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Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

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Abstract

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a “cardiac” drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.

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Abbreviations

T2DM:

Type 2 diabetes mellitus

CV:

Cardiovascular

SGLT-2i:

Sodium-glucose cotransporter 2 inhibitors

MI:

Myocardial infarction

HR:

Hazard ratio

References

  1. Santos-Gallego CG, Picatoste B, Badimón JJ. Pathophysiology of acute coronary syndrome. Curr Atheroscler Rep. 2014 Apr;16(4):401.

  2. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2019. Circulation. 2018.

  3. Reusch JEB, Manson JE. Management of type 2 diabetes in 2017. JAMA. 2017;317:1015–6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:2011–30.

    Article  Google Scholar 

  5. Dalama B, Mesa J. New oral hypoglycemic agents and cardiovascular risk. Crossing the metabolic border. Rev Esp Cardiol. 2016;69(11):1088–97.

    Article  PubMed  Google Scholar 

  6. Defronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36:S127–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 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 

  9. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9.

    Article  Google Scholar 

  10. de Leeuw AE, de Boer RA. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. Eur Heart J Cardiovasc Pharmacother. 2016;2(4):244–55.

    Article  PubMed  CAS  Google Scholar 

  11. Paul SK, Klein K, Thorsted BL, Wolden ML, Khunti K. Delay in treatment intensification increases the risk of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:100.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. Long-term follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1565–76.

    Article  PubMed  CAS  Google Scholar 

  13. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein H, Miller M, Byington R, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59.

    Article  Google Scholar 

  14. Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016 May;39(5):738–42.

    Article  PubMed  Google Scholar 

  15. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Stoll BJ, et al. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40:S64–74.

    Article  Google Scholar 

  17. Zonszein J, Groop PH. Strategies for diabetes management: using newer oral combination therapies early in the disease. Diabetes Ther. 2016;7(4):621–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016 Oct;12(10):566–92.

    Article  PubMed  CAS  Google Scholar 

  19. Bain SC, Feher M, Russell-Jones D, Khunti K. Management of type 2 diabetes: the current situation and key opportunities to improve care in the UK. Diabetes Obes Metab. 2016;18(12):1157–66.

    Article  PubMed  CAS  Google Scholar 

  20. Nissen SE, Wolski K. Rosiglitazone revisited: un updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170914):1191–1201.

  21. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.

  22. Delea TE, Edelsberg JS, Hagiwara M, Oster G, Philips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2003;26(11):2983–9.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a posiion statement of the american diabetes association and the european association for the study of diabetes. Diabetes Care. 2015;38(1):140–9.

    Article  PubMed  Google Scholar 

  25. Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Obes Metab. 2014;16(1):30–7.

    Article  PubMed  CAS  Google Scholar 

  26. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.

  27. 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  PubMed  CAS  Google Scholar 

  28. 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  PubMed  CAS  Google Scholar 

  29. Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical. Cardiovasc Ther. 2014;32(4):147–58.

    Article  PubMed  CAS  Google Scholar 

  30. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med. 2014;370(9):794–7.

    Article  PubMed  CAS  Google Scholar 

  31. The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28.

    Article  CAS  Google Scholar 

  32. 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  PubMed  CAS  Google Scholar 

  33. 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  PubMed  CAS  Google Scholar 

  34. Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol. 2017;5(9):680–1.

    Article  PubMed  Google Scholar 

  35. Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18(4):317–32.

    Article  PubMed  CAS  Google Scholar 

  36. 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  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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(19):1834–44.

    Article  PubMed  CAS  Google Scholar 

  38. 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):1228–39.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  40. Bethel M, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105–13.

    Article  PubMed  Google Scholar 

  41. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8:495-502.

  42. Lee YJ, Han HJ. Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl. 2007;106:S27–35.

    Article  CAS  Google Scholar 

  43. American Diabetes Association. Standards of medical care in diabetes-2017 a bridged for primary care providers. Clin Diabetes. 2017;35(1):5–26.

    Article  PubMed Central  Google Scholar 

  44. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure. Circulation. 2017;136(17):1643–58.

    Article  PubMed  CAS  Google Scholar 

  45. Cefalu WT, Riddle MC. SGLT2 inhibitors: The latest “New kids on the block”! Diabetes Care. 2015;38(3):352–4.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Badimon JJ, Santos-Gallego CG, Badimon L. [Importance of HDL cholesterol in atherothrombosis: how did we get here? Where are we going?]. Rev Esp Cardiol 2010;63 Suppl 2:20–35.

  47. Santos-Gallego CG. HDL: Quality or quantity? Atherosclerosis 2015;243(1):121–3.

  48. Badimon JJ, Santos-Gallego CG. HDL Dysfunction: Is the Answer in the Sphinx's Riddle? J Am Coll Cardiol 2015;66(13):1486–8.

  49. Santos-Gallego CG, Badimon JJ, Rosenson RS. Beginning to understand high-density lipoproteins. Endocrinol Metab Clin North Am 2014;43(4):913–47.

  50. Santos-Gallego CG, Rosenson RS. Role of HDL in Those with Diabetes. Curr Cardiol Rep 2014;16(8):512.

  51. Santos-Gallego CG, Giannarelli C, Badimon JJ. Experimental models for the investigation of high-density lipoprotein-mediated cholesterol efflux. Curr Atheroscler Rep 2011;13(3):266–76

  52. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediatin analysis of the EMPA-REG OUTCOME. Diabetes Care. 2018;41(2):356–63.

    Article  PubMed  Google Scholar 

  53. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 1995;9:651–8.

  54. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care 2016;39:1108–14.

  55. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115–22.

    Article  PubMed  CAS  Google Scholar 

  56. 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  PubMed  CAS  Google Scholar 

  57. Packer M, Anker SD, Butler J, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025–9.

    Article  PubMed  Google Scholar 

  58. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia. 2018;61(3):722–6.

    Article  PubMed  CAS  Google Scholar 

  59. Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of te cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–73.

    Article  PubMed  CAS  Google Scholar 

  60. Santos-Gallego CG, Vahl TP, Goliasch G, Picatoste B, Arias T, Ishikawa K, et al. Sphingosine-1-phosphate receptor agonist fingolimod increases myocardial salvage and decreases adverse postinfarction left ventricular remodeling in a porcine model of ischemia/reperfusion. Circulation. 2016;133(10):954–66.

    Article  PubMed  CAS  Google Scholar 

  61. Santos-Gallego C, Requena-Ibanez JA, Rodolfo San Antonio R et al. Empagliflozin induces a myocardial metabolic shift from glucose consumption to ketone metabolism that mitigates adverse cardiac remodeling and improves myocardial contractility. ACC-2018 Moderated Poster # 1318M-07.

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Authors and Affiliations

  1. Cardiology Department, Clinic Hospital, Barcelona, Spain

    Eduardo Flores

  2. Atherothrombosis Research Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, USA

    Eduardo Flores, Carlos G. Santos-Gallego & Juan Jose Badimon

  3. Hospital Vall d’Hebron, Barcelona, Spain

    Nely Diaz-Mejía

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  1. Eduardo Flores
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  2. Carlos G. Santos-Gallego
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  3. Nely Diaz-Mejía
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  4. Juan Jose Badimon
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Correspondence to Juan Jose Badimon.

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Flores, E., Santos-Gallego, C.G., Diaz-Mejía, N. et al. Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?. Cardiovasc Drugs Ther 32, 213–222 (2018). https://doi.org/10.1007/s10557-018-6786-x

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