Skip to main content
SpringerLink
Log in

Metformin, Sulfonylureas, DPP-4 Inhibitors and Cardiovascular Outcomes in Type 2 DM

  • Chapter
  • First Online:
Diabetes and Cardiovascular Disease

Part of the book series: Contemporary Cardiology ((CONCARD))

Abstract

Cardiovascular protection has become a major objective in the management of patients with type 2 diabetes (T2DM). Because of the demonstration of a significant reduction in major cardiovascular adverse events (MACEs) with GLP-1 receptor agonists and SGLT2 inhibitors in large prospective outcome placebo-controlled trials, confirmed in observational retrospective studies, the place in clinical practice of older glucose-lowering agents becomes a matter of discussion. While metformin has not been studied in dedicated cardiovascular outcome trials, several observational studies suggested a favourable cardiovascular effect of this compound, beyond its glucose-lowering effect. For sulfonylureas, the cardiovascular safety is more debatable, perhaps depending on the molecule, even is some reassuring data were reported in recent studies. DPP-4 inhibitors have proven their cardiovascular safety in several prospective placebo-controlled trials, without evidence for a reduction in MACEs. A possible increase in the risk of hospitalization for heart failure with this pharmacological class appears not confirmed, yet some caution about the use of saxagliptin is still recommended. In conclusion, in patients with T2DM and high cardiovascular risk, preference should be given to glucose-lowering agents that have proven cardiovascular protection. Nevertheless, metformin remains a valuable background therapy, even in patients at cardiovascular risk. Sulfonylureas are increasingly considered not being a good therapeutic option, especially because of a higher risk of hypoglycaemia. DPP-4 inhibitors have an excellent overall safety profile, including in an elderly and more frailty population. A personalized approach targeting the individual patient profile is recommended for the optimal management of patients with T2DM.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S105–S18.

    Article  Google Scholar 

  2. Cefalu WT, Kaul S, Gerstein HC, Holman RR, Zinman B, Skyler JS, et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2018;41:14–31.

    Article  CAS  PubMed  Google Scholar 

  3. Home P. Cardiovascular outcome trials of glucose-lowering medications: an update. Diabetologia. 2019;62:357–69.

    Article  CAS  PubMed  Google Scholar 

  4. Scheen AJ. Cardiovascular outcome studies in type 2 diabetes: comparison between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract. 2018;143:88–100.

    Article  CAS  PubMed  Google Scholar 

  5. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139:2022–31.

    Article  CAS  PubMed  Google Scholar 

  6. Ghosh-Swaby OR, Goodman SG, Leiter LA, Cheng A, Connelly KA, Fitchett D, et al. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2020;8:418–35.

    Article  CAS  PubMed  Google Scholar 

  7. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669–701.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2020;63:221–8.

    Article  PubMed  Google Scholar 

  9. Das SR, Everett BM, Birtcher KK, Brown JM, Januzzi JL Jr, Kalyani RR, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:1117–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.

    Article  PubMed  Google Scholar 

  11. Scheen AJ. Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors. Circ Res. 2018;122:1439–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic agents, from metformin to SGLT2 inhibitors and GLP1 receptor agonists: JACC Focus Seminar. J Am Coll Cardiol. 2020;75:1956–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schernthaner G, Schernthaner GH. The right place for metformin today. Diabetes Res Clin Pract. 2020;159:107946.

    Article  PubMed  Google Scholar 

  14. Ahmad E, Sargeant JA, Zaccardi F, Khunti K, Webb DR, Davies MJ. Where does metformin stand in modern day management of type 2 diabetes? Pharmaceuticals (Basel). 2020;13:427.

    Article  CAS  PubMed  Google Scholar 

  15. Luo F, Das A, Chen J, Wu P, Li X, Fang Z. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol. 2019;18:54.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zaccardi F, Khunti K, Marx N, Davies MJ. First-line treatment for type 2 diabetes: is it too early to abandon metformin? Lancet. 2020;396:1705–7.

    Article  CAS  PubMed  Google Scholar 

  17. Rena G, Mordi IR, Lang CC. Metformin: still the sweet spot for CV protection in diabetes? Curr Opin Pharmacol. 2020;54:202–8.

    Article  CAS  PubMed  Google Scholar 

  18. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–66.

    Article  CAS  PubMed  Google Scholar 

  19. Zilov AV, Abdelaziz SI, AlShammary A, Al Zahrani A, Amir A, Assaad Khalil SH, et al. Mechanisms of action of metformin with special reference to cardiovascular protection. Diabetes Metab Res Rev. 2019;35:e3173.

    Article  PubMed  PubMed Central  Google Scholar 

  20. UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–65.

    Article  Google Scholar 

  21. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    Article  CAS  PubMed  Google Scholar 

  22. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13:221–8.

    Article  CAS  PubMed  Google Scholar 

  23. Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel JP, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012;9:e1001204.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017;60:1620–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Han Y, Xie H, Liu Y, Gao P, Yang X, Shen Z. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol. 2019;18:96.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang K, Yang W, Dai H, Deng Z. Cardiovascular risk following metformin treatment in patients with type 2 diabetes mellitus: results from meta-analysis. Diabetes Res Clin Pract. 2020;160:108001.

    Article  PubMed  Google Scholar 

  27. Packer M. Is metformin beneficial for heart failure in patients with type 2 diabetes? Diabetes Res Clin Pract. 2018;136:168–70.

    Article  CAS  PubMed  Google Scholar 

  28. Bergmark BA, Bhatt DL, McGuire DK, Cahn A, Mosenzon O, Steg PG, et al. Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial. Circulation. 2019;140:1004–14.

    Article  CAS  PubMed  Google Scholar 

  29. Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC Jr, Goto S, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9.

    Article  CAS  PubMed  Google Scholar 

  30. Scheen AJ, Paquot N. Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab. 2013;39:179–90.

    Article  CAS  PubMed  Google Scholar 

  31. Inzucchi SE, Fitchett D, Jurisic-Erzen D, Woo V, Hantel S, Janista C, et al. Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy? Diabetes Obes Metab. 2020;22:631–9.

    Article  CAS  PubMed  Google Scholar 

  32. Packer M. Does metformin interfere with the cardiovascular benefits of SGLT2 inhibitors? Questions about its role as the cornerstone of diabetes treatment. Am J Med. 2020;133:781–2.

    Article  PubMed  Google Scholar 

  33. Crowley MJ, Williams JW Jr, Kosinski AS, D’Alessio DA, Buse JB. Metformin use may moderate the effect of DPP-4 Inhibitors on cardiovascular outcomes. Diabetes Care. 2017;40:1787–9.

    Article  PubMed  Google Scholar 

  34. Scheen AJ. Metformin—a cardiovascular moderator of DPP-4 inhibitors ? Nat Rev Endocrinol. 2018;14:8–9.

    Article  PubMed  Google Scholar 

  35. Scheen AJ. Could metformin modulate cardiovascular outcomes differently with DPP-4 inhibitors compared with SGLT2 inhibitors? Diabetes Metab. 2021;47:101209.

    Article  CAS  PubMed  Google Scholar 

  36. Singh AK, Singh R. Does background metformin therapy influence the cardiovascular outcomes with SGLT-2 inhibitors in type 2 diabetes? Diabetes Res Clin Pract. 2021;172:108536.

    Article  CAS  PubMed  Google Scholar 

  37. Neuen BL, Arnott C, Perkovic V, Figtree G, de Zeeuw D, Fulcher G, et al. Sodium-glucose co-transporter-2 inhibitors with and without metformin: a meta-analysis of cardiovascular, kidney and mortality outcomes. Diabetes Obes Metab. 2021;23:382–90.

    Article  CAS  PubMed  Google Scholar 

  38. Zaccardi F, Kloecker DE, Buse JB, Mathieu C, Khunti K, Davies MJ. Use of metformin and cardiovascular effects of new classes of glucose-lowering agents: a meta-analysis of cardiovascular outcome trials in type 2 diabetes. Diabetes Care. 2021;44:e32–4.

    Article  PubMed  Google Scholar 

  39. Bromage DI, Yellon DM. The pleiotropic effects of metformin: time for prospective studies. Cardiovasc Diabetol. 2015;14:109.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky MJ, et al. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab. 2015;17:523–32.

    Article  CAS  PubMed  Google Scholar 

  41. Leiter LA. Latest evidence on sulfonylureas: what’s new? Diabetes Ther. 2020;11:15–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA. 2019;322:1155–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fernandez CJ, Veettil RA, Htwe N. Efficacy and cardiovascular safety of sulfonylureas. Curr Drug Saf. 2021;16:142–53.

    Article  CAS  PubMed  Google Scholar 

  44. Webb DR, Davies MJ, Jarvis J, Seidu S, Khunti K. The right place for sulphonylureas today. Diabetes Res Clin Pract. 2019;157:107836.

    Article  CAS  PubMed  Google Scholar 

  45. Cordiner RLM, Pearson ER. Reflections on the sulphonylurea story: a drug class at risk of extinction or a drug class worth reviving? Diabetes Obes Metab. 2019;21:761–71.

    Article  PubMed  Google Scholar 

  46. Melander A, Bitzen PO, Faber O, Groop L. Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use. Drugs. 1989;37:58–72.

    Article  CAS  PubMed  Google Scholar 

  47. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res. 1991;69:571–81.

    Article  CAS  PubMed  Google Scholar 

  48. Program UGD. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: sections I and II. Diabetes. 1970;19:747–830.

    Google Scholar 

  49. University Group Diabetes Program. A study of the effects of hypoglycemia agents on vascular complications in patients with adult-onset diabetes. VI. Supplementary report on nonfatal events in patients treated with tolbutamide. Diabetes. 1976;25:1129–53.

    Article  Google Scholar 

  50. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

    Article  Google Scholar 

  51. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

    Article  CAS  PubMed  Google Scholar 

  52. Vaccaro O, Masulli M, Nicolucci A, Bonora E, Del Prato S, Maggioni AP, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;5:887–97.

    Article  PubMed  Google Scholar 

  53. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–65.

    Article  Google Scholar 

  54. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:938–53.

    Article  CAS  PubMed  Google Scholar 

  55. Lee G, Oh SW, Hwang SS, Yoon JW, Kang S, Joh HK, et al. Comparative effectiveness of oral antidiabetic drugs in preventing cardiovascular mortality and morbidity: a network meta-analysis. PLoS One. 2017;12:e0177646.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wu S, Cipriani A, Yang Z, Yang J, Cai T, Xu Y, et al. The cardiovascular effect of incretin-based therapies among type 2 diabetes: a systematic review and network meta-analysis. Expert Opin Drug Saf. 2018;17:243–9.

    Article  CAS  PubMed  Google Scholar 

  57. Bain S, Druyts E, Balijepalli C, Baxter CA, Currie CJ, Das R, et al. Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: a Bayesian meta-analysis of survival data. Diabetes Obes Metab. 2017;19:329–35.

    Article  CAS  PubMed  Google Scholar 

  58. Zhang Y, Hong J, Chi J, Gu W, Ning G, Wang W. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas—a meta-analysis from randomized clinical trials. Diabetes Metab Res Rev. 2014;30:241–56.

    Article  CAS  PubMed  Google Scholar 

  59. Wang F, He Y, Zhang R, Zeng Q, Zhao X. Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients. Medicine (Baltimore). 2017;96:e7638.

    Article  CAS  PubMed  Google Scholar 

  60. Chou CY, Chang YT, Yang JL, Wang JY, Lee TE, Wang RY, et al. Effect of long-term incretin-based therapies on ischemic heart diseases in patients with type 2 diabetes mellitus: a network meta-analysis. Sci Rep. 2017;7:15795.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36:1304–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Scheen AJ. Cardiovascular safety of DPP-4 inhibitors compared to sulphonylureas: results of randomized controlled trials and observational studies. Diabetes Metab. 2018;44:386–92.

    Article  CAS  PubMed  Google Scholar 

  63. Mannucci E, Monami M, Candido R, Pintaudi B, Targher G, SID-AMD joint panel for Italian Guidelines on Treatment of Type 2 Diabetes. Effect of insulin secretagogues on major cardiovascular events and all-cause mortality: a meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2020;30:1601–8.

    Article  CAS  PubMed  Google Scholar 

  64. Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012;157:601–10.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Roumie CL, Chipman J, Min JY, Hackstadt AJ, Hung AM, Greevy RA Jr, et al. Association of treatment with metformin vs sulfonylurea with major adverse cardiovascular events among patients with diabetes and reduced kidney function. JAMA. 2019;322:1167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Varas-Lorenzo C, Margulis AV, Pladevall M, Riera-Guardia N, Calingaert B, Hazell L, et al. The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord. 2014;14:129.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Azoulay L, Suissa S. Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies. Diabetes Care. 2017;40:706–14.

    Article  CAS  PubMed  Google Scholar 

  68. Kim KJ, Choi J, Lee J, Bae JH, An JH, Kim HY, et al. Dipeptidyl peptidase-4 inhibitor compared with sulfonylurea in combination with metformin: cardiovascular and renal outcomes in a propensity-matched cohort study. Cardiovasc Diabetol. 2019;18:28.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Pop LM, Lingvay I. The infamous, famous sulfonylureas and cardiovascular safety: much ado about nothing? Curr Diab Rep. 2017;17:124.

    Article  PubMed  Google Scholar 

  70. Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Featherstone TR. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol. 2015;3:43–51.

    Article  CAS  PubMed  Google Scholar 

  71. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36:2288–96.

    Article  CAS  PubMed  Google Scholar 

  72. Douros A, Yin H, Yu OHY, Filion KB, Azoulay L, Suissa S. Pharmacologic differences of sulfonylureas and the risk of adverse cardiovascular and hypoglycemic events. Diabetes Care. 2017;40:1506–13.

    Article  CAS  PubMed  Google Scholar 

  73. Leonard CE, Brensinger CM, Aquilante CL, Bilker WB, Boudreau DM, Deo R, et al. Comparative safety of sulfonylureas and the risk of sudden cardiac arrest and ventricular arrhythmia. Diabetes Care. 2018;41:713–22.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Huang HK, Yeh JI. Comparison of mortality and cardiovascular event risk associated with various insulin secretagogues: a nationwide real-world analysis. Diabetes Res Clin Pract. 2019;152:103–10.

    Article  CAS  PubMed  Google Scholar 

  75. van Dalem J, Brouwers M, Stehouwer CDA, Krings A, Klungel OH, Driessen JHM, et al. Risk of a first-ever acute myocardial infarction and all-cause mortality with sulphonylurea treatment: a population-based cohort study. Diabetes Obes Metab. 2018;20:1056–60.

    Article  PubMed  Google Scholar 

  76. Singh AK, Singh R. Is gliclazide a sulfonylurea with difference? A review in 2016. Expert Rev Clin Pharmacol. 2016;9:839–51.

    Article  CAS  PubMed  Google Scholar 

  77. Colagiuri S, Matthews D, Leiter LA, Chan SP, Sesti G, Marre M. The place of gliclazide MR in the evolving type 2 diabetes landscape: a comparison with other sulfonylureas and newer oral antihyperglycemic agents. Diabetes Res Clin Pract. 2018;143:1–14.

    Article  CAS  PubMed  Google Scholar 

  78. Philip J, Fernandez CJ. Efficacy and cardiovascular safety of meglitinides. Curr Drug Saf. 2021;16:207–16.

    Article  CAS  PubMed  Google Scholar 

  79. Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362:1463–76.

    Article  CAS  PubMed  Google Scholar 

  80. Deacon CF. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16:642–53.

    Article  CAS  PubMed  Google Scholar 

  81. Scheen AJ. The safety of gliptins: updated data in 2018. Expert Opin Drug Saf. 2018;17:387–405.

    Article  CAS  PubMed  Google Scholar 

  82. Scheen AJ. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. Clin Pharmacokinet. 2015;54:1–21.

    Article  CAS  PubMed  Google Scholar 

  83. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.

    Article  CAS  PubMed  Google Scholar 

  84. Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013;10:73–84.

    Article  CAS  PubMed  Google Scholar 

  85. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35:992–1019.

    Article  CAS  PubMed  Google Scholar 

  86. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114:1788–803.

    Article  CAS  PubMed  Google Scholar 

  87. Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849–70.

    Article  CAS  PubMed  Google Scholar 

  88. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.

    Article  CAS  PubMed  Google Scholar 

  89. White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, et al. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:668–73.

    Article  CAS  PubMed  Google Scholar 

  90. Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol. 2014;13:33.

    Article  PubMed Central  Google Scholar 

  91. Engel SS, Golm GT, Shapiro D, Davies MJ, Kaufman KD, Goldstein BJ. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol. 2013;12:3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, et al. Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015;17:1085–92.

    Article  CAS  PubMed  Google Scholar 

  94. Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:112–20.

    Article  CAS  PubMed  Google Scholar 

  95. Xu S, Zhang X, Tang L, Zhang F, Tong N. Cardiovascular effects of dipeptidyl peptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review. Postgrad Med. 2017;129:205–15.

    Article  PubMed  Google Scholar 

  96. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.

    Article  CAS  PubMed  Google Scholar 

  97. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

    Article  CAS  PubMed  Google Scholar 

  98. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

    Article  CAS  PubMed  Google Scholar 

  99. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2018;321:69–79.

    Article  PubMed Central  Google Scholar 

  100. Gantz I, Chen M, Suryawanshi S, Ntabadde C, Shah S, O’Neill EA, et al. A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2017;16:112.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Mahmoud AN, Saad M, Mansoor H, Elgendy AY, Barakat AF, Abuzaid A, et al. Cardiovascular safety of incretin-based therapy for type 2 diabetes: a meta-analysis of randomized trials. Int J Cardiol. 2017;230:324–6.

    Article  PubMed  Google Scholar 

  102. Abbas AS, Dehbi HM, Ray KK. Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. Diabetes Obes Metab. 2016;18:295–9.

    Article  CAS  PubMed  Google Scholar 

  103. 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:e0240141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kohsaka S, Lam CSP, Kim DJ, Cavender MA, Norhammar A, Jorgensen ME, et al. Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors: an analysis from the CVD-REAL 2 multinational cohort study. Lancet Diabetes Endocrinol. 2020;8:606–15.

    Article  CAS  PubMed  Google Scholar 

  105. Persson F, Nystrom T, Jorgensen ME, Carstensen B, Gulseth HL, Thuresson M, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in type 2 diabetes patients (CVD-REAL Nordic) when compared to DPP-4 inhibitors: a multinational observational study. Diabetes Obes Metab. 2018;20:344–51.

    Article  CAS  PubMed  Google Scholar 

  106. Liu D, Jin B, Chen W, Yun P. Dipeptidyl peptidase 4 (DPP-4) inhibitors and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM): a systematic review and meta-analysis. BMC Pharmacol Toxicol. 2019;20:15.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Ou HT, Chang KC, Li CY, Wu JS. Comparative cardiovascular risks of dipeptidyl peptidase 4 inhibitors with other second- and third-line antidiabetic drugs in patients with type 2 diabetes. Br J Clin Pharmacol. 2017;83:1556–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Savarese G, Schrage B, Cosentino F, Lund LH, Rosano GMC, Seferovic P, et al. Non-insulin antihyperglycaemic drugs and heart failure: an overview of current evidence from randomized controlled trials. ESC Heart Fail. 2020;7:3438–51.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Seferovic PM, Coats AJS, Ponikowski P, Filippatos G, Huelsmann M, Jhund PS, et al. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur J Heart Fail. 2020;22:196–213.

    Article  PubMed  Google Scholar 

  110. Packer M. Worsening heart failure during the use of DPP-4 inhibitors: pathophysiological mechanisms, clinical risks, and potential influence of concomitant antidiabetic medications. JACC Heart Fail. 2018;6:445–51.

    Article  PubMed  Google Scholar 

  111. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Verma S, Goldenberg RM, Bhatt DL, Farkouh ME, Quan A, Teoh H, et al. Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open. 2017;5:E152–E77.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Standl E, Erbach M, Schnell O. Dipeptidyl-peptidase-4 inhibitors and heart failure: class effect, substance-specific effect, or chance effect? Curr Treat Options Cardiovasc Med. 2014;16:353.

    Article  PubMed  Google Scholar 

  114. Giugliano D, Maiorino MI, Longo M, Bellastella G, Chiodini P, Esposito K. Type 2 diabetes and risk of heart failure: a systematic review and meta-analysis from cardiovascular outcome trials. Endocrine. 2019;65:15–24.

    Article  CAS  PubMed  Google Scholar 

  115. Kongwatcharapong J, Dilokthornsakul P, Nathisuwan S, Phrommintikul A, Chaiyakunapruk N. Effect of dipeptidyl peptidase-4 inhibitors on heart failure: a meta-analysis of randomized clinical trials. Int J Cardiol. 2016;211:88–95.

    Article  CAS  PubMed  Google Scholar 

  116. Ou SM, Chen HT, Kuo SC, Chen TJ, Shih CJ, Chen YT. Dipeptidyl peptidase-4 inhibitors and cardiovascular risks in patients with pre-existing heart failure. Heart. 2017;103:414–20.

    Article  CAS  PubMed  Google Scholar 

  117. McMurray JJV, Ponikowski P, Bolli GB, Lukashevich V, Kozlovski P, Kothny W, et al. Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail. 2018;6:8–17.

    Article  PubMed  Google Scholar 

  118. Zhang DP, Xu L, Wang LF, Wang HJ, Jiang F. Effects of antidiabetic drugs on left ventricular function/dysfunction: a systematic review and network meta-analysis. Cardiovasc Diabetol. 2020;19:10.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Scheen AJ. Sodium-glucose co-transporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16:556–77.

    Article  PubMed  Google Scholar 

  120. Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7:776–85.

    Article  CAS  PubMed  Google Scholar 

  121. Nilsson M, Rungby J, Lassota N, Jorgensen AD, Ibsen R, Kjellberg J. No Impact of Pre-existing cardiovascular disease on prescribing patterns of sulphonylureas in Denmark—a registry-based nationwide study. Basic Clin Pharmacol Toxicol. 2018;122:606–11.

    Article  CAS  PubMed  Google Scholar 

  122. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17:543–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. 2020;8:782–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Scheen AJ, Marre M, Thivolet C. Prognostic factors in patients with diabetes hospitalized for COVID-19: findings from the CORONADO study and recent reports. Diabetes Metab. 2020;46:265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Singh AK, Singh R, Saboo B, Misra A. Non-insulin anti-diabetic agents in patients with type 2 diabetes and COVID-19: a critical appraisal of literature. Diabetes Metab Syndr. 2020;15:159–67.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Scheen AJ. Metformin and COVID-19: from cellular mechanisms to reduced mortality. Diabetes Metab. 2020;46:423–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Scheen AJ. DPP-4 inhibition and COVID-19: From initial concerns to recent expectations. Diabetes Metab. 2021;47:101213.

    Article  CAS  PubMed  Google Scholar 

  128. Solerte SB, D’Addio F, Trevisan R, Lovati E, Rossi A, Pastore I, et al. Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study. Diabetes Care. 2020;43:2999–3006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nauck MA, Meier JJ. Reduced COVID-19 mortality with sitagliptin treatment? Weighing the dissemination of potentially lifesaving findings against the assurance of high scientific standards. Diabetes Care. 2020;43:2906–9.

    Article  PubMed  Google Scholar 

  130. Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2021;17:11–30.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium

    André J. Scheen

  2. Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium

    André J. Scheen

Authors
  1. André J. Scheen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André J. Scheen .

Editor information

Editors and Affiliations

  1. Steward St. Elizabeth’s Medical Center, Tufts University Medical School, Brighton, MA, USA

    Michael Johnstone

  2. Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA, USA

    Aristidis Veves

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Scheen, A.J. (2023). Metformin, Sulfonylureas, DPP-4 Inhibitors and Cardiovascular Outcomes in Type 2 DM. In: Johnstone, M., Veves, A. (eds) Diabetes and Cardiovascular Disease. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-13177-6_32

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-13177-6_32

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-13176-9

  • Online ISBN: 978-3-031-13177-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation