Mechanisms of cardiovascular protection of non-insulin antidiabetic medications

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Abstract

Patients with type 2 diabetes mellitus die most frequently from cardiovascular disease (CVD). Metabolic control is a cornerstone of both primary and secondary prevention of CVD: its important is two-fold since the normalization of HbA1c not only counteracts the onset, and the progression of microvascular complication, but has also important and positive role in reducing the risk of major adverse cardiovascular events (MACE). However, among the available glucose-lowering medications, some exert a direct CV protection independently from their ability to normalize metabolic control. In this review I will highlight the pathophysiological mechanisms underlying the claimed cardiovascular protection of the different glucose-lowering drugs, the available evidence-based data for their protection, the potential adverse effects, and the different phenotypes of patients eligible for a specific treatment. The knowledge of pathophysiological mechanisms for CV protection of each glucose-lowering medication, and the constraints of their use supports the health care professionals to individualize the normalization of metabolic control in patients with type 2 diabetes mellitus.

About the authors

Angelo Avogaro

University of Padova. Italy

Author for correspondence.
Email: angelo.avogaro@unipd.it
ORCID iD: 0000-0002-1177-0516

Professor of Endocrinology & Metabolic Diseases

Unit of Metabolic Diseases

Department of Internal Medicine

University of Padova. Italy

Italy, Department of Medicine Via Giustiniani 2 35128 Padova Italy

References

  1. Schramm TK, Gislason GH, Kober L, Rasmussen S, Rasmussen JN, Abildstrom SZ, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008;117(15):1945-54.
  2. Rawshani A, Rawshani A, Franzen S, Sattar N, Eliasson B, Svensson AM, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2018;379(7):633-44.
  3. Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. European heart journal. 2013;34(31):2436-43.
  4. Virmani R, Burke AP, Kolodgie F. Morphological characteristics of coronary atherosclerosis in diabetes mellitus. Can J Cardiol. 2006;22 Suppl B:81B-4B.
  5. Triggle CR, Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium. Acta Physiol (Oxf). 2017;219(1):138-51.
  6. Gallo A, Ceolotto G, Pinton P, Iori E, Murphy E, Rutter GA, et al. Metformin prevents glucose-induced protein kinase C-beta2 activation in human umbilical vein endothelial cells through an antioxidant mechanism. Diabetes. 2005;54(4):1123-31.
  7. 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(9131):854-65.
  8. 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(9):1620-9.
  9. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative Safety and Effectiveness of Metformin in Patients With Diabetes Mellitus and Heart Failure Systematic Review of Observational Studies Involving 34 000 Patients. Circ-Heart Fail. 2013;6(3):395-+.
  10. Roumie CL, Min JY, McGowan LD, Presley C, Grijalva CG, Hackstadt AJ, et al. Comparative Safety of Sulfonylurea and Metformin Monotherapy on the Risk of Heart Failure: A Cohort Study. Journal of the American Heart Association. 2017;6(4).
  11. 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(5):706-14.
  12. Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. The lancet Diabetes & endocrinology. 2014;2(2):116-24.
  13. Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a K-ATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol-Heart C. 2007;292(4):H1883-H90.
  14. Scognamiglio R, Avogaro A, de Kreutzenberg SV, Negut C, Palisi M, Bagolin E, et al. Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. Diabetes. 2002;51(3):808-12.
  15. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabetic Med. 2013;30(10):1160-71.
  16. Fadini GP, Avogaro A, Degli Esposti L, Russo P, Saragoni S, Buda S, et al. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database. Eur Heart J. 2015;36(36):2454-62.
  17. Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Featherstone TR. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. The lancet Diabetes & endocrinology. 2015;3(1):43-51.
  18. Rados DV, Pinto LC, Remonti LR, Canani LH, Leitao CB, Gross JL. Sulphonylureas Are Not Associated with Increased Mortality: Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials. Diabetes. 2015;64:A5-A.
  19. Nagendran M, Dimick JB, Gonzalez AA. Mortality Among Older Adults Before Versus After Transition to Intensivist Staffing (vol 54, pg 67, 2016). Med Care. 2016;54(5):545-.
  20. Mogensen UM, Andersson C, Fosbol EL, Schramm TK, Vaag A, Scheller NM, et al. Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality-A retrospective nationwide study. Diabetes research and clinical practice. 2015;107(1):104-12.
  21. Eriksson JW, Bodegard J, Nathanson D, Thuresson M, Nystrom T, Norhammare A. Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality. Diabetes research and clinical practice. 2016;117:39-47.
  22. Quast U, Stephan D, Bieger S, Russ U. The impact of ATP-sensitive K(+) channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium. Diabetes. 2004;53:S156-S64.
  23. 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. (vol 362, pg 1463, 2010). New Engl J Med. 2010;362(18):1748-.
  24. Zeymer U, Schwarzmaier-D'assie A, Petzinna D, Chiasson JL, Grp S-NTR. Effect of acarbose treatment on the risk of silent myocardial infarctions in patients with impaired glucose tolerance: results of the randomised STOP-NIDDM trial electrocardiography substudy. Eur J Cardiov Prev R. 2004;11(5):412-5.
  25. Frantz S, Schmidt I, Calvillo L, Dienesch C, Elbing I, Bischoff H, et al. Acarbose treatment reduces cardiac ischemia/reperfusion injury in mice. Diabetologia. 2004;47:A424-A.
  26. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, et al. Acarbose for patients with hypertension and impaired glucose tolerance - Reply. Jama-J Am Med Assoc. 2003;290(23):3067-9.
  27. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. European heart journal. 2004;25(1):10-6.
  28. van de Laar FV, Lucassen PLBJ. No evidence for a reduction of myocardial infarctions by acarbose. European heart journal. 2004;25(13):1179-.
  29. Chang CH, Chang YC, Lin JW, Chen ST, Chuang LM, Lai MS. Cardiovascular Risk Associated With Acarbose Versus Metformin as the First-Line Treatment in Patients With Type 2 Diabetes: A Nationwide Cohort Study. J Clin Endocr Metab. 2015;100(3):1121-9.
  30. Holman RR, Coleman RL, Chan JCN, Chiasson JL, Feng HM, Ge JB, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endo. 2017;5(11):877-86.
  31. McGuire DK, Inzucchi SE. New drugs for the treatment of diabetes mellitus: part I: Thiazolidinediones and their evolving cardiovascular implications. Circulation. 2008;117(3):440-9.
  32. Blaschke F, Spanheimer R, Khan M, Law RE. Vascular effects of TZDs: new implications. Vascul Pharmacol. 2006;45(1):3-18.
  33. Erdmann E, Wilcox R. Pioglitazone and mechanisms of CV protection. QJM. 2010;103(4):213-28.
  34. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, 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(9493):1279-89.
  35. 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. The lancet Diabetes & endocrinology. 2017;5(11):887-97.
  36. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. The New England journal of medicine. 2016;374(14):1321-31.
  37. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1-2):127-36.
  38. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37(10):2884-94.
  39. Fadini GP, Avogaro A. Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis. 2013;229(1):23-9.
  40. Brenner C, Franz WM, Kuhlenthal S, Kuschnerus K, Remma F, Gross L, et al. DPP-4 inhibition ameliorates atherosclerosis by priming monocytes into M2 macrophages. International Journal of Cardiology. 2015;199:163-9.
  41. Fadini GP, Menegazzo L, Rigato M, Scattolini V, Poncina N, Bruttocao A, et al. NETosis Delays Diabetic Wound Healing in Mice and Humans. Diabetes. 2016;65(4):1061-71.
  42. Marfella R, Sasso FC, Rizzo MR, Paolisso P, Barbieri M, Padovano V, et al. Dipeptidyl Peptidase 4 Inhibition May Facilitate Healing of Chronic Foot Ulcers in Patients with Type 2 Diabetes. Experimental Diabetes Research. 2012.
  43. Chang CC, Chen YT, Hsu CY, Su YW, Chiu CC, Leu HB, et al. Dipeptidyl Peptidase-4 Inhibitors, Peripheral Arterial Disease, and Lower Extremity Amputation Risk in Diabetic Patients. Am J Med. 2017;130(3):348-55.
  44. Long M, Cai LQ, Li WJ, Zhang LL, Guo SD, Zhang R, et al. DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring. Diabetes. 2018;67(3):518-31.
  45. Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P. Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med. 2014;3(8):949-57.
  46. Lovshin JA, Rajasekeran H, Lytvyn Y, Lovblom LE, Khan S, Alemu R, et al. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1alpha(1-67) in Patients With Type 2 Diabetes. Diabetes Care. 2017;40(8):1073-81.
  47. Devin JK, Pretorius M, Nian H, Yu C, Billings FTt, Brown NJ. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014;3(4).
  48. Beleigoli A, Diniz M, Nunes M, Barbosa M, Fernandes S, Abreu M, et al. Reduced brain natriuretic peptide levels in class III obesity: the role of metabolic and cardiovascular factors. Obes Facts. 2011;4(6):427-32.
  49. Fadini GP, Bonora BM, Albiero M, Zaninotto M, Plebani M, Avogaro A. DPP-4 inhibition has no acute effect on BNP and its N-terminal pro-hormone measured by commercial immune-assays. A randomized cross-over trial in patients with type 2 diabetes. Cardiovasc Diabetol. 2017;16(1):22.
  50. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24(7):689-97.
  51. Fadini GP, Saragoni S, Russo P, Degli Esposti L, Vigili de Kreutzenberg S, Melazzini M, et al. Intraclass differences in the risk of hospitalization for heart failure among patients with type 2 diabetes initiating a dipeptidyl peptidase-4 inhibitor or a sulphonylurea: Results from the OsMed Health-DB registry. Diabetes Obes Metab. 2017;19(10):1416-24.
  52. Scirica BM, Mosenzon O, Bhatt DL, Udell JA, Steg PG, McGuire DK, et al. Cardiovascular Outcomes According to Urinary Albumin and Kidney Disease in Patients With Type 2 Diabetes at High Cardiovascular Risk: Observations From the SAVOR-TIMI 53 Trial. JAMA Cardiol. 2017.
  53. 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.
  54. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2015.
  55. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579-88.
  56. 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. 2017.
  57. Kim YG, Yoon D, Park S, Han SJ, Kim DJ, Lee KW, et al. Dipeptidyl Peptidase-4 Inhibitors and Risk of Heart Failure in Patients With Type 2 Diabetes Mellitus: A Population-Based Cohort Study. Circ Heart Fail. 2017;10(9).
  58. Koyani CN, Kolesnik E, Wolkart G, Shrestha N, Scheruebel S, Trummer C, et al. Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. Biochem Pharmacol. 2017;145:64-80.
  59. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA (R)). Diabetes Vasc Dis Re. 2015;12(3):164-74.
  60. Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest. 2017;127(12):4217-27.
  61. 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.
  62. Bao WK, Aravindhan K, Alsaid H, Chendrimada T, Szapacs M, Citerone DR, et al. Albiglutide, a Long Lasting Glucagon-Like Peptide-1 Analog, Protects the Rat Heart against Ischemia/Reperfusion Injury: Evidence for Improving Cardiac Metabolic Efficiency. Plos One. 2011;6(8).
  63. Timmers L, Henriques JPS, de Kleijn DPV, DeVries JH, Kemperman H, Steendijk P, et al. Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury. Journal of the American College of Cardiology. 2009;53(6):501-10.
  64. Nikolic D, Volti GL, Corrado E, Giglio RV, Chianetta R, Castellino G, et al. Exenatide LAR Improves Endothelial Function: An Eight-Month Prospective Study. Diabetes. 2017;66:A300-A1.
  65. Torimoto K, Okada Y, Mori H, Otsuka T, Kawaguchi M, Matsuda M, et al. Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovascular Diabetology. 2015;14.
  66. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962-5.
  67. Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart. 2012;98(5):408-13.
  68. Read PA, Hoole SP, White PA, Khan FZ, O'Sullivan M, West NE, et al. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv. 2011;4(3):266-72.
  69. Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33(12):1491-9.
  70. Kyhl K, Lonborg J, Vejlstrup N, Kelbaek H, Helqvist S, Holmvang L, et al. A post hoc analysis of long-term prognosis after exenatide treatment in patients with ST-segment elevation myocardial infarction. EuroIntervention. 2016;12(4):449-55.
  71. Woo JS, Kim W, Ha SJ, Kim JB, Kim SJ, Kim WS, et al. Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol. 2013;33(9):2252-60.
  72. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694-9.
  73. Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316(5):500-8.
  74. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38-47.
  75. 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.
  76. Buse JB, the LSC. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(18):1798-9.
  77. 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.
  78. 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.
  79. Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA. 2018;319(15):1580-91.
  80. Zhang L, Zhang M, Lv Q, Tong N. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and moderate renal function impairment: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2018;140:295-303.
  81. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018;94(1):26-39.
  82. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials. Circulation. 2017;136(17):1643-58.
  83. 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.
  84. 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.
  85. Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):610-21.
  86. Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018.
  87. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-34.
  88. Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia. 2017;60(3):568-73.
  89. Avogaro A, Fadini GP, Sesti G, Bonora E, Del Prato S. Continued efforts to translate diabetes cardiovascular outcome trials into clinical practice. Cardiovasc Diabetol. 2016;15(1):111.

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