Spectrum of effects of dipeptidyl peptidase-4 inhibitors: within and beyond glycemic control (part 1)

The current focus of type 2 diabetes mellitus (T2DM) control has shifted from HbA1c to glycemic variability (GV) due to its key role in the accelerated development of diabetic complications, in addition to chronic hyperglycemia. The central link in the early stage of dysglycemia is β-cell dysfunction with subsequent loss of their mass with an important role of hyperglucagonemia at all stages of the diabetic continuum. Coordinated work of α and β-cells with the help of two endogenous incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) is of decisive importance for maintaining glucose homeostasis. The ability of dipeptidyl peptidase-4 (DPP-4) inhibitors to not only maintain β-cell mass and promote insulin release, but also simultaneously correct glucagon secretion from α-cells, preventing hypoglycemia, by preserving bioactive GLP-1 and GIP intact, attracts special attention to these drugs.

The place of DPP-4 inhibitors among various pharmacological treatment options for T2DM is considered: details of glycemic control and the role in reducing GV with safety in relation to the risk of cardiovascular diseases (CVD) are clarified. New data on the mechanisms of action of dipeptidase-4 are presented, which, as a new adipokine with systemic activity and cellular specificity in the regulation of not only metabolic homeostasis, but also inflammatory processes, may represent a key link between central obesity, insulin resistance (IR) and atherosclerosis. Accordingly, the pathophysiological relationship between T2DM and CVD through IR and low-level inflammation has determined a shift in therapy goals from blood glucose control to general risk factor management, which clarifies the role and place of DPP-4 inhibitors.

1. Fu WJ, Huo JL, Mao ZH, et al. Emerging role of antidiabetic drugs in cardiorenal protection. Front Pharmacol. 2024;15:1349069. doi: https://doi.org/10.3389/fphar.2024.1349069

2. Zhao L, Hu H, Zhang L, et al. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (2020). 2024;5(4):e516. doi: https://doi.org/10.1002/mco2.516

3. Pellegrini V, La Grotta R, Carreras F, et al. Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment. Cells. 2024;13(19):1662. doi: https://doi.org/10.3390/cells13191662

4. Yun JS, Ko SH. Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes. Metabolism. 2021;123:154838. doi: https://doi.org/10.1016/j.metabol.2021.154838

5. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761-772. doi: https://doi.org/10.1038/s41569-020-0406-8

6. Dedov I, Shestakova M, Mayorov A, et al. Standards of Specialized Diabetes Care / Edited by Dedov I.I., Shestakova M.V., Mayorov A.Yu. 11th Edition. Diabetes mellitus. 2023;26(2S):1-157. (In Russ.) doi: https://doi.org/10.14341/DM13042

7. Psoma O, Makris M, Tselepis A, Tsimihodimos V. Short-term Glycemic Variability and Its Association With Macrovascular and Microvascular Complications in Patients With Diabetes. J Diabetes Sci Technol. 2024;18(4):956-967. doi: https://doi.org/10.1177/19322968221146808

8. Nusca A, Tuccinardi D, Albano M, et al. Glycemic variability in the development of cardiovascular complications in diabetes. Diabetes Metab Res Rev. 2018;34(8):e3047. doi: https://doi.org/10.1002/dmrr.3047

9. Kovatchev B. Glycemic Variability: Risk Factors, Assessment, and Control. J Diabetes Sci Technol. 2019;13(4):627-635. doi: https://doi.org/10.1177/1932296819826111

10. Mo Y, Lu J, Zhou J. Glycemic variability: Measurement, target, impact on complications of diabetes and does it really matter? J Diabetes Investig. 2024;15(1):5-14. doi: https://doi.org/10.1111/jdi.14112

11. Lazar S, Ionita I, Reurean-Pintilei D, Timar B. How to Measure Glycemic Variability? A Literature Review. Medicina (Kaunas). 2023;60(1):61. doi: https://doi.org/10.3390/medicina60010061

12. Hjort A, Iggman D, Rosqvist F. Glycemic variability assessed using continuous glucose monitoring in individuals without diabetes and associations with cardiometabolic risk markers: A systematic review and meta-analysis. Clin Nutr. 2024;43(4):915-925. doi: https://doi.org/10.1016/j.clnu.2024.02.014

13. Okada K, Hibi K, Gohbara M, et al. Association between blood glucose variability and coronary plaque instability in patients with acute coronary syndromes. Cardiovasc Diabetol. 2015;14:111. doi: https://doi.org/10.1186/s12933-015-0275-3

14. Mita T, Katakami N, Okada Y, et al. Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes. Diabetologia. 2023;66(12):2356-2367. doi: https://doi.org/10.1007/s00125-023-06013-3

15. Jadav RK, Yee KC, Turner M, Mortazavi R. Potential Benefits of Continuous Glucose Monitoring for Predicting Vascular Outcomes in Type 2 Diabetes: A Rapid Review of Primary Research. Healthcare (Basel). 2024;12(15):1542. doi: https://doi.org/10.3390/healthcare12151542

16. Lu J, Wang C, Shen Y, et al. Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study. Diabetes Care. 2021;44(2):549-555. doi: https://doi.org/10.2337/dc20-1862

17. Klimontov VV, Saik OV, Korbut AI. Glucose Variability: How Does It Work?. Int J Mol Sci. 2021;22(15):7783. doi: https://doi.org/10.3390/ijms22157783

18. Chehregosha H, Khamseh ME, Malek M, et al. A View Beyond HbA1c: Role of Continuous Glucose Monitoring. Diabetes Ther. 2019;10(3):853-863. doi: https://doi.org/10.1007/s13300-019-0619-1

19. Tokarek J, Budny E, Saar M, et al. Molecular Processes Involved in the Shared Pathways between Cardiovascular Diseases and Diabetes. Biomedicines. 2023;11(10):2611. doi: https://doi.org/10.3390/biomedicines11102611

20. Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules. 2022;27(10):3055. doi: https://doi.org/10.3390/molecules27103055

21. Ussher JR, Greenwell AA, Nguyen MA, Mulvihill EE. Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials. Diabetes. 2022;71(2):173-183. doi: https://doi.org/10.2337/dbi20-0049

22. Andreadi A, Muscoli S, Tajmir R, et al. Recent Pharmacological Options in Type 2 Diabetes and Synergic Mechanism in Cardiovascular Disease. Int J Mol Sci. 2023;24(2):1646. doi: https://doi.org/10.3390/ijms24021646

23. Caturano A, Vetrano E, Galiero R, et al. Advances in the Insulin-Heart Axis: Current Therapies and Future Directions. Int J Mol Sci. 2024;25(18):10173. doi: https://doi.org/10.3390/ijms251810173

24. Rajbhandari J, Fernandez CJ, Agarwal M, Yeap BXY, Pappachan JM. Diabetic heart disease: A clinical update. World J Diabetes. 2021;12(4):383-406. doi: https://doi.org/10.4239/wjd.v12.i4.383

25. Fernandez CJ, Shetty S, Pappachan JM. Diabetic cardiomyopathy: Emerging therapeutic options. World J Diabetes. 2024;15(8):1677-1682. doi: https://doi.org/10.4239/wjd.v15.i8.1677

26. Balogh DB, Wagner LJ, Fekete A. An Overview of the Cardioprotective Effects of Novel Antidiabetic Classes: Focus on Inflammation, Oxidative Stress, and Fibrosis. Int J Mol Sci. 2023;24(9):7789. doi: https://doi.org/10.3390/ijms24097789

27. Dhar A, Venkadakrishnan J, Roy U, et al. A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy. Ther Adv Cardiovasc Dis. 2023;17:17539447231210170. doi: https://doi.org/10.1177/17539447231210170

28. Nikolaidou A, Ventoulis I, Karakoulidis G, et al. Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review. Medicina (Kaunas). 2024;60(6):912. doi: https://doi.org/10.3390/medicina60060912

29. Razavi M, Wei YY, Rao XQ, Zhong JX. DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits. Mil Med Res. 2022;9(1):45. doi: https://doi.org/10.1186/s40779-022-00410-2

30. Ferreira JP, Mehta C, Sharma A, Nissen SE, Rossignol P, Zannad F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial. BMC Med. 2020;18(1):165. doi: https://doi.org/10.1186/s12916-020-01616-8

31. Huang TL, Hsiao FY, Chiang CK, Shen LJ, Huang CF. Risk of cardiovascular events associated with dipeptidyl peptidase-4 inhibitors in patients with diabetes with and without chronic kidney disease: A nationwide cohort study. PLoS One. 2019;14(5):e0215248. doi: https://doi.org/10.1371/journal.pone.0215248

32. Baksh SN, Segal JB, McAdams-DeMarco M, Kalyani RR, Alexander GC, Ehrhardt S. Dipeptidyl peptidase-4 inhibitors and cardiovascular events in patients with type 2 diabetes, without cardiovascular or renal disease. PLoS One. 2020;15(10):e0240141. doi: https://doi.org/10.1371/journal.pone.0240141

33. Lin PJ, Pope E, Zhou FL. Comorbidity Type and Health Care Costs in Type 2 Diabetes: A Retrospective Claims Database Analysis. Diabetes Ther. 2018;9(5):1907-1918. doi: https://doi.org/10.1007/s13300-018-0477-2

34. Wen S, Wang C, Gong M, Zhou L. An overview of energy and metabolic regulation. Sci. China Life Sci. 2018;62:771–790. doi: https://doi.org/10.1007/s11427-018-9371-4

35. Jamison RA, Stark R, Dong J, et al. Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol Metab. 2011;301(6):E1174-E1183. doi: https://doi.org/10.1152/ajpendo.00175.2011

36. Mulvihill EE. Dipeptidyl peptidase inhibitor therapy in type 2 diabetes: Control of the incretin axis and regulation of postprandial glucose and lipid metabolism. Peptides. 2018;100:158-164. doi: https://doi.org/10.1016/j.peptides.2017.11.023

37. Ferrannini E. A Journey in Diabetes: From Clinical Physiology to Novel Therapeutics: The 2020 Banting Medal for Scientific Achievement Lecture. Diabetes. 2021;70(2):338-346. doi: https://doi.org/10.2337/dbi20-0028

38. Lv C, Sun Y, Zhang ZY, Aboelela Z, Qiu X, Meng ZX. β-cell dynamics in type 2 diabetes and in dietary and exercise interventions. J Mol Cell Biol. 2022;14(7):mjac046. doi: https://doi.org/10.1093/jmcb/mjac046

39. Chai S, Zhang R, Zhang Y, et al. Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis. Front Endocrinol (Lausanne). 2022;13:994944. doi: https://doi.org/10.3389/fendo.2022.994944

40. Hædersdal S, Andersen A, Knop FK, Vilsbøll T. Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases. Nat Rev Endocrinol. 2023;19(6):321-335. doi: https://doi.org/10.1038/s41574-023-00817-4

41. Wewer Albrechtsen NJ, Holst JJ, Cherrington AD, et al. 100 years of glucagon and 100 more. Diabetologia. 2023 Aug;66(8):1378-1394. doi: https://doi.org/10.1007/s00125-023-05947-y

42. Monnier L, Colette C, Dunseath GJ, Owens DR. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care. 2007;30(2):263-269. doi: https://doi.org/10.2337/dc06-1612

43. Takebayashi K, Suzuki T, Naruse R, et al. Long-Term Effect of Alogliptin on Glycemic Control in Japanese Patients With Type 2 Diabetes: A 3.5-Year Observational Study. J Clin Med Res. 2017;9(9):802-808. doi: https://doi.org/10.14740/jocmr3118w

44. Su J, Luo Y, Hu S, Tang L, Ouyang S. Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents. Int J Mol Sci. 2023;24(17):13381. doi: https://doi.org/10.3390/ijms241713381

45. Huang CJ, Wang WT, Sung SH, et al. Revisiting ‘intensive’ blood glucose control: A causal directed acyclic graph-guided systematic review of randomized controlled trials. Diabetes Obes Metab. 2022;24(12):2341-2352. doi: https://doi.org/10.1111/dom.14819

46. Mohan V, Khunti K, Chan SP, et al. Management of Type 2 Diabetes in Developing Countries: Balancing Optimal Glycaemic Control and Outcomes with Affordability and Accessibility to Treatment. Diabetes Ther. 2020;11(1):15-35. doi: https://doi.org/10.1007/s13300-019-00733-9

47. Shao DW, Zhao LJ, Sun JF. Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM). Eur J Med Chem. 2024;272:116464. doi: https://doi.org/10.1016/j.ejmech.2024.116464

48. Lee S, Lee H, Kim Y, Kim E. Effect of DPP-IV Inhibitors on Glycemic Variability in Patients with T2DM: A Systematic Review and Meta-Analysis. Sci Rep. 2019;9(1):13296. doi: https://doi.org/10.1038/s41598-019-49803-9

49. Chai S, Zhang R, Zhang Y, et al. Influence of dipeptidyl peptidase-4 inhibitors on glycemic variability in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne). 2022;13:935039. doi: https://doi.org/10.3389/fendo.2022.935039

50. Yoshikawa F, Uchino H, Nagashima T, et al. Dipeptidyl peptidase-4 inhibitor improves glycemic variability in multiple daily insulin-treated type 2 diabetes: a prospective randomized-controlled trial. Diabetol Int. 2021;13(1):124-131. doi: https://doi.org/10.1007/s13340-021-00513-6

51. 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(9):644-656. doi: https://doi.org/10.1016/S2213-8587(23)00171-7

52. Koufakis T, Zografou I, Doumas M, Kotsa K. The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?. Am J Cardiovasc Drugs. 2023;23(6):601-608. doi: https://doi.org/10.1007/s40256-023-00610-8

53. Singh AK, Yadav D, Sharma N, Jin JO. Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes. Pharmaceuticals (Basel). 2021;14(6):586. doi: https://doi.org/10.3390/ph14060586

54. Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021;23 Suppl 3:5-29. doi: https://doi.org/10.1111/dom.14496

55. Chai S, Zhang R, Carr RD, et al. Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023;14:1203187. doi: https://doi.org/10.3389/fendo.2023.1203187

56. Nauck MA, Meier JJ. GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family. Diabetes. 2019;68(5):897-900. doi: https://doi.org/10.2337/dbi19-0005

57. Deacon CF. Metabolism of GIP and the contribution of GIP to the glucose-lowering properties of DPP-4 inhibitors. Peptides. 2020;125:170196. doi: https://doi.org/10.1016/j.peptides.2019.170196

58. Subrahmanyan NA, Koshy RM, Jacob K, Pappachan JM. Efficacy and Cardiovascular Safety of DPP-4 Inhibitors. Curr Drug Saf. 2021;16(2):154-164. doi: https://doi.org/10.2174/1574886315999200819150544

59. Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci. 2023;10:1130625. doi: https://doi.org/10.3389/fmolb.2023.1130625

60. Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(11):642-653. doi: https://doi.org/10.1038/s41574-020-0399-8

61. Love KM, Liu Z. DPP4 Activity, Hyperinsulinemia, and Atherosclerosis. J Clin Endocrinol Metab. 2021;106(6):1553-1565. doi: https://doi.org/10.1210/clinem/dgab078

62. Chen SY, Kong XQ, Zhang KF, Luo S, Wang F, Zhang JJ. DPP4 as a Potential Candidate in Cardiovascular Disease. J Inflamm Res. 2022;15:5457-5469. doi: https://doi.org/10.2147/JIR.S380285

63. Barchetta I, Cimini FA, Dule S, Cavallo MG. Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis. Biomedicines. 2022;10(9):2306. doi: https://doi.org/10.3390/biomedicines10092306

64. Yan Y, Lu H, Zheng Y, Lin S. Association Between Systemic Immune Inflammation Index and Diabetes Mellitus in the NHANES 2003-2018 Population. J Endocr Soc. 2024;8(8):bvae124. doi: https://doi.org/10.1210/jendso/bvae124

65. Tang Y, Feng X, Liu N, et al. Relationship between systemic immune inflammation index and mortality among US adults with different diabetic status: Evidence from NHANES 1999-2018. Exp Gerontol. 2024;185:112350. doi: https://doi.org/10.1016/j.exger.2023.112350

66. Dalle S, Abderrahmani A. Receptors and Signaling Pathways Controlling Beta-Cell Function and Survival as Targets for Anti-Diabetic Therapeutic Strategies. Cells. 2024;13(15):1244. doi: https://doi.org/10.3390/cells13151244

67. Shao S, Xu Q, Yu X, Pan R, Chen Y. Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions. Pharmacol Ther. 2020;209:107503. doi: https://doi.org/10.1016/j.pharmthera.2020.107503

68. Huang J, Liu X, Wei Y, et al. Emerging Role of Dipeptidyl Peptidase-4 in Autoimmune Disease. Front Immunol. 2022;13:830863. doi: https://doi.org/10.3389/fimmu.2022.830863

69. Trzaskalski NA, Fadzeyeva E, Mulvihill EE. Dipeptidyl Peptidase-4 at the Interface Between Inflammation and Metabolism. Clin Med Insights Endocrinol Diabetes. 2020;13:1179551420912972. doi: https://doi.org/10.1177/1179551420912972

70. Pechmann LM, Pinheiro FI, Andrade VFC, Moreira CA. The multiple actions of dipeptidyl peptidase 4 (DPP-4) and its pharmacological inhibition on bone metabolism: a review. Diabetol Metab Syndr. 2024;16(1):175. doi: https://doi.org/10.1186/s13098-024-01412-x

71. Rahim K, Shan M, Ul Haq I, et al. Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors. J Inflamm Res. 2024;17:1897-1917. doi: https://doi.org/10.2147/JIR.S442106