Современная парадигма патофизиологии, профилактики и лечения сердечной недостаточности при сахарном диабете 2 типа

Актуальной проблемой  при сахарном  диабете  2 типа (СД2) остается профилактика и выбор терапевтических  стратегий  при сердечной  недостаточности (СН). В настоящем  обзоре  изложена современная концепция формирования СН при СД2 начиная с его ранних этапов, а также рассмотрены группы сахароснижающих и кардиологических  препаратов  для профилактики и лечения СН в зависимости от ее фенотипов у пациентов с СД2.

1. Шестакова М. В., Дедов И. И. Сахарный диабет в Российской Федерации: аргументы и факты. Терапевтический архив. 2016;88(10):4-8. doi:10.17116/terarkh201688104-8.

2. Russell ND, Cooper ME. 50 years forward: mechanisms of hyperglycaemia-driven diabetic complications. Diabetologia. 2015;58(8):1708-14. doi:10.1007/s00125-015-3600-1.

3. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-23. doi:10.1056/ NEJMoa1310799.

4. Дедов И. И., Шестакова М. В., Викулова О. К., и др. Сахарный диабет в Российской Федерации: распространенность, заболеваемость, смертность, параметры углеводного обмена и структура сахароснижающей терапии по данным Федерального регистра сахарного диабета, статус 2017 г. Сахарный диабет. 2018;21(3):144-59. doi:10.14341/DM9686.

5. Alonso-Morán E, Orueta JF, Fraile Esteban JI, et al. The prevalence of diabetes-related complications and multimorbidity in the population with type 2 diabetes mellitus in the Basque Country. BMC Public Health. 2014;14:1059. doi:10.1186/1471-2458-14-1059.

6. Paneni F. Empagliflozin across the stages of diabetic heart disease. Eur Heart J. 2018;39(5):371-3. doi:10.1093/eurheartj/ehx519.

7. Dei Cas A, Khan SS, Butler J, et al. Impact of Diabetes on Epidemiology, Treatment and Outcomes of Patients with Heart Failure. JACC Heart Failure. 2015;3:136-45. doi:10.1016/j.jchf.2014.08.004.

8. Lundbaek K. Diabetic angiopathy. A specific vascular disease. Lancet 1954;263:377-9. doi:10.1016/S0140-6736(54)90924-1.

9. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035-8. doi:10.1001/jama.1979.03290450033020.

10. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-12. doi:10.1136/bmj.321.7258.405.

11. Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America. Circulation. 2019 Jun 6:CIR0000000000000691. doi:10.1161/CIR.0000000000000691. [Epub ahead of print].

12. Кобалава Ж. Д., Кохан Е. В., Киякбаев Г. К., Шаваров А. А. Фибрилляция предсердий и артериальная гипертония: гендерные особенности желудочково-предсердного ремоделирования при сохраненной фракции выброса левого желудочка. Рациональная фармакотерапия в кардиологии. 2017;13(4):541-9. doi:10.20996/1819-6446-2017-13-4-541-549.

13. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1,9 million people. Lancet Diabetes Endocrinol. 2015;3:105-13. doi:10.1016/S2213-8587(14)70219-0.

14. Rawshani A, Rawshani A, Franzén S, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2018;379(3):633-44. doi:10.1056/NEJMoa1800256.

15. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-57. doi:10.1056/NEJMoa1812389.

16. Zoppini G, Bergamini C, Bonapace S, et al. Association between subclinical left ventricular systolic dysfunction and glycemic control in asymptomatic type 2 diabetic patients with preserved left ventricular function. J Diabetes Complications. 2017;31(6):1035-40. doi:10.1016/j.jdiacomp.2017.01.021.

17. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol. 2010;55(4):300-5. doi:10.1016/j.jacc.2009.12.003.

18. Faden G, Faganello G, De Feo S, et al. The increasing detection of asymptomatic left ventricular dysfunction in patients with type 2 diabetes mellitus without overt cardiac disease: data from the SHORTWAVE study. Diabetes Res Clin Pract. 2013;101(3):309-16. doi:10.1016/j.diabres.2013.07.004.

19. Selvin E, Lazo M, Chen Y, et al. Diabetes mellitus, prediabetes, and incidence of subclinical myocardial damage. Circulation. 2014;130(16):1374-82. doi:10.1161/ CIRCULATIONAHA.114.010815.

20. Ohkuma T, Jun M, Woodward M, et al. Cardiac Stress and Inflammatory Markers as Predictors of Heart Failure in Patients With Type 2 Diabetes: The ADVANCE Trial. Diabetes Care. 2017;40(9):1203-9. doi:10.2337/dc17-0509.

21. Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J. 2018;39(48):4243-54. doi:10.1093/eurheartj/ehy596.

22. Margulies KB, Hernandez AF, Redfield MM, 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. doi:10.1001/jama.2016.10260.

23. Jorsal A, Kistorp C, Holmager P, 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(1):69-77. doi:10.1002/ejhf.657.

24. McMurray JJV, Ponikowski P, Bolli GB, 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. 2018;6(1):8-17. doi:10.1016/j.jchf.2017.08.004.

25. Мареев В. Ю., Фомин И. В., Агеев Ф. Т., и др. Клинические рекомендации ОССН-РКО-РНМОТ. Сердечная недостаточность: хроническая (ХСН) и острая декомпенсированная (ОДСН). Диагностика, профилактика и лечение. Кардиология. 2018;58(6S):8-158. doi:10.18087/cardio.2475.

26. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-239. doi:10.1016/j.jacc.2013.05.019.

27. Zoroufian A, Razmi T, Taghavi-Shavazi M, et al. Evaluation of subclinical left ventricular dysfunction in diabetic patients: longitudinal strain velocities and left ventricular dyssynchrony by two-dimensional speckle tracking echocardiography study. Echocardiography. 2014;31(4):456-63. doi:10.1111/echo.12389.

28. Leung M, Wong VW, Hudson M, Leung DY. Impact of Improved Glycemic Control on Cardiac Function in Type 2 Diabetes Mellitus. Circ Cardiovasc Imaging. 2016;9(3):e003643. doi:10.1161/CIRCIMAGING.115.003643.

29. Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015;36(27):1718-27, 1727a-1727c. doi:10.1093/eurheartj/ehv134.

30. Seferović PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(5):853-72. doi:10.1002/ejhf.1170.

31. Ofstad AP, Atar D, Gullestad L, et al. The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions. Heart Fail Rev. 2018;23(3):303-23. doi:10.1007/s10741-018-9685-0.

32. Bernardi S, Michelli A, Zuolo G, et al. Update on RAAS Modulation for the Treatment of Diabetic Cardiovascular Disease. J Diabetes Res. 2016;2016:8917578. doi:10.1155/2016/8917578.

33. Andersson C, Vasan RS. Epidemiology of heart failure with preserved ejection fraction. Heart Fail Clin. 2014;10(3):377-88. doi:10.1016/j.hfc.2014.04.003.

34. Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation. 2012;126(1):65-75. doi:10.1161/CIRCULATIONAHA.111.080770.8.

35. Kato ET, Silverman MG, Mosenzon O, et al. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circulation. 2019;139(22):2528-36. doi:10.1161/ CIRCULATIONAHA.119.040130.

36. Fang JC. Heart Failure With Preserved Ejection Fraction: A Kidney Disorder? Circulation. 2016;134(6):435-7. doi:10.1161/CIRCULATIONAHA.116.022249.

37. Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J. 2018;39(5):363-70. doi:10.1093/eurheartj/ehx511.

38. Lindman BR. The Diabetic Heart Failure With Preserved Ejection Fraction Phenotype: Is it Real and Is It Worth Targeting Therapeutically? Circulation. 2017;135(8):736-40. doi:10.1161/CIRCULATIONAHA.116.025957.

39. Ter Maaten JM, Damman K, Verhaar MC, et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail. 2016;18(6):588-98. doi:10.1002/ejhf.497.

40. AlZadjali MA, Godfrey V, Khan F, et al. Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J Am Coll Cardiol. 2009;53(9):747-53. doi:10.1016/j.jacc.2008.08.081.

41. Greenberg BH, Abraham WT, Albert NM, 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(2):277.e1-8. doi:10.1016/j.ahj.2007.05.001.

42. Dauriz M, Targher G, Laroche C, 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 ESC-HFA Heart Failure Long-Term Registry. Diabetes Care. 2017;40(5):671-8. doi:10.2337/dc16-2016.

43. Siedlecki Ł, Szyguła-Jurkiewicz B, Pyka Ł, et al. Clinical features, management and mortality in diabetic and non-diabetic patients with heart failure — observations from the COMMIT-HF registry. Kardiochir Torakochirurgia Pol. 2017;14(3):170-4. doi:10.5114/kitp.2017.70530.

44. Арутюнов А.Г., Драгунов Д.О., Арутюнов Г.П., и др. Первое открытое исследование синдрома острой декомпенсации сердечной недостаточности и сопутствующих заболеваний в Российской Федерации. Независимый регистр ОРАКУЛ-РФ. Кардиология. 2015;55(5):12-21.

45. Andersson C, Norgaard ML, Hansen PR, et al. Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study. Eur J Heart Fail. 2010;12(12):1333-8. doi:10.1093/eurjhf/hfq160.

46. Guglin M, Lynch K, Krischer J. Heart failure as a risk factor for diabetes mellitus. Cardiology. 2014;129(2):84-92. doi:10.1159/000363282.

47. Benedict CR, Weiner DH, Johnstone DE, et al. Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the studies of left ventricular dysfunction (SOLVD) registry. J Am Coll Cardiol. 1993;22:146A-153A.

48. Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circ Res. 2016;118(7):1151-69. doi:10.1161/CIRCRESAHA.116.306206.

49. Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005;111(11):1448-54. doi:10.1161/01.CIR.0000158483.13093.9D.

50. Feldman AM, Combes A, Wagner D, et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol. 2000;35(3):537-44. doi:10.1016/s0735-1097(99)00600-2.

51. Дедов И. И., Шестакова М. В., Майоров А. Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. М.: УП ПРИНТ, 2019. p. 212. doi:10.14341/DM221S1. ISBN 978-5-91487-136-6.

52. Action to Control Cardiovascular Risk in Diabetes Study Group, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-59. doi:10.1056/NEJMoa0802743.

53. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-39. doi:10.1056/NEJMoa0808431.

54. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-72. doi:10.1056/NEJMoa0802987.

55. Heller SR, ADVANCE Collaborative Group. A summary of the ADVANCE Trial. Diabetes Care. 2009;32(Suppl 2):S357-61. doi:10.2337/dc09-S339.

56. Macisaac RJ, Jerums G. Intensive glucose control and cardiovascular outcomes in type 2 diabetes. Heart Lung Circ. 2011;20(10):647-54. doi:10.1016/j.hlc.2010.07.013.

57. Castagno D, Baird-Gunning J, Jhund PS, 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 metaanalysis. Am Heart J. 2011;162:938-948. doi:10.1016/j.ahj.2011.07.030.

58. Bowes CD, Lien LF, Butler J. Assessment of Heart Failure in Diabetes Cardiovascular Outcomes Trials: Is What We Are Currently Capturing Adequate? Curr Diab Rep. 2019;19(7):39. doi:10.1007/s11892-019-1154-1.

59. Vijayakumar S, Vaduganathan M, Butler J. Glucose-Lowering Therapies and Heart Failure in Type 2 Diabetes Mellitus: Mechanistic Links, Clinical Data, and Future Directions. Circulation. 2018;137(10):1060-73. doi:10.1161/CIRCULATIONAHA.117.032099.

60. Кобалава Ж. Д., Киякбаев Г. К. Влияние сахароснижающих препаратов на прогноз сердечно-сосудистых осложнений при сахарном диабете 2-го типа: реалии и перспективы. Кардиология. 2018;58(1):53-65. doi:10.18087/cardio.2018.1.10082.

61. Галстян Г. Р., Гиляров М. Ю. Сердечная недостаточность у пациентов с сахарным диабетом 2 типа: влияние антидиабетической терапии. Сахарный диабет. 2016;19(3):229-36. doi:10.14341/DM2003451-57.

62. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and metaanalysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-9. doi:10.1016/S0140-6736(18)32590-X.

63. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35. doi:10.1056/NEJMoa1305889.

64. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067-76. doi:10.1016/S0140-6736(14)62225-X.

65. 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(14):1317-26. doi:10.1056/NEJMoa1307684.

66. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-42. doi:10.1056/NEJMoa1501352.

67. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373(23):2247-57. doi:10.1056/NEJMoa1509225.

68. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-22. doi:10.1056/NEJMoa1603827.

69. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-44. doi:10.1056/NEJMoa1607141.

70. 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. doi:10.1056/NEJMoa1612917.

71. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. doi:10.1056/NEJMoa1504720.

72. Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus. Circulation. 2018;138(5):458-68. doi:10.1161/CIRCULATIONAHA.118.034222.

73. Heerspink HJL, Kosiborod M, Inzucchi ES, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018;94(1):26-39. doi:10.1016/j.kint.2017.12.027.

74. Lytvyn Y, Bjornstad P, Udell JA, et al. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials. Circulation. 2017;136(17):1643-58. doi:10.1161/CIRCULATIONAHA.117.030012.

75. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-17. doi:10.1007/s00125-018-4670-7.

76. Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12(10):566-92. doi:10.1038/nrendo.2016.86.

77. Kaplan A, Abidi E, El-Yazbi A, et al. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev. 2018;23(3):419-37. doi:10.1007/s10741-017-9665-9.

78. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471-76. doi:10.1016/j.jjcc.2017.12.004.

79. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90-S102. doi:10.2337/dc19-S009.

80. Packer M. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care. 2018;41(1):11-3. doi:10.2337/dci17-0052.

81. Ponikowski P., Voors A., Anker S., и др. Рекомендации ESC по диагностике и лечению острой и хронической сердечной недостаточности 2016. Российский кардиологический журнал. 2017;(1):7-81. doi:10.15829/1560-4071-2017-1-7-81.

82. Strauss MH, Hall AS. The Divergent Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Adult Patients With Type 2 Diabetes Mellitus. Can J Diabetes. 2018;42(2):124-9. doi:10.1016/j.jcjd.2017.09.011.

83. Lam PH, Dooley DJ, Fonarow GC, et al. Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial. Eur J Heart Fail. 2018;20(2):359-69. doi:10.1002/ejhf.937.

84. Cheng J, Zhang W, Zhang X, et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis. JAMA Intern Med. 2014;174(5):773-85. doi:10.1001/jamainternmed.2014.348.

85. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077.

86. Kristensen SL, Preiss D, Jhund PS, et al. Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial. Circ Heart Fail. 2016;9(1). doi:10.1161/CIRCHEARTFAILURE.115.002560.

87. Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5(5):333-40. doi:10.1016/S2213-8587(17)30087-6.

88. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316(23):1429-35. doi:10.1056/NEJM198706043162301.

89. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction — Results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669-77. doi:10.1056/NEJM199209033271001.

90. Moyé LA, Pfeffer MA, Wun CC, et al. Uniformity of captopril benefit in the SAVE Study: subgroup analysis. Survival and Ventricular Enlargement Study. Eur Heart J. 1994;15 Suppl B:2-8; discussion 26-30. doi:10.1093/eurheartj/15.suppl_b.2.

91. Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol. 1996;77(11):1017-20. doi:10.1016/S0002-9149(97)89163-1.

92. Rydén L, Armstrong PW, Cleland JG, et al. Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J. 2000;21(23):1967-78. doi:10.1053/euhj.2000.2311.

93. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-75. doi:10.1056/NEJMoa010713.

94. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362(9386):767-71. doi:10.1016/S0140-6736(03)14283-3.

95. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374(9704):1840-8. doi:10.1016/S0140-6736(09)61913-9.

96. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-7. doi:10.1016/S0140-6736(99)04440-2.

97. Erdmann E, Lechat P, Verkenne P, Wiemann H. Results from post-hoc analyses of the CIBIS II trial: effect of bisoprolol in high-risk patient groups with chronic heart failure. Eur J Heart Fail. 2001;3(4):469-79. doi:10.1016/S1388-9842(01)00174-X.

98. Packer M, Fowler MB, Roecker EB, et al. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure. Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation. 2002;106:2194-9. doi:10.1161/01.CIR.0000035653.72855.BF.

99. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26(3):215-25. doi:10.1093/eurheartj/ehi115.

100. Pitt B, Zannad F, Remme WJ, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med. 1999;341:709-17. doi:10.1056/NEJM199909023411001.

101. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. doi:10.1056/NEJMoa1009492.

102. Diabetes Canada Clinical Practice Guidelines Expert Committee. Treatment of Diabetes in People With Heart Failure. Can J Diabetes. 2018;42 Suppl 1:S196-S200. doi:10.1016/j.jcjd.2017.10.026.

103. Torp-Pedersen C, Metra M, Charlesworth A, et al. Effects of metoprolol and carvedilol on pre-existing and new onset diabetes in patients with chronic heart failure: data from the Carvedilol Or Metoprolol European Trial (COMET). Heart. 2007;93:968-73. doi:10.1136/hrt.2006.092379

104. Merrill J, Dungan KM. Beta-Blocker Usage and Hypoglycemia in Hospitalized Patients with Diabetes Mellitus. Diabetes. 2018;67(Supplement 1). doi:10.2337/db18-382-P.

105. Casiglia E, Tikhonoff V. Long-Standing Problem of β-Blocker-Elicited Hypoglycemia in Diabetes Mellitus. Hypertension. 2017;70(1):42-3. doi:10.1161/HYPERTENSIONAHA.117.09378.

106. McMurray JJV, DeMets DL, Inzucchi SE, 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. doi:10.1002/ejhf.1432.

107. McMurray JJV, DeMets DL, Inzucchi SE, et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019 Jul 15. doi:10.1002/ejhf.1548. [Epub ahead of print]

108. McMurray JJV. DAPA HF — The Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial: ESC Congress 2019. https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Hot-Line-Session-1/204417-dapa-hf-the-dapagliflozin-and-prevention-of-adverse-outcomes-in-heart-failure-trial#slide (11 September 2019)

109. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-85. doi:10.1016/S0140-6736(10)61198-1.

110. Kosmas CE, Silverio D, Sourlas A, et al. Role of spironolactone in the treatment of heart failure with preserved ejection fraction. Ann Transl Med. 2018;6(23):461. doi:10.21037/atm.2018.11.16.

111. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362(9386):777-81. doi:10.1016/S0140-6736(03)14285-7.

112. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338-45. doi:10.1093/eurheartj/ ehl250.

113. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-67. doi:10.1056/NEJMoa0805450.

114. van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53:2150-8. doi:10.1016/j.jacc.2009.02.046.

115. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-92. doi:10.1056/NEJMoa1313731.

116. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Sep 1. doi:10.1056/NEJMoa1908655. [Epub ahead of print].