Tirzepatide: Dual GIP/GLP-1 Receptor Agonists, from Molecular to Clinical Practice for Treating Type-2 Diabetes and Obesity
DOI:
https://doi.org/10.66266/inajemd.v1i2.23Keywords:
Dual agonist GIP/GLP-1, obesity, tirzepatide, type-2 diabetesAbstract
Tirzepatide is a promising drug with dual-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor activation that has revolutionized the treatment of type 2 diabetes mellitus (T2DM). In phase 3 clinical trials (SURPASS 1-5), tirzepatide has been shown to achieve better glycaemic control in terms of glycosylated hemoglobin reduction (HbA1c) and improved fasting, postprandial glucose levels and weight reduction as compared to placebo and active comparators. The SURPASS 4 clinical trial has shown positive cardiovascular outcomes in people with T2DM with elevated cardiovascular risk. Tirzepatide has acceptable side effects and is well tolerated, with a low risk of hypoglycaemia. Additionally, encouraging results from SURMOUNT trials and ongoing SURPASS-CVOT studies will shed more light on cardiovascular safety in the future. In this review, we have summarized the pharmacology, efficacy, safety, and clinical trials for potential impact for clinical treatment T2DM.
Downloads
References
1. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, Stein C, Basit A, Chan JCN, Mbanya JC, Pavkov ME, Ramachandaran A, Wild SH, James S, Herman WH, Zhang P, Bommer C, Kuo S,
Boyko EJ, Magliano DJ. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.
2. Centers for Disease Control and Prevention. National diabetes statistics report. 2020. Accessed May 19, 2022
3. Papaetis GS, Papakyriakou P, Panagiotou TN. Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns. Arch Med Sci. 2015;11(3):463-482.
4. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L; Look AHEAD Research Group. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011 Jul;34(7):1481-6.
5. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Man-agement of hyperglycaemia in type 2 diabetes, 2022. A consensus report bythe American Diabetes Association (ADA) and the European association for thestudy of diabetes (EASD). Diabetologia 2022; 65:1925–66.
6. American Diabetes Association. Diabetes Care Volume 45, Supplement 1, January 2022
7. Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Dewasa di Indonesia2021 Penerbit PB Perkeni.
8. Darmon P, Bauduceau B, Bordier L, Detournay B, Gourdy P, Guerci B, et al.Prise de position de la Socié té francophone du diabé te (SFD) sur les straté giesd’utilisation des traitements anti-hyperglycé miants dans le diabé te de type2-2021. Med Mal Metab 2021;15:781–801
9. Baggio L.L. and Drucker D.J., Biology of incretins: GLP-1 and GIP. Gastroenterology, 2007. 132(6): 2131–57.
10. Mathiesen D.S., et al., The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review. Int J Mol Sci, 2019. 20(17)
11. Perez-MontesD.E.O.A., Pellitero S., and Puig-Domingo M., Obesity and GLP-1. Minerva Endocrinol (Torino), 2021. 46(2): 168–176.
12. Chadda K.R., Cheng T.S., and Ong K.K., GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis. Obes Rev, 2021. 22(6).
13. Nauck M.A., et al., GLP-1 receptor agonists in the treatment of type 2 diabetes—state-of-the-art. Mol Metab, 2021. 46: 101102.
14. US Food and Drug Administration. FDA approves novel, dual-targeted treatment for type 2 diabetes. Published May 13, 2022. Accessed May 18, 2022. Obes Rev, 2021. 22(6): e13177.
15. Administration, U.S.F.a.D., FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes. 2018. 20(9): 2113–2120.
16. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y: Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964, 24:1076-82.
17. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W: Incretin effects of increasing glucose load in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986, 63:492-8.
18. Nauck MA, Meier JJ: The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diab Endocrinol. 2016, 4:525-36.
19. Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP . Gastroenterol. 2007, 132:2131-57.
20. Calanna S, Christensen M, Holst JJ, Laferré re B, Gluud LL, Vilsbøll T, Knop FK: Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013, 56:965-72.
21. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ: Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001,86:3717-23.
22. Rachel Sinha, Dimitris Papamargaritis, Jack A. Sargeant, Melanie J. Davies. Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management Obes Metab Syndr 2023;32:25-45
23. André J. Scheena. Review article Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes. Annales d’Endocrinologie 84 (2023) 316–321
24. Muller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, et al. Glucagon like peptide 1 (GLP-1). Mol Metab 2019;30:72-130.
25. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-39.
26. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. 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 1993;91:301-7.
27. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-20.
28. Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE, et al. Gastric inhibitory polypeptide (GIP) dose-depend-ently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 2003;46:798-801.
29. Khoo B, Tan TM. Combination gut hormones: prospects and questions for the future of obesity and diabetes therapy. J Endocrinol 2020;246:R65-74.
30. Christensen MB, Gasbjerg LS, Heimburger SM, Stensen S, Vilsboll T, Knop FK. GIP’s involvement in the pathophysiology of type 2 diabetes. Peptides 2020;125:170178.
31. Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 2009;52:199-207
32. Lund A, Vilsboll T, Bagger JI, Holst JJ, Knop FK. The separate and combined impact of the intestinal hormones, GIP, GLP- 1, and GLP-2, on glucagon secretion in type 2 diabetes. Am J Physiol Endocrinol Metab 2011;300:E1038-46.
33. Zhang Q, Delessa CT, Augustin R, Bakhti M, Collden G, Drucker DJ, et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 2021;33:833-44.e5.
34. Holst JJ, Rosenkilde MM. GIP as a therapeutic target in diabetes and obesity:insight from incretin co-agonists. J Clin Endocrinol Metab 2020;105:e2710–6.
35. Holst JJ, Orskov C, Vagn-Nielsen O, Schwartz TW. Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Lett.1987;211:169–74.
36. Moody AJ, Thim L, Valverde I. The isolation and sequencing of human gastric inhibitory peptide (GIP). FEBS Lett. 1984;172:142–8. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. 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. 1992;267:7402–5
37. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, 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. 2018;18:3–14
38. Michael A. Nauck and David A. D‘Alessio.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. Cardiovascular Diabetology (2022) 21:169: 1-16.
39. Tamer Coskun, Kyle W. Sloop, Corina Loghin, Jorge Alsina-Fernandez, Shweta Urva, Krister B. Bokvist, Xuewei Cui, Daniel A. Briere 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. Molec Metab18 (2018):3e14.
40. Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptideand glucagon-like peptide-1 receptor agonist in patients with type 2 dia-betes: a 12-week, randomized, double-blind, placebo-controlled study toevaluate different dose-escalation regimens. Diabetes Obes Metab 2020;22:938–46.
41. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety ofLY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlledphase 2 trial. Lancet 2018;392:2180–93.
42. Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, TsapasA, et al. Management of type 2 diabetes with the dual GIP/GLP-1 recep-tor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 2022;65:1251–61.
43. Rosenstock J, Wysham C, Frias JP, Kaneko S, Lee CJ, Fernandez Lando L, et al.Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide inpatients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase3 trial. Lancet 2021;398:143–55.
44. Frias JP, Davies MJ, Rosenstock J, Perez Manghi FC, Fernandez Lando L, BergmanBK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2diabetes. N Engl J Med 2021;385:503–15.
45. Ludvik B, Giorgino F, Jodar E, Frias JP, Fernandez Lando L, Brown K, et al.Once-weekly tirzepatide versus once-daily insulin degludec as add-on to met-formin 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.
46. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatideversus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3trial. Lancet 2021;398:1811–24.
47. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of subcutaneoustirzepatide vs placebo added to titrated insulin glargine on glycemic control inpatients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA2022;327:534–45.
48. Battelino T, Bergenstal RM, Rodrí guez A, et al. Efficacy ofonce-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial [published correction appears in Lancet Diabetes Endocrinol. 2022;10(8):e8]. Lancet Diabetes Endocrinol. 2022;10(6):407-417.doi:10.1016/S2213-8587(22)00077-8.
49. Gastaldelli A, Cusi K, Ferná ndez Landö L, Bray R, Brouwers B, Rodrí guez Á . 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. 2022;10(6):393-406.
50. 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 Diab Endocrinol. 2022, 10:623-33.
51. 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 Diab Endocrinol. 2022
52. Jastreboff AM, Aronne LJ, Ahmad NN, et al.: Tirzepatide once weekly for the treatment of obesity . N Engl J Med. 2022, 387:205-16.
53. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, 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 2021;398:1811-24
54. Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, et al.Effects of tirzepatide versus insulin glargine on kidney outcomesin type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of anopen-label, randomised, phase 3 trial. Lancet Diab Endocrinol 2022 [S2213-8587(22)00243-1].
55. Dutta D, Surana V, Singla R, Aggarwal S, Sharma M. Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the manage-ment of type-2 diabetes: a cochrane meta-analysis. Indian J Endocrinol
Downloads
Published
Issue
Section
License
Copyright (c) 2024 InaJEMD - Indonesian Journal of Endocrinology Metabolic and Diabetes
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Authors retain copyright and grant the Indonesian Journal of Endocrinology, Metabolism and Diabetes (InaJEMD) the right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
© Indonesian Journal of Endocrinology, Metabolism and Diabetes (InaJEMD). Published by the Indonesian Society of Endocrinology (PERKENI).
