Перспективы лечения сахарного диабета 2-го типа и ожирения: настоящее и будущее инкретинотерапии - Журнал Терапевтический архив №10 Вопросы эндокринологии 2025

Перспективы лечения сахарного диабета 2-го типа и ожирения: настоящее и будущее инкретинотерапии

Шестакова М.В., Башлыкова Р.О. Перспективы лечения сахарного диабета 2-го типа и ожирения: настоящее и будущее инкретинотерапии. Терапевтический архив. 2025;97(10):823–829. DOI: 10.26442/00403660.2025.10.203366

© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.

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Shestakovа MV, Bashlykova RO. The perspectives in obesity and type 2 diabetes therapy: the present and future of incretin therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2025;97(10):823–829. DOI: 10.26442/00403660.2025.10.203366

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Аннотация

Темпы прироста заболеваемости сахарным диабетом 2-го типа (СД 2) и ожирением в мире неуклонно растут и превышают даже самые пессимистичные прогнозы, что вынуждает специалистов искать, разрабатывать и внедрять все более эффективные методы терапевтического воздействия на эти две взаимосвязанные неинфекционные пандемии. В статье рассматриваются перспективные направления в фармакотерапии ожирения и СД 2 с акцентом на разработку класса агонистов рецепторов инкретиновых гормонов. Обсуждаются как уже вошедшие в широкую практику врачей моноагонисты (лираглутид, дулаглутид, семаглутид) и двойные агонисты инкретиновых рецепторов (тирзепатид), так и разрабатываемые в настоящее время три- и тетра-агонисты гормонов желудочно-кишечного тракта, которые, предположительно, будут еще более эффективными в комплексном лечении СД 2 и ожирения.

Ключевые слова: ожирение, сахарный диабет, фармакотерапия, мультиагонист, глюкагоноподобный пептид-1, глюкозозависимый инсулинотропный полипептид, глюкагон, инкретин, масса тела, метаболический процесс, гликемический контроль

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The rates of increase in the incidence of type 2 diabetes mellitus (T2DM) and obesity in the world are steadily increasing and exceed even the wildest forecasts, which forces specialists to seek, develop and implement more effective therapeutic methods for these two interrelated non-communicable pandemics. This article discusses promising areas in the pharmacotherapy of obesity and T2DM with an emphasis on the development of a class of incretin hormone receptor agonists. Monoagonists (liraglutide, dulaglutide, semaglutide) and dual incretin receptor agonists (tirzepatide), as well as triple- and tetra-agonists of gastrointestinal hormones currently under development, which are expected to be even more effective in the complex treatment of both type T2DM and obesity, are being discussed.

Keywords: obesity, diabetes mellitus, pharmacotherapy, multiagnestics, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, glucagon, incretins, weight, metabolic process, glycemic control

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Список литературы

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22. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394(10193):131-3. DOI:10.1016/S0140-6736(19)31150-X
23. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-84. DOI:10.1056/NEJMoa1607141
24. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2. DOI:10.1056/NEJMoa2307563
25. Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes Metab. 2020;22(8):1263-77. DOI:10.1111/dom.14054
26. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-51. DOI:10.1056/NEJMoa1901118
27. Wharton S, Rosenstock J, Konige M, et al. Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes. Cardiovasc Diabetol. 2025;24(1):240. DOI:10.1186/s12933-025-02781-x
28. Andreasen CR, Andersen A, Vilsbøll T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diabetologia. 2023;66(10):1846-88. DOI:10.1007/s00125-023-05966-9
29. Ma J, Hu X, Zhang W, et al. Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice. Endocrine. 2025;87(1):159-69. DOI:10.1007/s12020-024-03998-8
30. Gutgesell RM, Nogueiras R, Tschöp MH, Müller TD. Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes. Diabetes Ther. 2024;15(5):1069-84. DOI:10.1007/s13300-024-01566-x
31. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-55. DOI:10.1016/S0140-6736(21)01324-6
32. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-15. DOI:10.1056/NEJMoa2107519
33. 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):583-98. DOI:10.1016/S0140-6736(21)01443-4
34. Del Prato S, Kahn SE, 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):1811-84. DOI:10.1016/S0140-6736(21)02188-7
35. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomized, placebo-controlled and active comparator controlled phase 2 trial. Lancet. 2018;392(10160):2180-93. DOI:10.1016/S0140-6736(18)32260-8
36. Nasser M, Soma W. Survodutide, a promising agent with novel mechanism of action for treatment of obesity and type 2 diabetes. J Endocrinology and Disorders. 2024;8(3):01-4. DOI:10.31579/2640-1045/184
37. Evans M, Chubb B, Malkin SJP, et al. Once-weekly semaglutide versus insulin aspart for the treatment of type 2 diabetes in the UK: A long-term cost-effectiveness analysis based on SUSTAIN 11. Diabetes Obes Metab. 2023;25(2):491-500. DOI:10.1111/dom.14892
38. Zhang B, Cheng Z, Chen J, et al. Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. Diabetes Care. 2024;47(1):160-8. DOI:10.2337/dc23-1287
39. Frias JP, Deenadayalan S, Erichsen L, 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. 2023;402(10403):720-30. DOI:10.1016/S0140-6736(23)01163-7
40. Davies MJ, Bajaj HS, Broholm C, et al. REDEFINE 2 Study Group. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025;393(7):648-59. DOI:10.1056/NEJMoa2502082
41. Kinsey EW, Widen EM, Quinn JW, et al. Neighborhood walkability and poverty predict excessive gestational weight gain: A cross-sectional study in New York City. Obesity (Silver Spring). 2022;30(2):503-14. DOI:10.1002/oby.23339
42. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023;389(6):514-26. DOI:10.1056/NEJMoa2301972
43. Bossart M, Wagner M, Elvert R, et al. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell Metab. 2022;34(1):59-74.e10. DOI:10.1016/j.cmet.2021.12.005
44. Power Guerra N, Leyens K, Müller L, et al. The effect of different weight loss strategies to treat non-alcoholic fatty liver disease focusing on fibroblast growth factor 21. Front Nutr. 2022,9:935805. DOI:10.3389/fnut.2022.935805
45. Ray A. Retatrutide: a triple incretin receptor agonist for obesity management. Expert Opin Investig Drugs. 2023;32(11):1003-8. DOI:10.1080/13543784.2023.2276754
46. Луговик И.А., Бабина А.В., Арутюнян С.С., и др. Первый дженерик тирзепатида GP30931: физико-химическое и биологическое сходство с референтным лекарственным средством. Разработка и регистрация лекарственных средств. 2025;14(2):52-74 [Lugovik IA, Babina AV, Arutyunyan SS, et al. The first generic tirzepatide GP30931: physicochemical and biological similarity to the reference drug. Drug Development & Registration. 2025;14(2):54-74 (in Russian)]. DOI:10.33380/2305-2066-2025-14-2-2084

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1. Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201-23. DOI:10.1038/s41573-021-00337-8
2. Gudzune KA, Kushner RF. Medications for Obesity: A Review. JAMA. 2024;332(7):571-84. DOI:10.1001/jama.2024.10816
3. Papamargaritis D, le Roux CW, Holst JJ, Davies MJ. New therapies for obesity. Cardiovasc Res. 2024;119(18):2825-82. DOI:10.1093/cvr/cvac176
4. Bailey CJ, Flatt PR, Conlon JM. An update on peptide-based therapies for type 2 diabetes and obesity. Peptides. 2023;161. DOI:10.1016/j.peptides.2023.170939
5. Frezza EE. Are we closer to finding the treatment for type 2 diabetes mellitus in morbid obesity? Are the incretins the key to success? Obes Surg. 2004;14(7):999-1005. DOI:10.1381/0960892041719699
6. Alhomoud IS, Talasaz AH, Chandrasekaran P, et al. Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management. Pharmacotherapy. 2024;44(9):738-52. DOI:10.1002/phar.4607
7. Gong B, Yao Z, Zhou C, et al. Glucagon-like peptide-1 analogs: Miracle drugs are blooming? Eur J Med Chem. 2024;269. DOI:10.1016/j.ejmech.2024.116342
8. Bu T, Sun Z, Pan Y, et al. Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab J. 2024;48(3):354-72. DOI:10.4093/dmj.2023.0277
9. Cong Z, Zhao F, Li Y, et al. Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins. Cell Discov. 2024;10(1):18. DOI:10.1038/s41421-024-00649-0
10. Sood A, Kaur P, Syed O, et al. Revolutionizing diabetes care: unveiling tirzepatide's potential in glycemic control and beyond. Expert Rev Clin Pharmacol. 2024;17(3):235-46. DOI:10.1080/17512433.2024.2310070
11. Ibrahim SS, Ibrahim RS, Arabi B, et al. The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer Metastasis Rev. 2024;43(4):1297-314. DOI:10.1007/s10555-024-10192-9
12. Bailey CJ, Flatt PR, Conlon JM. Recent advances in peptide-based therapies for obesity and type 2 diabetes. Peptides. 2024;173:171149. DOI:10.1016/j.peptides.2024.171149
13. Ahrén B. The future of incretin-based therapy: novel avenues – novel targets. Diabetes Obes Metab. 2011;13(Suppl. 1):158-66. DOI:10.1111/j.1463-1326.2011.01457.x
14. Meier JJ. The role of incretin-based therapies in the management of type 2 diabetes mellitus: perspectives on the past, present and future. Diabetes Mellitus. 2020;22(5):461-6. DOI:10.14341/dm11493
15. Garber AJ. Incretin therapy – present and future. Rev Diabet Stud. 2011;8(3):307-22. DOI:10.1900/RDS.2011.8.307
16. Abdel-Malek M, Yang L, Miras AD. Pharmacotherapy for chronic obesity management: a look into the future. Intern Emerg Med. 2023;18(4):1019-30. DOI:10.1007/s11739-023-03237-4
17. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. DOI:10.1056/NEJMoa1603827
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 Diabetes Endocrinol. 2016;4(6):525-36. DOI:10.1016/S2213-8587(15)00482-9
19. Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):234. DOI:10.1038/s41392-024-01931-z
20. Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410. DOI:10.1136/bmj-2023-076410
21. Holman RR, Bethel MA, Mentz RJ, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228-9. DOI:10.1056/NEJMoa1612917
22. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394(10193):131-3. DOI:10.1016/S0140-6736(19)31150-X
23. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-84. DOI:10.1056/NEJMoa1607141
24. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2. DOI:10.1056/NEJMoa2307563
25. Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes Metab. 2020;22(8):1263-77. DOI:10.1111/dom.14054
26. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-51. DOI:10.1056/NEJMoa1901118
27. Wharton S, Rosenstock J, Konige M, et al. Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes. Cardiovasc Diabetol. 2025;24(1):240. DOI:10.1186/s12933-025-02781-x
28. Andreasen CR, Andersen A, Vilsbøll T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diabetologia. 2023;66(10):1846-88. DOI:10.1007/s00125-023-05966-9
29. Ma J, Hu X, Zhang W, et al. Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice. Endocrine. 2025;87(1):159-69. DOI:10.1007/s12020-024-03998-8
30. Gutgesell RM, Nogueiras R, Tschöp MH, Müller TD. Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes. Diabetes Ther. 2024;15(5):1069-84. DOI:10.1007/s13300-024-01566-x
31. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-55. DOI:10.1016/S0140-6736(21)01324-6
32. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-15. DOI:10.1056/NEJMoa2107519
33. 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):583-98. DOI:10.1016/S0140-6736(21)01443-4
34. Del Prato S, Kahn SE, 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):1811-84. DOI:10.1016/S0140-6736(21)02188-7
35. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomized, placebo-controlled and active comparator controlled phase 2 trial. Lancet. 2018;392(10160):2180-93. DOI:10.1016/S0140-6736(18)32260-8
36. Nasser M, Soma W. Survodutide, a promising agent with novel mechanism of action for treatment of obesity and type 2 diabetes. J Endocrinology and Disorders. 2024;8(3):01-4. DOI:10.31579/2640-1045/184
37. Evans M, Chubb B, Malkin SJP, et al. Once-weekly semaglutide versus insulin aspart for the treatment of type 2 diabetes in the UK: A long-term cost-effectiveness analysis based on SUSTAIN 11. Diabetes Obes Metab. 2023;25(2):491-500. DOI:10.1111/dom.14892
38. Zhang B, Cheng Z, Chen J, et al. Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. Diabetes Care. 2024;47(1):160-8. DOI:10.2337/dc23-1287
39. Frias JP, Deenadayalan S, Erichsen L, 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. 2023;402(10403):720-30. DOI:10.1016/S0140-6736(23)01163-7
40. Davies MJ, Bajaj HS, Broholm C, et al. REDEFINE 2 Study Group. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025;393(7):648-59. DOI:10.1056/NEJMoa2502082
41. Kinsey EW, Widen EM, Quinn JW, et al. Neighborhood walkability and poverty predict excessive gestational weight gain: A cross-sectional study in New York City. Obesity (Silver Spring). 2022;30(2):503-14. DOI:10.1002/oby.23339
42. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023;389(6):514-26. DOI:10.1056/NEJMoa2301972
43. Bossart M, Wagner M, Elvert R, et al. Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist. Cell Metab. 2022;34(1):59-74.e10. DOI:10.1016/j.cmet.2021.12.005
44. Power Guerra N, Leyens K, Müller L, et al. The effect of different weight loss strategies to treat non-alcoholic fatty liver disease focusing on fibroblast growth factor 21. Front Nutr. 2022,9:935805. DOI:10.3389/fnut.2022.935805
45. Ray A. Retatrutide: a triple incretin receptor agonist for obesity management. Expert Opin Investig Drugs. 2023;32(11):1003-8. DOI:10.1080/13543784.2023.2276754
46. Lugovik IA, Babina AV, Arutyunyan SS, et al. The first generic tirzepatide GP30931: physicochemical and biological similarity to the reference drug. Drug Development & Registration. 2025;14(2):54-74 (in Russian). DOI:10.33380/2305-2066-2025-14-2-2084

Авторы

М.В. Шестакова*, Р.О. Башлыкова

ГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии им. акад. И.И. Дедова» Минздрава России, Москва, Россия
*shestakova.mv@gmail.com

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Marina V. Shestakovа*, Roza O. Bashlykova

Endocrinology Research Centre, Moscow, Russia
*shestakova.mv@gmail.com

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