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Glucose-Lowering Medications and Cardiovascular Outcomes

  • Ischemic Heart Disease (D Mukherjee, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

The purpose of this review is to examine recent evidence supporting CV safety profile and improvement of CV outcomes of some of the newer classes of diabetic medications.

Recent Findings

Diabetes mellitus (DM) is associated with increased risk of cardiovascular disease (CVD). Thus, CVD management is critical in diabetic patients. Since 2008, the US Food and Drug Administration (FDA) has mandated that all newer diabetic medications should establish cardiovascular safety before it is approved for use. Diabetic medications that also lower CV risk would be a significant advancement as shown in recent studies. There are 3 new class of diabetic medications: Dipeptidyl peptidase-4 inhibitors (DPP-4), glucagon-like peptide receptor agonists (GLP-1 RA), and sodium-glucose cotransporter type 2 (SGLT 2) inhibitors which have established both CV safety and improvement in CV outcomes with some drugs.

Summary

In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, multiple atherosclerotic cardiovascular disease risk factors, or diabetic kidney disease, a sodium-glucose cotransporter 2 inhibitor, or a glucagon-like peptide 1 receptor agonist with demonstrated cardiovascular benefit is recommended to reduce the risk of major adverse cardiovascular events.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139–596.

    Article  PubMed  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(1):14–31.

    Article  CAS  PubMed  Google Scholar 

  3. Azimova K, San Juan Z, Mukherjee D. Cardiovascular safety profile of currently available diabetic drugs. Ochsner J. 2014;14(4):616–32.

    PubMed  PubMed Central  Google Scholar 

  4. Syed SH, Gosavi S, Shami W, Bustamante M, Farah Z, Teleb M, et al. A review of sodium glucose co-transporter 2 inhibitors canagliflozin, dapagliflozin and empagliflozin. Cardiovasc Hematol Agents Med Chem. 2015;13(2):105–12.

    Article  CAS  PubMed  Google Scholar 

  5. 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(9548):1696–705.

    Article  CAS  PubMed  Google Scholar 

  6. Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14(4):505–24.

    Article  CAS  PubMed  Google Scholar 

  7. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114(11):1788–803.

    Article  CAS  PubMed  Google Scholar 

  8. Anderluh M, Kocic G, Tomovic K, Kocic R, Deljanin-Ilic M, Smelcerovic A. Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: potential impact of dipeptidyl peptidase-4 inhibitors. Pharmacol Ther. 2016;167:100–7.

    Article  CAS  PubMed  Google Scholar 

  9. • 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 This paper reviewed the mechanisms of cardiovascular effects of GLP-1RA and DPP-4 inhibitors.

    Article  CAS  PubMed  Google Scholar 

  10. 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(7):668–73.

    Article  CAS  PubMed  Google Scholar 

  11. 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  PubMed Central  Google Scholar 

  12. 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 

  13. 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(14):1327–35.

    Article  CAS  PubMed  Google Scholar 

  14. 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(14):1317–26.

    Article  CAS  PubMed  Google Scholar 

  15. 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(3):232–42.

    Article  CAS  PubMed  Google Scholar 

  16. Savarese G, D’Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C, et al. Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter-2 inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol. 2016;220:595–601.

    Article  PubMed  Google Scholar 

  17. Elgendy IY, Mahmoud AN, Barakat AF, Elgendy AY, Saad M, Abuzaid A, et al. Cardiovascular safety of dipeptidyl-peptidase IV inhibitors: a meta-analysis of placebo-controlled randomized trials. Am J Cardiovasc Drugs. 2017;17(2):143–55.

    Article  CAS  PubMed  Google Scholar 

  18. 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. 2019;321(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. •• Pulipati VP, Ravi V, Pulipati P. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Eur J Prev Cardiol. 2020;27(18):1992–30. https://doi.org/10.1177/2047487320903638. This is the most recent meta-analysis of trials that examined GLP-1RA in patients with DM-2.

  27. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest. 1994;93(1):397–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14(11):2873–82.

    Article  CAS  Google Scholar 

  29. Scholl-Bürgi S, Santer R, Ehrich JH. Long-term outcome of renal glucosuria type 0: the original patient and his natural history. Nephrol Dial Transplant. 2004;19(9):2394–6.

    Article  PubMed  Google Scholar 

  30. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79(5):1510–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  32. Hummel CS, Lu C, Liu J, Ghezzi C, Hirayama BA, Loo DD, et al. Structural selectivity of human SGLT inhibitors. Am J Physiol Cell Physiol. 2012;302(2):C373–82.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. • McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2020;e204511. https://doi.org/10.1001/jamacardio.2020.4511. This meta-analysis examined the studies analyzing the SGLT2 inhibitors and their cardiovascular and renal outcomes.

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Ghezzi C, Yu AS, Hirayama BA, Kepe V, Liu J, Scafoglio C, et al. Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule. J Am Soc Nephrol. 2017;28(3):802–10.

    Article  CAS  PubMed  Google Scholar 

  42. Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93(1):231–44.

    Article  CAS  PubMed  Google Scholar 

  43. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25.

    Article  CAS  PubMed  Google Scholar 

  44. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(4):422–34.

    Article  CAS  PubMed  Google Scholar 

  45. Karg MV, Bosch A, Kannenkeril D, Striepe K, Ott C, Schneider MP, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol. 2018;17(1):5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35(10):2059–68.

    Article  CAS  PubMed  Google Scholar 

  47. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6(6):e004007. https://doi.org/10.1161/JAHA.116.004007.

  48. Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21(8):70.

    Article  PubMed  Google Scholar 

  49. Packer M. Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors. Eur J Heart Fail. 2020;22(4):618–28.

    Article  CAS  PubMed  Google Scholar 

  50. Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation. 2017;136(16):1548–59.

    Article  CAS  PubMed  Google Scholar 

  51. Osataphan S, Macchi C, Singhal G, Chimene-Weiss J, Sales V, Kozuka C, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. 2019;4(5):e123130. https://doi.org/10.1172/jci.insight.123130.

  52. Uthman L, Baartscheer A, Schumacher CA, Fiolet JWT, Kuschma MC, Hollmann MW, et al. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol. 2018;9:1575.

    Article  PubMed  PubMed Central  Google Scholar 

  53. American DA. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S111–S34.

    Article  Google Scholar 

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Correspondence to Madhan Shanmugasundaram.

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Shanmugasundaram, M., Pineda, J.R.E. & Murugapandian, S. Glucose-Lowering Medications and Cardiovascular Outcomes. Curr Cardiol Rep 23, 24 (2021). https://doi.org/10.1007/s11886-021-01452-z

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