Сахарный диабет 2‑го типа и сердечная недостаточность: инновационные возможности управления прогнозом

В современном мире сахарный диабет (СД) 2‑го типа вышел за рамки профессиональных интересов одной специальности. СД 2‑го типа, сердечно-сосудистые заболевания и хроническая болезнь почек, рассматриваемые с позиций единого кардиорено-метаболического континуума, ложатся тяжким экономическим бременем на общество. В то же время совершенствование методов диагностики и медицинских технологий привело к отчетливому снижению частоты и смертности от ряда осложнений СД 2‑го типа, включая инфаркт миокарда и инсульт, но их место заняли иные состояния. Так, сердечная недостаточность (СН) при СД 2‑го типа заняла позицию одного из самых частых осложнений с распространенностью в среднем 24–40 %. У пациентов с СД 2‑го типа установлена неоднородность СН со значительным преобладанием СН с сохраненной фракцией выброса (СН-сФВ) с формированием ее новой парадигмы. Согласно этой парадигме СН-сФВ представляет собой системное заболевание, центральным звеном которого является нарушение функции почек. Все это в совокупности обладает потенциальным значением при выборе оптимальной терапии. В последние годы стали известны результаты исследований сердечно-сосудистой безопасности сахароснижающих препаратов из групп ингибиторов дипептилпептидазы-4, агонистов глюкагоноподобного пептида-1 и ингибиторов натрий-глюкозного котранспортера 2‑го типа (иНГЛТ2). Данные препараты, кроме иНГЛТ2, по механизму своего действия влияющие на инсулинорезистентность и гипергликемию, продемонстрировали нейтральный или отрицательный результат влияния на частоту госпитализаций из‑за СН. Исследование EMPA-REG OUTCOME с иНГЛТ2, обладающим особым инсулиннезависимым механизмом действия, продемонстрировало снижение не только сердечно-сосудистой смертности на 38 %, но и частоты госпитализаций по поводу СН на 35 %. Дальнейшие исследования с иНГЛТ2 подтвердили положительное влияние на СН, свидетельствуя о класс-эффекте препаратов. Завершившееся недавно исследование DECLARE-TIMI 58 убедительно доказало преимущества применения дапаглифлозина с целью первичной и вторичной профилактики СН. В настоящем обзоре освещены вопросы распространенности СН при СД 2‑го типа, новой концепции патофизиологии СН, рассмотрены основные группы сахароснижающих препаратов и их влияние на сердечно-сосудистые исходы, в частности на СН.

1. Lundbæk K. Diabetic angiopathy: a specific vascular disease. The Lancet. 1954;263(6808):377–9. DOI: 10.1016/S0140-6736(54)90924-1

2. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. The American Journal of Cardiology. 1972;30(6):595–602. DOI: 10.1016/0002-9149(72)90595-4

3. Kannel WB. Diabetes and Cardiovascular Disease: The Framingham Study. JAMA. 1979;241(19):2035–8. DOI: 10.1001/jama.1979.03290450033020

4. Zhang P-Y. Cardiovascular disease in diabetes. European Review for Medical and Pharmacological Sciences. 2014;18(15):2205–14. PMID: 25070828

5. Fan W. Epidemiology in diabetes mellitus and cardiovascular disease: Cardiovascular Endocrinology. 2017;6(1):8–16. DOI: 10.1097/XCE.0000000000000116

6. Gregg EW, Li Y, Wang J, Rios Burrows N, Ali MK, Rolka D et al. Changes in Diabetes-Related Complications in the United States, 1990–2010. New England Journal of Medicine. 2014;370 (16):1514–23. DOI: 10.1056/NEJMoa1310799

7. Alonso-Morán E, Orueta JF, Esteban JIF, Axpe JMA, González MLM, Polanco NT 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(1):1059. DOI: 10.1186/1471-2458-14-1059

8. Rosano GM, Clinical Academic Group Cardiovascular, St George’s Hospital NHS Trust Medical School, London, UK, Vitale C, Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy, Seferovic P, Department of Cardiology, University of Belgrade, Belgrade, Serbia. Heart Failure in Patients with Diabetes Mellitus. Cardiac Failure Review. 2017;03(01):52–5. DOI: 10.15420/cfr.2016:20:2

9. Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1,9 million people. The Lancet Diabetes & Endocrinology. 2015;3(2):105–13. DOI: 10.1016/S2213-8587(14)70219-0

10. Фомин И. В. Хроническая сердечная недостаточность в Российской Федерации: что сегодня мы знаем и что должны делать. Российский кардиологический журнал. 2016;8:7-13. DOI: 10.15829/1560-4071-2016-8-7-13

11. Мареев В.Ю., Фомин И.В., Агеев Ф.Т., Арутюнов Г.П., Беграмбекова Ю.Л., Беленков Ю.Н. и др. Клинические рекомендации. Хроническая сердечная недостаточность (ХСН). Журнал Сердечная Недостаточность. 2017;18(1):3–40. DOI: 10.18087/rhfj.2017.1.2346

12. Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a twofaced disease with restrictive and dilated phenotypes. European Heart Journal. 2015;36(27):1718–27. DOI: 10.1093/eurheartj/ehv134

13. Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure. 2018;20(5):853–72. DOI: 10.1002/ejhf.1170

14. Ofstad AP, Atar D, Gullestad L, Langslet G, Johansen OE. The heart failure burden of type 2 diabetes mellitus – a review of pathophysiology and interventions. Heart Failure Reviews. 2018;23(3):303–23. DOI: 10.1007/s10741-018-9685-0

15. Guja C, Miulescu RD. Heart Failure in Type 2 Diabetes – The “Forgotten” Complication. Rom J Diabetes Nutr Metab Dis. 2018;25(2):123–30. DOI: 10.2478/rjdnmd-2018-0014

16. McMurray JJV, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. The Lancet Diabetes & Endocrinology. 2014;2(10):843–51. DOI: 10.1016/S2213-8587(14)70031-2

17. Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC. Heart failure. 2015;3(2):136–45. DOI: 10.1016/j.jchf.2014.08.004

18. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of Medicine. 2006;355(3):251–9. DOI: 10.1056/NEJMoa052256

19. 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

20. MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS et al. Treatment of Type 2 Diabetes and Outcomes in Patients With Heart Failure: A Nested Case-Control Study From the U.K. General Practice Research Database. Diabetes Care. 2010;33(6):1213–8. DOI: 10.2337/dc09-2227

21. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. New England Journal of Medicine. 2007;356(24):2457–71. DOI: 10.1056/NEJMoa072761

22. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373(22):2117–28. DOI: 10.1056/NEJMoa1504720

23. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular

24. Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus – Mechanisms, Management, and Clinical Considerations. Circulation. 2016;133(24):2459–502. DOI: 10.1161/CIRCULATIONAHA.116.022194

25. Boyer JK, Thanigaraj S, Schechtman KB, Pérez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. The American Journal of Cardiology. 2004;93(7):870–5. DOI: 10.1016/j.amjcard.2003.12.026

26. Liu JE, Palmieri V, Roman MJ, Bella JN, Fabsitz R, Howard BV et al. The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the strong heart study. Journal of the American College of Cardiology. 2001;37(7):1943–9. DOI: 10.1016/S0735-1097(01)01230-X

27. Knapp M, Tu X, Wu R. Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy. Acta Pharmacologica Sinica. 2019;40(1):1–8. DOI: 10.1038/s41401-018-0042-6

28. Campbell P, Krim S, Ventura H. The Bi-directional Impact of Two Chronic Illnesses: Heart Failure and Diabetes – A review of the Epidemiology and Outcomes. Cardiac Failure Review. 2015;1(1):8–10. DOI: 10.15420/cfr.2015.01.01.8

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

30. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C 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. European Heart Journal. 2018;39(5):363–70. DOI: 10.1093/eurheartj/ehx511

31. Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clinical Journal of the American Society of Nephrology. 2017;12(12):2032–45. DOI: 10.2215/CJN.11491116

32. Lim A. Diabetic nephropathy – complications and treatment. International Journal of Nephrology and Renovascular Disease. 2014;7:361–81. DOI: 10.2147/IJNRD.S40172

33. 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

34. Komici K, Femminella GD, de Lucia C, Cannavo A, Bencivenga L, Corbi G et al. Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity. Aging Clinical and Experimental Research. 2018;[Epub ahead of print]. DOI: 10.1007/s40520-018-0973-2

35. ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation: HFpEF and renal dysfunction. European Journal of Heart Failure. 2016;18(6):588–98. DOI: 10.1002/ejhf.497

36. Boudina S, Abel ED. Mitochondrial Uncoupling: A Key Contributor to Reduced Cardiac Efficiency in Diabetes. Physiology. 2006;21(4):250–8. DOI: 10.1152/physiol.00008.2006

37. Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation Research. 2016;118(7):1151–69. DOI: 10.1161/CIRCRESAHA.116.306206

38. Gupta S, Jhawat V. Induction of Type 2 Diabetes Mellitus with Antihypertensive Therapy: Is There Any Role of Alpha Adducin, ACE, and IRS-1 Gene? Value in Health Regional Issues. 2017;12:90–8. DOI: 10.1016/j.vhri.2016.10.005

39. Camici PG, Crea F. Coronary Microvascular Dysfunction. New England Journal of Medicine. 2007;356(8):830–40. DOI: 10.1056/NEJMra061889

40. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. European Heart Journal. 2014;35(17):1101–11. DOI: 10.1093/eurheartj/eht513

41. Gawlowski T, Stratmann B, Stork I, Engelbrecht B, Brodehl A, Niehaus K et al. Heat Shock Protein 27 Modification is Increased in the Human Diabetic Failing Heart. Hormone and Metabolic Research. 2009;41(08):594–9. DOI: 10.1055/s-0029-1216374

42. Tarquini R, Lazzeri C, Pala L, Rotella CM, Gensini GF. The diabetic cardiomyopathy. Acta Diabetologica. 2011;48(3):173–81. DOI: 10.1007/s00592-010-0180-x

43. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. American Heart Journal. 2005;149(1):168–74. DOI: 10.1016/j.ahj.2004.07.005

44. Mangiavacchi M, Gasparini M, Genovese S, Pini D, Klersy C, Bragato R et al. Insulin-Treated Type 2 Diabetes Is Associated with a Decreased Survival in Heart Failure Patients after Cardiac Resynchronization Therapy. Pacing and Clinical Electrophysiology. 2008;31(11):1425–32. DOI: 10.1111/j.1540-8159.2008.01206.x

45. Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. BMJ. 2016;354:i3477. DOI: 10.1136/bmj.i3477

46. Tiwari S, Riazi S, Ecelbarger CA. Insulin’s impact on renal sodium transport and blood pressure in health, obesity, and diabetes. American Journal of Physiology-Renal Physiology. 2007;293(4):F974–84. DOI: 10.1152/ajprenal.00149.2007

47. 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: Insulin treatment and prognosis in chronic HF. European Journal of Heart Failure. 2018;20(5):888–95. DOI: 10.1002/ejhf.1146

48. 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. Circulation: Heart Failure. 2013;6(3):395–402. DOI: 10.1161/CIRCHEARTFAILURE.112.000162

49. Ouyang J, Parakhia RA, Ochs RS. Metformin Activates AMP Kinase through Inhibition of AMP Deaminase. Journal of Biological Chemistry. 2011;286(1):1–11. DOI: 10.1074/jbc.M110.121806

50. Дедов И.И., Шестакова М.В., Майоров А.Ю., Викулова О.К., Галстян Г.Р., Кураева Т.Л. и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. Под ред. Дедова И.И., Шестаковой М.В., Майорова А.Ю. – 8-й выпуск. Сахарный диабет. 2017;20(1S):1-121. DOI: 10.14341/DM20171S8

51. Niessner A, Tamargo J, Koller L, Saely CH, Schmidt TA, Savarese G et al. Non-insulin antidiabetic pharmacotherapy in patients with established cardiovascular disease: a position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy. European Heart Journal. 2018;39(24):2274–81. DOI: 10.1093/eurheartj/ehx625

52. Sola D, Rossi L, Schianca GPC, Maffioli P, Bigliocca M, Mella R et al. State of the art paper Sulfonylureas and their use in clinical practice. Archives of Medical Science. 2015;11(4):840–8. DOI: 10.5114/aoms.2015.53304

53. Phung OJ. Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes. JAMA. 2010;303(14):1410–8. DOI: 10.1001/jama.2010.405

54. NAVIGATOR Study Group, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B et al. Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events. New England Journal of Medicine. 2010;362(16):1463–76. DOI: 10.1056/NEJMoa1001122

55. Greenfield JR, Chisholm DJ. Experimental and clinical pharmacology: Thiazolidinediones – mechanisms of action. Australian Prescriber. 2004;27(3):67–70. DOI: 10.18773/austprescr.2004.059

56. Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends in Endocrinology & Metabolism. 2012;23(5):205–15. DOI: 10.1016/j.tem.2012.03.001

57. 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. The Lancet. 2005;366(9493):1279–89. DOI: 10.1016/S0140-6736(05)67528-9

58. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet. 2009;373(9681):2125–35. DOI: 10.1016/S0140-6736(09)60953-3

59. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials. JAMA. 2007;298(10):1180–8. DOI: 10.1001/jama.298.10.1180

60. Hernandez AV, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and Risk of Heart Failure in Patients with or at High Risk of Type 2 Diabetes Mellitus: A Meta-Analysis and Meta-Regression Analysis of Placebo-Controlled Randomized Clinical Trials. American Journal Cardiovascular Drugs. 2011;11(2):115–28. DOI: 10.2165/11587580-000000000-00000

61. DiNicolantonio JJ, Bhutani J, O’Keefe JH. Acarbose: safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open Heart. 2015;2(1):e000327. DOI: 10.1136/openhrt-2015-000327

62. Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nature Reviews Endocrinology. 2016;12(10):566–92. DOI: 10.1038/nrendo.2016.86

63. 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. New England Journal of Medicine. 2013;369(14):1327–35. DOI: 10.1056/NEJMoa1305889

64. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT 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. The Lancet. 2015;385(9982):2067–76. DOI: 10.1016/S0140-6736(14)62225-X

65. 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. New England Journal of Medicine. 2013;369(14):1317–26. DOI: 10.1056/NEJMoa1307684

66. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2015;373(3):232–42. DOI: 10.1056/NEJMoa1501352

67. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):311–22. DOI: 10.1056/NEJMoa1603827

68. Williams TC, Stewart E. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2017;376(9):890–2. DOI: 10.1056/NEJMc1615712

69. 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. New England Journal of Medicine. 2015;373(23):2247–57. DOI: 10.1056/NEJMoa1509225

70. 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. New England Journal of Medicine. 2017;377(13):1228–39. DOI: 10.1056/NEJMoa1612917

71. 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. New England Journal of Medicine. 2017;377(7):644–57. DOI: 10.1056/NEJMoa1611925

72. Rådholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program. Circulation. 2018;138(5):458–68. DOI: 10.1161/CIRCULATIONAHA.118.034222

73. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019;380(4):347–57. DOI: 10.1056/NEJMoa1812389

74. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology. 2012;8(12):728–42. DOI: 10.1038/nrendo.2012.140

75. McGuire DK, Van de Werf F, Armstrong PW, Standl E, Koglin J, Green JB et al. Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiology. 2016;1(2):126–35. DOI: 10.1001/jamacardio.2016.0103

76. Abel ED. Myocardial Insulin Resistance and Cardiac Complications of Diabetes. Current Drug Targets - Immune, Endocrine & Metabolic Disorders. 2005;5(2):219–26. DOI: 10.2174/1568008054064869

77. 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. Journal of Cardiac Failure. 2006;12(9):694–9. DOI: 10.1016/j.cardfail.2006.08.211

78. Velez M, Peterson EL, Wells K, Swadia T, Sabbah HN, Williams LK et al. Association of Antidiabetic Medications Targeting the Glucagon-Like Peptide 1 Pathway and Heart Failure Events in Patients With Diabetes. Journal of Cardiac Failure. 2015;21(1):2–8. DOI: 10.1016/j.cardfail.2014.10.012

79. 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. DOI: 10.1001/jama.2016.10260

80. Jorsal A, Kistorp C, Holmager P, Tougaard RS, Nielsen R, Hänselmann 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: Effect of liraglutide on LV function in stable HF patients with and without diabetes. European Journal of Heart Failure. 2017;19(1):69–77. DOI: 10.1002/ejhf.657

81. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney International. 2018;94(1):26–39. DOI: 10.1016/j.kint.2017.12.027

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. DOI: 10.1161/CIRCULATIONAHA.117.030012

83. 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

84. Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Failure Reviews. 2018;23(3):419–37. DOI: 10.1007/s10741-017-9665-9

85. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. Journal of Cardiology. 2018;71(5):471–6. DOI: 10.1016/j.jjcc.2017.12.004

86. Wittbrodt ET, Eudicone JM, Bell KF, Enhoffer DM, Latham K, Green JB. Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population. The American Journal of Managed Care. 2018;24(8 Suppl):S138–45. PMID: 29693360

87. 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. The Lancet. 2019;393(10166):31–9. DOI: 10.1016/S0140-6736(18)32590-X