New class of drugs for the treatment of diabetes mellitus

Diabetes and obesity are among the key issues for modern healthcare. Approximately 425 million people worldwide have diabetes, and the number of individuals with overweight or obesity exceeds one-third of the entire human population. This necessitates the search for new therapeutic options for treating these conditions and the improvement of existing treatment regimens. This review discusses both the concepts of “diabetes” and obesity, existing treatment schemes, and a new class of antidiabetic drugs—glucose-dependent insulinotropic peptide receptor agonists and glucagon-like peptide-1, as well as its main representative—tirzepatide. The review presents the history of development, justification of the mechanism of action, and existing clinical studies on tirzepatide, a key representative of this emerging class of drugs. This medication has demonstrated a statistically significant reduction in glycated hemoglobin in patients with diabetes and weight loss in patients with obesity and/ or diabetes compared to several classes of antidiabetic drugs. However, it should be noted that adverse reactions in clinical studies were more frequent in the tirzepatide group, especially at high doses, highlighting the need for an individualized approach when prescribing this medication. Additionally, comparisons were made only with insulin and glucagon-like peptide-1 receptor agonists, indicating the limited clinical significance of these studies. The introduction of tirzepatide into clinical practice may potentially reduce obesity levels and help control the progression of diabetes in many patients, thereby decreasing complications and mortality associated with these conditions.

1. Chobot A., Górowska-Kowolik K., Sokołowska M., Jarosz-Chobot P. Obesity and diabetes-Not only a simple link between two epidemics. Diabetes Metab. Res. Rev. 2018;34(7):e3042. DOI: 10.1002/dmrr.3042

2. Cho N.H., Shaw J.E., Karuranga S. et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018;138:271–281. DOI: 10.1016/j.diabres.2018.02.023

3. Forouhi N.G., Wareham N.J. Epidemiology of diabetes. Medicine (Abingdon). 2014;42(12):698–702. DOI: 10.1016/j.mpmed.2014.09.007

4. Dedov I.I., Shestakova M.V., Vikulova O.K., Zheleznyakova A.V., Isakov M.A. Epidemiological characteristics of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the Federal Diabetes Register data of 01.01.2021. Saharnyj diabet. 2021;24(3):204–221. (In Russian)]. DOI: 10.14341/DM12759

5. Chooi Y.C., Ding C., Magkos F. The epidemiology of obesity. Metabolism. 2019;92:6–10. DOI: 10.1016/j.metabol.2018.09.005

6. Dahlén A.D., Dashi G., Maslov I., et al. Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales. Front Pharmacol. 2022;12:807548. DOI: 10.3389/fphar.2021.807548

7. Syed Y.Y. Tirzepatide: First Approval. Drugs. 2022;82(11):1213– 1220. DOI: 10.1007/s40265-022-01746-8

8. Jastreboff A.M., Aronne L.J., Ahmad N.N. et al. Tirzepatide Once Weekly for the Treatment of Obesity. N. Engl. J. Med. 2022;387(3):205–216. DOI: 10.1056/NEJMoa2206038

9. Chow E., Chan J.C.N. The emerging role of incretins and twincretins. Nat. Rev. Endocrinol. 2022;18(2):73–74. DOI: 10.1038/s41574-021-00607-w

10. Sattar N. Advances in the clinical management of type 2 diabetes: a brief history of the past 15 years and challenges for the future. BMC Med. 2019;17(1):46. DOI: 10.1186/s12916-019-1281-1

11. Min T., Bain S.C. 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(1):143–157. DOI: 10.1007/s13300-020-00981-0

12. Day J.W., Ottaway N., Patterson J.T. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 2009;5(10):749–757. DOI: 10.1038/nchembio.209

13. Finan B., Clemmensen C., Müller T.D. Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide-1 based multi-agonists. Mol. Cell. Endocrinol. 2015;418(1):42–54. DOI: 10.1016/j.mce.2015.07.003

14. Nauck M.A., Bartels E., Orskov C. et al. Additive insulinotropic eff ects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at nearphysiological insulinotropic hormone and glucose concentrations. J. Clin. Endocrinol. Metab. 1993;76(4):912–917. DOI: 10.1210/jcem.76.4.8473405

15. Gasbjerg L.S., Bergmann N.C., Stensen S. et al. Evaluation of the incretin eff ect in humans using GIP and GLP-1 receptor antagonists. Peptides. 2020;125:170183. DOI: 10.1016/j.peptides.2019.170183

16. Nauck M.A., Meier J.J. Incretin hormones: Their role in health and disease. Diabetes Obes. Metab. 2018;20(1):5–21. DOI: 10.1111/dom.13129

17. Gallwitz B., Witt M., Fölsch U.R., Creutzfeldt W., Schmidt W.E. Binding specifi city and signal transduction of receptors for glucagonlike peptide-1(7-36) amide and gastric inhibitory polypeptide on RINm5F insulinoma cells. J. Mol. Endocrinol. 1993;10(3):259–268. DOI: 10.1677/jme.0.0100259

18. Finan B., Ma T., Ottaway N. et al. Unimolecular dual incretins maximize metabolic benefi ts in rodents, monkeys, and humans. Sci. Transl. Med. 2013;5(209):209ra151. DOI: 10.1126/scitranslmed.3007218

19. Harrison C. Obesity and diabetes: Two-for-one strike at incretins. Nat. Rev. Drug Discov. 2014;13(1):18–19. DOI: 10.1038/nrd4208

20. Nørregaard P.K., Deryabina M.A., Tofteng Sh.P. et al. A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents. Diabetes Obes. Metab. 2018;20(1):60–68. DOI: 10.1111/dom.13034

21. Samms R.J., Coghlan M.P., Sloop K.W. How may GIP enhance the therapeutic effi cacy of GLP-1? Trends Endocrinol. Metab. 2020;31(6):410–421. DOI: 10.1016/j.tem.2020.02.006

22. Knerr P.J., Mowery S.A., Douros JD. et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol. Metab. 2022;63:101533. DOI: 10.1016/j.molmet.2022.101533

23. Chavda V.P., Ajabiya J., Teli D., Bojarska J., Apostolopoulos V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: a mini-review. Molecules. 2022;27(13):4315. DOI: 10.3390/molecules27134315

24. Orme M.E., Nguyen H., Lu J.Y. et al. Comparative eff ectiveness of glycemic control in patients with type 2 diabetes treated with GLP-1 receptor agonists: a network meta-analysis of placebo-controlled and active-comparator trials. Diabetes Metab. Syndr. Obes. 2017;10:111–122. Published 2017 Mar 29. DOI: 10.2147/DMSO.S116810

25. Coskun T., Sloop K.W., Loghin C. 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. DOI: 10.1016/j.molmet.2018.09.009

26. Druzhilov M.A., Kuznetsova T.Y., Chumakova G.A. Multiagonists of the “incretin axis” as a promising tool for managing cardiometabolic risk in visceral obesity. Rossijskij kardiologicheskij zhurnal. 2022;27(4):4755. (In Russian)] DOI: 10.15829/1560-4071-2022-4755

27. fda.gov [Internet]. U.S. Food and Drug Administration; MOUNJARO. MOUNJAROTM (tirzepatide) Injection, for subcutaneous use [updated 2022 May 13; cited 2022 Nov 3]. [Electronic resource]. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf

28. Useinova A.N., Egorova E.A., Yelisheva E.A., Beitullaev А.М., Koryanova K.N. The main directions and prospects in polycystic ovary syndrome treatment. Sibirskiy nauchnyy meditsinskiy zhurnal. 2021;41(6):18–29. (In Russian)]. DOI: 10.18699/SSMJ20210602

29. Rosenstock J., Wysham C., Frías J.P. et al. Effi cacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2021 Jul 17;398(10296):212]. Lancet. 2021;398(10295):143–155. DOI: 10.1016/S0140-6736(21)01324-6

30. Frías J.P., Davies M.J., Rosenstock J. et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N. Engl. J. Med. 2021;385(6):503–515. DOI: 10.1056/NEJMoa2107519

31. Ludvik B., Giorgino F., Jódar E. 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(10300):583–598. DOI: 10.1016/S0140-6736(21)01443-4

32. Del Prato S., Kahn S.E., Pavo I. 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(10313):1811–1824. DOI: 10.1016/S0140-6736(21)02188-7

33. Dahl D., Onishi Y., Norwood P. et al. Eff ect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022;327(6):534–545. DOI: 10.1001/jama.2022.0078

34. National Library of Medicine (U.S.). (2020, October). A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) With or Without Metformin (SURPASS-6). Identifi er NCT04537923. [updated 2021 Oct 19; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04537923

35. National Library of Medicine (U.S.). (2022, April). A Study to Evaluate Tirzepatide (LY3298176) in Pediatric and Adolescent Participants With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin or Basal Insulin or Both (SURPASS-PEDS). Identifi er NCT05260021. [updated 2022 Oct 20; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT05260021

36. National Library of Medicine (U.S.). (2019, December — 2021, November). A study of Tirzepatide (LY3298176) in participants with type 2 diabetes on metformin with or without sulfonylurea (surpassAP-combo). Identifi er NCT04093752. [updated 2021 Dec 14; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04093752

37. Inagaki N., Takeuchi M., Oura T. et al. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(9):623–633. DOI: 10.1016/S2213-8587(22)00188-7

38. Kadowaki T., Chin R., Ozeki A., Imaoka T., Ogawa Y. Safety and effi cacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. 2022;10(9):634–644. DOI: 10.1016/S2213-8587(22)00187-5

39. National Library of Medicine (U.S.). (2020, May — 2024, October). A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes (SURPASS-CVOT). Identifi er NCT04255433. [updated 2022 Dec 12; cited 2022 Dec 21]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04255433

40. Jastreboff A.M., Aronne L.J., Ahmad N.N. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 2022;387(3):205–216. DOI: 10.1056/NEJMoa2206038

41. National Library of Medicine (U.S.). (2021, March). A study of tirzepatide (ly3298176) in participants with type 2 diabetes who have obesity or are overweight (SURMOUNT-2). Identifi er NCT04657003. [updated 2022 Apr 19; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04657003

42. National Library of Medicine (U.S.). (2021, March). A study of tirzepatide (ly3298176) in participants after a lifestyle weight loss program (SURMOUNT-3). Identifi er NCT04657016. [updated 2022 Mar 23; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04657016

43. National Library of Medicine (U.S.). (2021, March). A study of tirzepatide (ly3298176) in participants with obesity or overweight for the maintenance of weight loss (SURMOUNT-4). Identifi er NCT04660643. [updated 2022 Oct 6; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04660643

44. National Library of Medicine (U.S.). (2021, September). A study of tirzepatide (LY3298176) in chinese participants without type 2 diabetes who have obesity or overweight (SURMOUNT-CN). Identifi er NCT05024032. [updated 2022 Oct 18; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT05024032

45. National Library of Medicine (U.S.). (2021, May). A study of tirzepatide (LY3298176) in participants with obesity disease (SURMOUNT-J). Identifi er NCT04844918. [updated 2022 Feb 7; cited 2022 Nov 3]. [Electronic resource]. URL: https://www.clinicaltrials.gov/ct2/show/NCT04844918

46. National Library of Medicine (U.S.). (2022, June). Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea (SURMOUNT-OSA). Identifi er NCT05412004. [updated 2022 Oct 19; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/study/NCT05412004

47. National Library of Medicine (U.S.). (2021, April). A study of tirzepatide (LY3298176) in participants with heart failure with preserved ejection fraction and obesity (SUMMIT). Identifi er NCT04847557. [updated 2022 Oct 20; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04847557

48. Frias J.P., Nauck M.A., Van J. et al. Effi cacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate diff erent dose-escalation regimens. Diabetes Obes. Metab. 2020;22(6):938–946. DOI: 10.1111/dom.13979

49. Frias J.P., Nauck M.A., Van J. et al. Effi cacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparatorcontrolled phase 2 trial. Lancet. 2018;392(10160):2180–2193. DOI:10.1016/S0140-6736(18)32260-8

50. National Library of Medicine (U.S.). (2019, November). A study of tirzepatide (LY3298176) in participants with nonalcoholic steatohepatitis (NASH) (SYNERGY-NASH). Identifi er NCT04166773. [updated 2022 Oct 20; cited 2022 Nov 3]. [Electronic resource]. URL: https://clinicaltrials.gov/ct2/show/NCT04166773

51. Jung H.N., Jung C.H. The upcoming weekly tides (Semaglutide vs. Tirzepatide) against obesity: STEP or SURPASS? J. Obes. Metab. Syndr. 2022;31(1):28–36. DOI: 10.7570/jomes22012

52. Ametov A.S. The level of glycated hemoglobin as a signifi cant marker of complete glycemic control and a predictor of late vascular complications of type 2 diabetes mellitus. RMZH. 2011;13:832. (In Russian)].

53. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, et al. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(1):S83–S96. DOI: 10.2337/dc22-S006

54. Dutta D., Surana V., Singla R. et al. Effi cacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis. Indian J. Endocrinol. Metab. 2021;25(6):475–489. DOI: 10.4103/ijem.ijem_423_21

55. Karagiannis T., Avgerinos I., Liakos 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(8):1251–1261. DOI: 10.1007/s00125-022-05715-4

56. Bhagavathula A.S., Vidyasagar K., Tesfaye W. Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Phase II/III Trials. Pharmaceuticals (Basel). 2021;14(10):991. DOI: 10.3390/ph14100991