Skip to main content
SpringerLink
Log in

New Antidiabetic Agents: Relevance to Cardiovascular Outcomes

  • Chapter
  • First Online:
Blood Pressure Disorders in Diabetes Mellitus

Part of the book series: Updates in Hypertension and Cardiovascular Protection ((UHCP))

  • 519 Accesses

Abstract

Both sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor antagonists were originally developed as glucose lowering, i.e., antihyperglycemic, drugs for the treatment of type 2 diabetes mellitus (T2DM). However, their use in cardiovascular outcome trials subsequently demonstrated their potential to improve cardiovascular and renal endpoints in patients with T2DM. While the beneficial effects of GLP-1 are primarily related to improve ischemia-related outcomes in arteriosclerotic vascular disease, the effects of SGLT2 inhibitors are more related to improvement in cardiorenal outcomes, e.g., heart failure and progression of kidney disease and apply similarly also to patients without diabetes. Undoubtedly, these agents have within a relative short period and with convincing evidence been developed as game-changing therapies for cardiovascular and renal protection.

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 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.

    CAS  PubMed  Google Scholar 

  2. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22(1):104–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Drozdowski LA, Thomson AB. Intestinal sugar transport. World J Gastroenterol. 2006;12(11):1657–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non–insulin-dependent diabetes. Diabetes. 2005;54(12):3427–34.

    CAS  PubMed  Google Scholar 

  5. Vallon V. Glucose transporters in the kidney in health and disease. Pflügers Arch. 2020;472:1345–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium–glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.

    PubMed  Google Scholar 

  7. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62(10):3324–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    CAS  PubMed  Google Scholar 

  9. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–23.e11.

    CAS  PubMed  Google Scholar 

  10. Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular assessment study-renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19(3):387–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.

    CAS  PubMed  Google Scholar 

  12. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.

    CAS  PubMed  Google Scholar 

  13. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31–9.

    Google Scholar 

  14. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306.

    CAS  PubMed  Google Scholar 

  15. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21(5):665–75.

    CAS  PubMed  Google Scholar 

  16. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425–35.

    CAS  PubMed  Google Scholar 

  17. Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, Pratley R, Dagogo-Jack S, et al. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020;142(23):2205–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rendell MS. Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes. Expert Rev Endocrinol Metab. 2018;13(6):333–9.

    CAS  PubMed  Google Scholar 

  19. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117–28.

    CAS  PubMed  Google Scholar 

  20. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129–39.

    CAS  PubMed  Google Scholar 

  21. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–24.

    CAS  PubMed  Google Scholar 

  22. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-preserved trial. Eur J Heart Fail. 2019;21(10):1279–87.

    CAS  PubMed  Google Scholar 

  23. Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691–700.

    PubMed  Google Scholar 

  24. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208–19.

    CAS  PubMed  Google Scholar 

  25. Piperidou A, Sarafidis P, Boutou A, Thomopoulos C, Loutradis C, Alexandrou ME, et al. The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. 2019;37(7):1334–43.

    CAS  PubMed  Google Scholar 

  26. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.

    CAS  PubMed  Google Scholar 

  27. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138(15):1537–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606–17.

    CAS  PubMed  Google Scholar 

  29. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.

    CAS  PubMed  Google Scholar 

  30. Tuttle KR, Brosius FC 3rd, Cavender MA, Fioretto P, Fowler KJ, Heerspink HJL, et al. SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the national kidney foundation. Am J Kidney Dis. 2021;77(1):94–109.

    CAS  PubMed  Google Scholar 

  31. Mohebi R, Januzzi JL. Cardiovascular benefit of SGLT2 inhibitors. Crit Rev Clin Lab Sci. 2021:1–14.

    Google Scholar 

  32. Girard J. The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions. Diabetes Metab. 2008;34(6):550–9.

    CAS  PubMed  Google Scholar 

  33. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153–65.

    CAS  PubMed  Google Scholar 

  34. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470–512.

    CAS  PubMed  Google Scholar 

  35. Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2008;57(5):1340–8.

    CAS  PubMed  Google Scholar 

  36. Heuvelman VD, Van Raalte DH, Smits MM. Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes. Cardiovasc Res. 2020;116(5):916–30.

    CAS  PubMed  Google Scholar 

  37. Gilbert MP, Pratley RE. GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Front Endocrinol (Lausanne). 2020;11:178.

    PubMed  Google Scholar 

  38. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes–state-of-the-art. Mol Metab. 2021;46:101102.

    CAS  PubMed  Google Scholar 

  39. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.

    CAS  PubMed  Google Scholar 

  40. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.

    CAS  PubMed  Google Scholar 

  42. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–51.

    CAS  PubMed  Google Scholar 

  43. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30.

    CAS  PubMed  Google Scholar 

  45. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (harmony outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519–29.

    CAS  PubMed  Google Scholar 

  46. Kristensen SL, Rørth 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(10):776–85.

    CAS  PubMed  Google Scholar 

  47. Yin WL, Bain SC, Min T. The effect of glucagon-like peptide-1 receptor agonists on renal outcomes in type 2 diabetes. Diabetes Ther. 2020;11(4):835–44.

    PubMed  PubMed Central  Google Scholar 

  48. Mann JF, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839–48.

    CAS  PubMed  Google Scholar 

  49. Muskiet MHA, Tonneijck L, Huang Y, Liu M, Saremi A, Heerspink HJL, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(11):859–69.

    Google Scholar 

  50. Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6(8):605–17.

    CAS  PubMed  Google Scholar 

  51. Davies MJ, Bain SC, Atkin SL, Rossing P, Scott D, Shamkhalova MS, et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care. 2016;39(2):222–30.

    CAS  PubMed  Google Scholar 

  52. 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(9):849–70.

    CAS  PubMed  Google Scholar 

  53. Sattar N, Petrie MC, Zinman B, Januzzi JL. Novel diabetes drugs and the cardiovascular specialist. J Am Coll Cardiol. 2017;69(21):2646–56.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology and Toxicology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Reinhold Kreutz & Engi Abd El-Hady Algharably

Authors
  1. Reinhold Kreutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Engi Abd El-Hady Algharably
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinhold Kreutz .

Editor information

Editors and Affiliations

  1. American University of Beirut Medical Center, Beirut, Lebanon

    Adel E. Berbari

  2. University of Milano-Bicocca, Milano, Italy

    Giuseppe Mancia

Rights and permissions

Reprints and permissions

Copyright information

© 2023 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kreutz, R., Algharably, E.A.EH. (2023). New Antidiabetic Agents: Relevance to Cardiovascular Outcomes. In: Berbari, A.E., Mancia, G. (eds) Blood Pressure Disorders in Diabetes Mellitus. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-031-13009-0_20

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-13009-0_20

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-031-13008-3

  • Online ISBN: 978-3-031-13009-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation