Diabetes Metab J.  2021 Mar;45(2):158-172. 10.4093/dmj.2020.0296.

Diabetes Management in Patients with Heart Failure

• Shen J
• Greenberg BH

• KMID: 2514192
• DOI: http://doi.org/10.4093/dmj.2020.0296

Abstract

Diabetes and heart failure (HF) are common diseases, each affecting large segments of the world population. Moreover, prevalence rates for both are expected to rise dramatically over coming decades. The high prevalence rates of both diseases and wellrecognized association of diabetes as a risk factor for HF make it inevitable that both diseases co-exist in a large number of patients, complicating their management and increasing the risk of a poor outcome. Management of diabetes has been shown to impact clinical events in patients with HF and there is emerging evidence that agents used to treat diabetes can reduce HF events, even in non-diabetic patients. In this review we summarize the clinical course and treatment of patients with type 2 diabetes mellitus (T2DM) and HF and review the efficacy and safety of pharmacological agents in patients with T2DM at risk for HF and those with established disease.

Keyword

Diabetes mellitus; Heart failure; Risk factors; Sodium glucose cotransporter 2 inhibitor

Figure

• 

Reference

1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019; 157:107843.

2. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014; 63:1123–33.

3. SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325:293–302.

4. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11–21.

5. Lee JH, Lim NK, Cho MC, Park HY. Epidemiology of heart failure in Korea: present and future. Korean Circ J. 2016; 46:658–64.

6. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014; 371:993–1004.

7. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003; 362:772–6.

8. McMurray JJ, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995–2008.

9. From AM, Leibson CL, Bursi F, Redfield MM, Weston SA, Jacobsen SJ, et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006; 119:591–9.

10. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, et al. The EuroHeart Failure survey programme: a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003; 24:442–63.

11. Davies M, Hobbs F, Davis R, Kenkre J, Roalfe AK, Hare R, et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet. 2001; 358:439–44.

12. Amato L, Paolisso G, Cacciatore F, Ferrara N, Ferrara P, Canonico S, et al. Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly. The Osservatorio Geriatrico Regione Campania Group. Diabetes Metab. 1997; 23:213–8.

13. Shi C, Wang LJ, Hu DF, Li JP, Zhu TQ, Shan Y, et al. Prevalence, clinical characteristics and outcome in patients with chronic heart failure and diabetes. Chin Med J (Engl). 2010; 123:646–50.

14. Shiba N, Shimokawa H. Chronic heart failure in Japan: implications of the CHART studies. Vasc Health Risk Manag. 2008; 4:103–13.

15. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000; 283:1295–302.

16. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, DubostBrama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010; 376:875–85.

17. Felker GM, Benza RL, Chandler AB, Leimberger JD, Cuffe MS, Califf RM, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol. 2003; 41:997–1003.

18. Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et al. Association between diabetes mellitus and postdischarge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial. Eur J Heart Fail. 2013; 15:194–202.

19. Greenberg BH, Abraham WT, Albert NM, Chiswell K, Clare R, Stough WG, et al. Influence of diabetes on characteristics and outcomes in patients hospitalized with heart failure: a report from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J. 2007; 154:277.

20. Allen LA, Magid DJ, Gurwitz JH, Smith DH, Goldberg RJ, Saczynski J, et al. Risk factors for adverse outcomes by left ventricular ejection fraction in a contemporary heart failure population. Circ Heart Fail. 2013; 6:635–46.

21. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J. 2008; 29:1377–85.

22. Dauriz M, Targher G, Laroche C, Temporelli PL, Ferrari R, Anker S, et al. Association between diabetes and 1-year adverse clinical outcomes in a multinational cohort of ambulatory patients with chronic heart failure: results from the ESCHFA heart failure long-term registry. Diabetes Care. 2017; 40:671–8.

23. Dauriz M, Mantovani A, Bonapace S, Verlato G, Zoppini G, Bonora E, et al. Prognostic impact of diabetes on long-term survival outcomes in patients with heart failure: a meta-analysis. Diabetes Care. 2017; 40:1597–605.

24. Stettler C, Allemann S, Juni P, Cull CA, Holman RR, Egger M, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J. 2006; 152:27–38.

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

26. 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.

27. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010; 376:419–30.

28. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007; 298:1189–95.

29. Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, et al. Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials. Int J Cardiol. 2010; 143:135–40.

30. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010; 304:411–8.

31. Kaul S, Bolger AF, Herrington D, Giugliano RP, Eckel RH. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation. 2010; 121:1868–77.

32. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001; 103:2668–73.

33. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol. 2009; 54:422–8.

34. Eshaghian S, Horwich TB, Fonarow GC. An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure. Am Heart J. 2006; 151:91.

35. Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL, Olofsson B, et al. The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med. 2008; 168:1699–704.

36. Elder DH, Singh JS, Levin D, Donnelly LA, Choy AM, George J, et al. Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study. Eur J Heart Fail. 2016; 18:94–102.

37. Castagno D, Baird-Gunning J, Jhund PS, Biondi-Zoccai G, MacDonald MR, Petrie MC, et al. Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis. Am Heart J. 2011; 162:938–48.

38. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2020. Diabetes Care. 2020; 43(Suppl 1):S66–S76.

39. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care. 2020; 43(Suppl 1):S98–S110.

40. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012; 22:820–7.

41. 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). Lancet. 1998; 352:854–65.

42. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005; 28:2345–51.

43. Romero SP, Andrey JL, Garcia-Egido A, Escobar MA, Perez V, Corzo R, et al. Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus: a propensity-matched study in the community. Int J Cardiol. 2013; 166:404–12.

44. Tseng CH. Metformin use is associated with a lower risk of hospitalization for heart failure in patients with type 2 diabetes mellitus: a retrospective cohort analysis. J Am Heart Assoc. 2019; 8:e011640.

45. 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; 6:395–402.

46. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes. 2002; 51(Suppl 3):S368–76.

47. BARI 2D Study Group, Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009; 360:2503–15.

48. Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009; 339:b4731.

49. Roumie CL, Min JY, D’Agostino McGowan L, Presley C, Grijalva CG, Hackstadt AJ, et al. Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J Am Heart Assoc. 2017; 6:e005379.

50. 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.

51. Riehle C, Abel ED. Insulin signaling and heart failure. Circ Res. 2016; 118:1151–69.

52. Cooper LB, Mi X, Mentz RJ, Green JB, Anstrom KJ, Hernandez AF, et al. Management of newly treated diabetes in Medicare beneficiaries with and without heart failure. Clin Cardiol. 2017; 40:38–45.

53. Cosmi F, Shen L, Magnoli M, Abraham WT, Anand IS, Cleland JG, et al. Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes. Eur J Heart Fail. 2018; 20:888–95.

54. Gerstein HC, Jung H, Ryden L, Diaz R, Gilbert RE, Yusuf S, et al. Effect of basal insulin glargine on first and recurrent episodes of heart failure hospitalization: the ORIGIN trial (Outcome Reduction with Initial Glargine Intervention). Circulation. 2018; 137:88–90.

55. Della-Morte D, Palmirotta R, Rehni AK, Pastore D, Capuani B, Pacifici F, et al. Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics. 2014; 15:2063–82.

56. Erdmann E, Charbonnel B, Wilcox RG, Skene AM, MassiBenedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007; 30:2773–8.

57. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356:2457–71.

58. Wallach JD, Wang K, Zhang AD, Cheng D, Grossetta Nardini HK, Lin H, et al. Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses. BMJ. 2020; 368:l7078.

59. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, MassiBenedetti 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 randomized controlled trial. Lancet. 2005; 366:1279–89.

60. Komajda M, McMurray JJ, Beck-Nielsen H, Gomis R, Hanefeld M, Pocock SJ, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J. 2010; 31:824–31.

61. 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.

62. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2015; 6:19–28.

63. 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; 373:2247–57.

64. 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; 377:1228–39.

65. 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; 375:311–22.

66. 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; 375:1834–44.

67. 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, randomized placebo-controlled trial. Lancet. 2019; 394:121–30.

68. 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; 381:841–51.

69. Li L, Li S, Liu J, Deng K, Busse JW, Vandvik PO, et al. Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies. BMC Cardiovasc Disord. 2016; 16:91.

70. Munaf M, Pellicori P, Allgar V, Wong K. A meta-analysis of the therapeutic effects of glucagon-like peptide-1 agonist in heart failure. Int J Pept. 2012; 2012:249827.

71. 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; 316:500–8.

72. Jorsal A, Kistorp C, Holmager P, Tougaard RS, Nielsen R, Hanselmann A, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017; 19:69–77.

73. Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab. 2009; 23:479–86.

74. Widlansky ME, Puppala VK, Suboc TM, Malik M, Branum A, Signorelli K, et al. Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy. Vasc Med. 2017; 22:189–96.

75. 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.

76. 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.

77. 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.

78. 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; 321:69–79.

79. Packer M. Do DPP-4 inhibitors cause heart failure events by promoting adrenergically mediated cardiotoxicity?: clues from laboratory models and clinical trials. Circ Res. 2018; 122:928–32.

80. 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.

81. 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 metaanalysis. JAMA. 2018; 319:1580–91.

82. Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2014; 5:355–66.

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

84. Chao EC. SGLT-2 inhibitors: a new mechanism for glycemic control. Clin Diabetes. 2014; 32:4–11.

85. 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; 373:2117–28.

86. 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; 377:644–57.

87. 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; 380:347–57.

88. 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; 380:2295–306.

89. 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; 384:117–28.

90. 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; 383:1425–35.

91. Cosentino F, Cannon CP, Cherney DZ, 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; 142:2205–15.

92. 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; 393:31–9.

93. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017; 136:249–59.

94. Patorno E, Pawar A, Franklin JM, Najafzadeh M, Deruaz-Luyet A, Brodovicz KG, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation. 2019; 139:2822–30.

95. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPERORreduced and DAPA-HF trials. Lancet. 2020; 396:819–29.

96. Damman K, Valente MA, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014; 35:455–69.

97. Jhund PS, Solomon SD, Docherty KF, Heerspink HJ, Anand IS, Bohm M, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation. 2021; 143:298–309.

98. 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; 383:1413–24.

99. Tamargo J. Sodium-glucose cotransporter 2 inhibitors in heart failure: potential mechanisms of action, adverse effects and future developments. Eur Cardiol. 2019; 14:23–32.

100. McMurray J. EMPA-REG: the “diuretic hypothesis”. J Diabetes Complications. 2016; 30:3–4.

101. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010; 90:207–58.

102. Scheen AJ. Pharmacodynamics, efficacy and safety of sodiumglucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015; 75:33–59.

103. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPAREG OUTCOME Study?: a unifying hypothesis. Diabetes Care. 2016; 39:1115–22.