, C, Takayanagi, Y, Oikawa, Y, Shimada, A, Mihara, K. Adherence and treatment discontinuation of oral semaglutide and once‐weekly semaglutide injection at 12 month follow‐up: Japanese real‐world data. J Diabetes Investig. 2024;15:1578–84. https://doi.org/10.1111/jdi.14265.Search in Google Scholar PubMed PubMed Central

19. Parks, M, Rosebraugh, C. Weighing risks and benefits of liraglutide – the FDA’s review of a new antidiabetic therapy. New Engl J Med [Internet] 2010;362:774–7. https://doi.org/10.1056/nejmp1001578. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMp1001578.Search in Google Scholar PubMed

20. Kelly, CA, Sipos, JA. Approach to the patient with thyroid nodules: considering GLP-1 receptor agonists. J Clin Endocrinol Metab [Internet] 2024:dgae722. Available from: https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgae722/7821115.10.1210/clinem/dgae722Search in Google Scholar PubMed

21. McConnell, EE, Solleveld, HA, Swenberg, JA, Boorman, GA. Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. JNCI: J Nat Cancer Inst [Internet] 1986;76:283–9. Available from: https://doi.org/10.1093/jnci/76.2.283.Search in Google Scholar

22. Pasternak, B, Wintzell, V, Hviid, A, Eliasson, B, Gudbjörnsdottir, S, Jonasson, C, et al.. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: scandinavian cohort study. BMJ 2024:e078225. https://doi.org/10.1136/bmj-2023-078225.Search in Google Scholar PubMed PubMed Central

23. Popular Glp 1 Agonists List. Drug prices and medication information – GoodRx [Internet]. [cited 2025 Jan 19]. Available from: https://www.goodrx.com/classes/glp-1-agonists.Search in Google Scholar

24. Popular Gliptins List. Drug prices and medication information – GoodRx [Internet]. [cited 2025 Jan 19]. Available from: https://www.goodrx.com/classes/gliptins.Search in Google Scholar

25. Fadini, GP, Bonora, BM, Ghiani, M, Anichini, R, Melchionda, E, Fattor, B, et al.. Oral or injectable semaglutide for the management of type 2 diabetes in routine care: a multicentre observational study comparing matched cohorts. Diabetes Obes Metab 2024;26:2390–400. https://doi.org/10.1111/dom.15554.Search in Google Scholar PubMed

26. Wharton, S, Blevins, T, Connery, L, Rosenstock, J, Raha, S, Liu, R, et al.. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. New Engl Med [Internet] 2023;389:877–88. https://doi.org/10.1056/nejmoa2302392. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2302392.Search in Google Scholar PubMed

27. Saxena, AR, Frias, JP, Brown, LS, Gorman, DN, Vasas, S, Tsamandouras, N, 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. JAMA Netw Open 2023;6:e2314493. https://doi.org/10.1001/jamanetworkopen.2023.14493.Search in Google Scholar PubMed PubMed Central

28. Kamrul-Hasan, ABM, Dutta, D, Nagendra, L, Bhattacharya, S, Singla, R, Kalra, S. Efficacy and safety of albiglutide, a once-weekly glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes: a systematic review and meta-analysis. Medicine 2024;103:e38568. https://doi.org/10.1097/md.0000000000038568.Search in Google Scholar PubMed PubMed Central

29. Rosenstock, J, Balas, B, Charbonnel, B, Bolli, GB, Boldrin, M, Ratner, R, et al.. The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial. Diabetes Care 2013;36:498–504. https://doi.org/10.2337/dc12-0709.Search in Google Scholar PubMed PubMed Central

30. Fisman, EZ, Tenenbaum, A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol [Internet] 2015;14:129. https://doi.org/10.1186/s12933-015-0294-0. Available from: http://www.cardiab.com/content/14/1/129.Search in Google Scholar PubMed PubMed Central

31. Ding, Y, Zhang, H, Zhu, X, Wu, M, Yang, L, Yao, Z, et al.. Safety, tolerability, pharmacodynamics, and pharmacokinetics of CJC-1134-PC in healthy Chinese subjects and type-2 diabetic subjects. Expert Opin Investig Drugs [Internet] 2021;30:1241–8. https://doi.org/10.1080/13543784.2021.2008906. Available from: https://www.tandfonline.com/doi/full/10.1080/13543784.2021.2008906.Search in Google Scholar PubMed

32. Sánchez-Garrido, MA, Brandt, SJ, Clemmensen, C, Müller, TD, DiMarchi, RD, Tschöp, MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia [Internet] 2017;60:1851–61. https://doi.org/10.1007/s00125-017-4354-8. Available from: http://link.springer.com/10.1007/s00125-017-4354-8.Search in Google Scholar PubMed PubMed Central

33. Jones, RM, Leonard, JN, Buzard, DJ, Lehmann, J. GPR119 agonists for the treatment of type 2 diabetes. Expert Opin Ther Pat [Internet] 2009;19:1339–59. https://doi.org/10.1517/13543770903153878. Available from: http://www.tandfonline.com/doi/full/10.1517/13543770903153878.Search in Google Scholar PubMed

34. Nunez, DJ, Bush, MA, Collins, DA, McMullen, SL, Gillmor, D, Apseloff, G, et al.. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS One 2014;9:e92494. https://doi.org/10.1371/journal.pone.0092494.Search in Google Scholar PubMed PubMed Central

35. Vildagliptin: liver failure and elevated liver function tests: 2 case reports. React Wkly [Internet]. 2019;1771:304. Available from: http://link.springer.com/10.1007/s40278-019-68123-1.10.1007/s40278-019-68123-1Search in Google Scholar

36. Asakura, M, Karaki, F, Fujii, H, Atsuda, K, Itoh, T, Fujiwara, R. Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells. Sci Rep [Internet] 2016;6:35633. https://doi.org/10.1038/srep35633. Available from: https://www.nature.com/articles/srep35633.Search in Google Scholar PubMed PubMed Central

37. Hryciw, DH, Patten, RK, Rodgers, RJ, Proietto, J, Hutchinson, DS, McAinch, AJ. GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates. Expert Opin Investig Drugs [Internet] 2024;33:183–90. https://doi.org/10.1080/13543784.2024.2321271. Available from: https://www.tandfonline.com/doi/full/10.1080/13543784.2024.2321271.Search in Google Scholar PubMed

38. Nauck, MA, Meier, JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab [Internet] 2018;20:5–21. https://doi.org/10.1111/dom.13129. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29364588.Search in Google Scholar PubMed

39. Holst, JJ. The physiology of glucagon-like peptide 1. Physiol Rev [Internet] 2007;87:1409–39. https://doi.org/10.1152/physrev.00034.2006. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17928588.Search in Google Scholar PubMed

40. Andersen, A, Lund, A, Knop, FK, Vilsbøll, T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol [Internet] 2018;14:390–403. https://doi.org/10.1038/s41574-018-0016-2. Available from: https://www.nature.com/articles/s41574-018-0016-2.Search in Google Scholar PubMed

41. Holst, JJ, Deacon, CF, Vilsbøll, T, Krarup, T, Madsbad, S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med [Internet] 2008;14:161–8. https://doi.org/10.1016/j.molmed.2008.01.003. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18353723.Search in Google Scholar PubMed

42. Drucker, DJ, Nauck, MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet [Internet] 2006;368:1696–705. https://doi.org/10.1016/s0140-6736(06)69705-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17098089.Search in Google Scholar

43. Mulvihill, EE, Drucker, DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev [Internet] 2014;35:992–1019. https://doi.org/10.1210/er.2014-1035. Available from: https://academic.oup.com/edrv/article-pdf/35/6/992/8865205/edrv0992.pdf.Search in Google Scholar PubMed PubMed Central

44. Holst, JJ, Knop, FK, Vilsbøll, T, Krarup, T, Madsbad, S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care [Internet] 2011;34:S251–7. https://doi.org/10.2337/dc11-s227. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632188/.Search in Google Scholar PubMed PubMed Central

45. Campbell, JE, Drucker, DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab [Internet] 2013;17:819–37. https://doi.org/10.1016/j.cmet.2013.04.008. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23684623.Search in Google Scholar PubMed

46. Drucker, DJ. The biology of incretin hormones. Cell Metab [Internet] 2006;3:153–65. https://doi.org/10.1016/j.cmet.2006.01.004. Available from: https://www.cell.com/cell-metabolism/abstract/S1550-4131(06)00028-3.Search in Google Scholar PubMed

47. Nauck, MA, Müller, TD. Incretin hormones and type 2 diabetes. Diabetologia [Internet] 2023;66:1780–95. https://doi.org/10.1007/s00125-023-05956-x. Available from: https://link.springer.com/content/pdf/10.1007/s00125-023-05956-x.pdf.Search in Google Scholar PubMed PubMed Central

48. Drucker, DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab [Internet] 2018;27:740–56. https://doi.org/10.1016/j.cmet.2018.03.001. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29617641.Search in Google Scholar PubMed

49. Baggio, LL, Drucker, DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab [Internet] 2021;46:101090. https://doi.org/10.1016/j.molmet.2020.101090. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8085566/pdf/main.pdf.Search in Google Scholar PubMed PubMed Central

50. Flint, A, Raben, A, Astrup, A, Holst, JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest [Internet] 1998;101:515–20. https://doi.org/10.1172/jci990. Available from: https://www.jci.org/articles/view/990/files/pdf.Search in Google Scholar

51. Holst, JJ, Deacon, CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes [Internet] 1998;47:1663–70. https://doi.org/10.2337/diabetes.47.11.1663. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9792533.Search in Google Scholar PubMed

52. Patel, D, Smith, A. Patient initiation and maintenance of GLP-1 RAs for treatment of obesity. Expert Rev Clin Pharmacol [Internet] 2021;14:1193–204. https://doi.org/10.1080/17512433.2021.1947796. Available from: https://www.tandfonline.com/doi/full/10.1080/17512433.2021.1947796.Search in Google Scholar PubMed

53. Spezani, R, Marinho, TS, Reis, TS, Aguila, MB, Mandarim-de-Lacerda, CA. Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice. Peptides (NY) [Internet] 2024;173:171138. https://doi.org/10.1016/j.peptides.2023.171138. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0196978123002036.Search in Google Scholar PubMed

54. Yang, GR, Zhao, XL, Jin, F, Shi, LH, Yang, JK. Pharmacokinetics and pharmacodynamics of a polyethylene glycol (PEG)-conjugated GLP-receptor agonist once weekly in Chinese patients with type 2 diabetes. J Clin Pharmacol [Internet] 2015;55:152–8. https://doi.org/10.1002/jcph.386. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jcph.386.Search in Google Scholar PubMed

55. Le, R, Nguyen, MT, Allahwala, MA, Psaltis, JP, Marathe, CS, Marathe, JA, et al.. Cardiovascular protective properties of GLP-1 receptor agonists: more than just diabetic and weight loss drugs. J Clin Med 2024;13:4674. https://doi.org/10.3390/jcm13164674.Search in Google Scholar PubMed PubMed Central

56. Marso, SP, Daniels, GH, Brown-Frandsen, K, Kristensen, P, Mann, JFE, Nauck, MA, et al.. Liraglutide and cardiovascular outcomes in type 2 diabetes. New Engl J Med [Internet] 2016;375:311–22. https://doi.org/10.1056/nejmoa1603827. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1603827.Search in Google Scholar PubMed PubMed Central

57. Mannucci, E. Results of the LEADER study: current evidence and perspectives in research. G Ital Cardiol 2016;17. https://doi.org/10.1714/2616.26913.Search in Google Scholar PubMed

58. Marso, SP, Bain, SC, Consoli, A, Eliaschewitz, FG, Jódar, E, Leiter, LA, et al.. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New Engl J Med [Internet] 2016;375:1834–44. https://doi.org/10.1056/nejmoa1607141. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1607141.Search in Google Scholar PubMed

59. Sposito, AC, Berwanger, O, De Carvalho, LSF, Saraiva, JFK. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol [Internet] 2018;17:157. https://doi.org/10.1186/s12933-018-0800-2. Available from: https://cardiab.biomedcentral.com/articles/10.1186/s12933-018-0800-2.Search in Google Scholar PubMed PubMed Central

60. Holman, RR, Bethel, MA, Mentz, RJ, Thompson, VP, Lokhnygina, Y, Buse, JB, et al.. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. New Engl J Med [Internet] 2017;377:1228–39. https://doi.org/10.1056/nejmoa1612917. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1612917.Search in Google Scholar PubMed PubMed Central

61. Jonik, S, Marchel, M, Grabowski, M, Opolski, G, Mazurek, T. Gastrointestinal incretins – glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) beyond pleiotropic physiological effects are involved in pathophysiology of atherosclerosis and coronary artery disease—state of the art. Biology (Basel) [Internet] 2022;11:288. https://doi.org/10.3390/biology11020288. Available from: https://www.mdpi.com/2079-7737/11/2/288.Search in Google Scholar PubMed PubMed Central

62. Samms, RJ, Christe, ME, Collins, KA, Pirro, V, Droz, BA, Holland, AK, et al.. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest [Internet] 2021;131:e146353. https://doi.org/10.1172/jci146353. Available from: http://www.jci.org/articles/view/146353/files/pdf.Search in Google Scholar

63. Everard, A, Cani, PD. Gut microbiota and GLP-1. Rev Endocr Metab Disord [Internet] 2014;15:189–96. https://doi.org/10.1007/s11154-014-9288-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24789701.Search in Google Scholar PubMed

64. Fansa, S, Acosta, A. The melanocortin-4 receptor pathway and the emergence of precision medicine in obesity management. Diabetes Obes Metab [Internet] 2024;26:46–63. https://doi.org/10.1111/dom.15555. Available from: https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15555.Search in Google Scholar PubMed PubMed Central

65. Lavalle, CA, Masson, W, Lobo, M, Barbagelata, L, Forte, E, Corral, P, et al.. Ethnic/racial and geographic disparities on major cardiovascular events in glucagon like peptide-1 receptor agonists trials: a meta-analysis. Curr Probl Cardiol 2023;48:101940. https://doi.org/10.1016/j.cpcardiol.2023.101940.Search in Google Scholar PubMed

66. Brown, E, Wilding, JPH, Barber, TM, Alam, U, Cuthbertson, DJ. Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities. Obes Rev 2019;20:816–28. https://doi.org/10.1111/obr.12841.Search in Google Scholar PubMed

67. Karagiannis, T, Bekiari, E, Tsapas, A. Socioeconomic aspects of incretin-based therapy. Diabetologia [Internet] 2023;66:1859–68. https://doi.org/10.1007/s00125-023-05962-z. Available from: https://link.springer.com/10.1007/s00125-023-05962-z.Search in Google Scholar PubMed PubMed Central

68. Mazzei, KA, Trippett, AN, Hedrick, TD, Wen, S. Analysis of patient-specific factors contributing to effectiveness of glucagon-like peptide-1 receptor agonists. J Am Pharm Assoc [Internet] 2020;60:937–42. https://doi.org/10.1016/j.japh.2020.06.023. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1544319120303137.Search in Google Scholar PubMed PubMed Central

69. Stoian, AP, Sachinidis, A, Stoica, RA, Nikolic, D, Patti, AM, Rizvi, AA. The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes. Metabolism [Internet] 2020;109:154295. https://doi.org/10.1016/j.metabol.2020.154295. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0026049520301591.Search in Google Scholar PubMed

70. Siriyotha, S, Anothaisintawee, T, Looareesuwan, P, Nimitphong, H, McKay, GJ, Attia, J, et al.. Effectiveness of glucagon-like peptide-1 receptor agonists for reduction of body mass index and blood glucose control in patients with type 2 diabetes mellitus and obesity: a retrospective cohort study and difference-in-difference analysis. BMJ Open 2024;14:e086424. https://doi.org/10.1136/bmjopen-2024-086424.Search in Google Scholar PubMed PubMed Central

71. Xie, Y, Bowe, B, Xian, H, Loux, T, McGill, JB, Al-Aly, Z. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records. Lancet Diabetes Endocrinol 2023;11:644–56. https://doi.org/10.1016/s2213-8587(23)00171-7.Search in Google Scholar

72. Nisal, K, Kela, R, Khunti, K, Davies, MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Med [Internet] 2012;10:152. https://doi.org/10.1186/1741-7015-10-152. Available from: https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-152.Search in Google Scholar PubMed PubMed Central

73. Coleman, CH. Cost-effectiveness comes to America: the promise and perils of cost-effectiveness analysis in medication coverage decisions. Ga State Univ Law Rev [Internet] 2021;38:811. Available from: https://heinonline.org/HOL/Page?handle=hein.journals/gslr38&id=843&div=&collection=.Search in Google Scholar

74. Morton, JI, Marquina, C, Shaw, JE, Liew, D, Polkinghorne, KR, Ademi, Z, et al.. Projecting the incidence and costs of major cardiovascular and kidney complications of type 2 diabetes with widespread SGLT2i and GLP-1 RA use: a cost-effectiveness analysis. Diabetologia 2023;66:642–56. https://doi.org/10.1007/s00125-022-05832-0.Search in Google Scholar PubMed PubMed Central

75. Drugs.com – prescription drug information [internet]. Drugs.com. Available from: https://www.drugs.com/.Search in Google Scholar

76. Frías, JP, Davies, MJ, Rosenstock, J, Pérez Manghi, FC, Fernández Landó, L, Bergman, BK, et al.. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New Engl J Med [Internet] 2021;385:503–15. https://doi.org/10.1056/nejmoa2107519. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2107519.Search in Google Scholar

77. Innovent’s Phase III obesity treatment trial meets all endpoints [Internet]. [cited 2025 Jan 21]. Available from: https://www.clinicaltrialsarena.com/news/innovent-obesity-trial-endpoints/.Search in Google Scholar

78. Chen, K, Shen, Z, Gu, W, Lyu, Z, Qi, X, Mu, Y, et al.. Prevalence of obesity and associated complications in China: a cross-sectional, real-world study in 15.8 million adults. Diabetes Obes Metabol 2023;25:3390–9. https://doi.org/10.1111/dom.15238.Search in Google Scholar PubMed

79. Head-to-head superiority over dulaglutide: innovent’s phase 3 clinical trial DREAMS-2 of mazdutide in Chinese patients with type 2 diabetes were orally presented at EASD 2024 [internet]. [cited 2025 Jan 21]. Available from: https://www.prnewswire.com/news-releases/head-to-head-superiority-over-dulaglutide-innovents-phase-3-clinical-trial-dreams-2-of-mazdutide-in-chinese-patients-with-type-2-diabetes-were-orally-presented-at-easd-2024-302244860.html.Search in Google Scholar

80. Lilly’s phase 2 retatrutide results published in the New England Journal of Medicine show the investigational molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight | Eli Lilly and Company [Internet]. [cited 2025 Jan 21]. Available from: https://investor.lilly.com/news-releases/news-release-details/lillys-phase-2-retatrutide-results-published-new-england-journal.Search in Google Scholar

81. Muzurović, EM, Volčanšek, Š, Tomšić, KZ, Janež, A, Mikhailidis, DP, Rizzo, M, et al.. Glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists in the treatment of obesity/metabolic syndrome, prediabetes/diabetes and non-alcoholic fatty liver disease—current evidence. 10742484221146372. J Cardiovasc Pharmacol Ther [Internet] 2022;27. Available from: https://journals.sagepub.com/doi/10.1177/10742484221146371.10.1177/10742484221146371Search in Google Scholar PubMed

82. Kajani, S, Laker, RC, Ratkova, E, Will, S, Rhodes, CJ. Hepatic glucagon action: beyond glucose mobilization. Physiol Rev [Internet] 2024;104:1021–60. https://doi.org/10.1152/physrev.00028.2023. Available from: https://journals.physiology.org/doi/10.1152/physrev.00028.2023.Search in Google Scholar PubMed

83. Fan, MY, Ru, J, Wang, S, Chen, Y, Zhang, XX, Li, GL, et al.. Research progress of traditional Chinese medicine in the treatment of endocrine metabolic diseases in 2023. Tradit Med Res [Internet] 2024;9:72. https://doi.org/10.53388/tmr20240412001. Available from: https://www.tmrjournals.com/article.html?J_num=1&a_id=3234.Search in Google Scholar

84. Popoviciu, MS, Păduraru, L, Yahya, G, Metwally, K, Cavalu, S. Emerging role of GLP-1 agonists in obesity: a comprehensive review of randomised controlled trials. Int J Mol Sci [Internet] 2023;24:10449. https://doi.org/10.3390/ijms241310449. Available from: https://www.mdpi.com/1422-0067/24/13/10449.Search in Google Scholar PubMed PubMed Central

85. Liu, QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne) [Internet] 2024;15:1431292. https://doi.org/10.3389/fendo.2024.1431292. Available from: https://www.frontiersin.org/articles/10.3389/fendo.2024.1431292/full.Search in Google Scholar PubMed PubMed Central

86. Zarei, M, Sahebi Vaighan, N, Farjoo, MH, Talebi, S, Zarei, M. Incretin-based therapy: a new horizon in diabetes management. J Diabetes Metab Disord [Internet] 2024;23:1665–86. https://doi.org/10.1007/s40200-024-01479-3. Available from: https://link.springer.com/10.1007/s40200-024-01479-3.Search in Google Scholar PubMed PubMed Central

87. Karagiannis, T, Avgerinos, I, Liakos, A, Del Prato, S, Matthews, DR, Tsapas, A, et al.. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 2022;65:1251–61. https://doi.org/10.1007/s00125-022-05715-4.Search in Google Scholar PubMed PubMed Central

88. Corrao, S, Pollicino, C, Maggio, D, Torres, A, Argano, C. Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence. Front Endocrinol (Lausanne) [Internet] 2024;15:1402583. https://doi.org/10.3389/fendo.2024.1402583. Available from: https://www.frontiersin.org/articles/10.3389/fendo.2024.1402583/full.Search in Google Scholar PubMed PubMed Central

89. Patel, H, Khunti, K, Rodbard, HW, Bajaj, HS, Bray, R, Kindracki, Z, et al.. Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials. Diabetes Obes Metabol 2024;26:473–81. https://doi.org/10.1111/dom.15333.Search in Google Scholar PubMed

90. Ludvik, B, Giorgino, F, Jódar, E, Frias, JP, Fernández Landó, L, Brown, K, 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 2021;398:583–98. https://doi.org/10.1016/s0140-6736(21)01443-4.Search in Google Scholar

91. Finan, B, Capozzi, ME, Campbell, JE. Repositioning glucagon action in the physiology and pharmacology of diabetes. Diabetes [Internet] 2020;69:532–41. https://doi.org/10.2337/dbi19-0004. Available from: https://diabetesjournals.org/diabetes/article/69/4/532/40617/Repositioning-Glucagon-Action-in-the-Physiology.Search in Google Scholar PubMed PubMed Central

92. Psaltis, JP, Marathe, JA, Nguyen, MT, Le, R, Bursill, CA, Marathe, CS, et al.. Incretin-based therapies for the management of cardiometabolic disease in the clinic: past, present, and future. Med Res Rev 2025;45:29–65. https://doi.org/10.1002/med.22070.Search in Google Scholar PubMed PubMed Central

93. Corsonello, A, Pedone, C, Incalzi, R. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr Med Chem [Internet] 2010;17:571–84. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=0929-8673&volume=17&issue=6&spage=571.10.2174/092986710790416326Search in Google Scholar PubMed

94. Ahmed, Z, Mohamed, K, Zeeshan, S, Dong, X. Artificial intelligence with multi-functional machine learning platform development for better healthcare and precision medicine. Database [Internet] 2020;2020:baaa010. Available from: https://academic.oup.com/database/article/doi/10.1093/database/baaa010/5809229.10.1093/database/baaa010Search in Google Scholar PubMed PubMed Central

95. Sinha, R, Papamargaritis, D, Sargeant, JA, Davies, MJ. Efficacy and safety of tirzepatide in type 2 diabetes and obesity management. J Obes Metab Syndr [Internet] 2023;32:25–45. https://doi.org/10.7570/jomes22067. Available from: http://www.jomes.org/journal/view.html?doi=10.7570/jomes22067.Search in Google Scholar PubMed PubMed Central

96. Lyssenko, V, Bianchi, C, Del Prato, S. Personalized therapy by phenotype and genotype. Diabetes Care 2016;39:S127–S136. https://doi.org/10.2337/dcS15-3002.Search in Google Scholar PubMed

97. Lin, CH, Lee, YS, Huang, YY, Hsieh, SH, Chen, ZS, Tsai, CN. Polymorphisms of GLP-1 receptor gene and response to GLP-1 analogue in patients with poorly controlled type 2 diabetes. J Diabetes Res [Internet] 2015;2015:1–10. https://doi.org/10.1155/2015/176949. Available from: http://www.hindawi.com/journals/jdr/2015/176949/.Search in Google Scholar PubMed PubMed Central

98. Drucker, DJ. Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity. Diabetes Care 2024;47:1873–88. https://doi.org/10.2337/dci24-0003.Search in Google Scholar PubMed

99. Drucker, DJ, Sherman, SI, Gorelick, FS, Bergenstal, RM, Sherwin, RS, Buse, JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010;33:428–33. https://doi.org/10.2337/dc09-1499.Search in Google Scholar PubMed PubMed Central

100. Yang, CY, Chen, YR, Ou, HT, Kuo, S. Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review. Cardiovasc Diabetol 2021;20:21. https://doi.org/10.1186/s12933-020-01211-4.Search in Google Scholar PubMed PubMed Central

101. DeFronzo, RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab [Internet] 2017;19:1353–62. https://doi.org/10.1111/dom.12982. Available from: https://europepmc.org/articles/pmc5643008?pdf=render.Search in Google Scholar PubMed PubMed Central

102. Coskun, T, Sloop, KW, Loghin, C, Alsina-Fernandez, J, Urva, S, Bokvist, KB, 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 Metabol 2018;18:3–14. https://doi.org/10.1016/j.molmet.2018.09.009.Search in Google Scholar PubMed PubMed Central

103. Gallwitz, B. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol 2010;25:1207–17. https://doi.org/10.1007/s00467-009-1435-z.Search in Google Scholar PubMed PubMed Central

104. Chawla, A, Nguyen, KD, Goh, YPS. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol [Internet] 2011;11:738–49. https://doi.org/10.1038/nri3071. Available from: https://www.nature.com/articles/nri3071.Search in Google Scholar PubMed PubMed Central

105. Min, T, Bain, SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: the SURPASS clinical trials. Diabetes Ther 2021;12:143–57. https://doi.org/10.1007/s13300-020-00981-0.Search in Google Scholar PubMed PubMed Central

106. Nauck, MA, Quast, DR, Wefers, J, Meier, JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab [Internet] 2021;46:101102. https://doi.org/10.1016/j.molmet.2020.101102. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8085572/pdf/main.pdf.Search in Google Scholar PubMed PubMed Central

107. Miles, KE, Kerr, JL. Semaglutide for the treatment of type 2 diabetes mellitus. J Pharm Technol [Internet] 2018;34:281–9. https://doi.org/10.1177/8755122518790925. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231279/.Search in Google Scholar PubMed PubMed Central

108. Temprosa, M, Knowler, WC, Edelstein, S, Crandall, JP, Dabelea, D, Goldberg, RB, et al.. Long-term effects of metformin on diabetes prevention: identification of subgroups that benefited most in the diabetes prevention program and diabetes prevention program outcomes study. Diabetes Care 2019;42. https://doi.org/10.2337/dc18-1970.Search in Google Scholar PubMed PubMed Central

109. Elashoff, M, Matveyenko, AV, Gier, B, Elashoff, R, Butler, PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1–based therapies. Gastroenterology [Internet] 2011;141:150–6. https://doi.org/10.1053/j.gastro.2011.02.018. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0016508511001727.Search in Google Scholar PubMed PubMed Central

110. Nissen, SE, Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New Engl J Med [Internet] 2007;356:2457–71. https://doi.org/10.1056/nejmoa072761. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa072761.Search in Google Scholar

111. Buse, JB, Bergenstal, RM, Glass, LC, Heilmann, CR, Lewis, MS, Kwan, AYM, et al.. Use of twice-daily exenatide in basal insulin–treated patients with type 2 diabetes. Ann Intern Med 2011;154:103. https://doi.org/10.7326/0003-4819-154-2-201101180-00300.Search in Google Scholar PubMed