Влияние эмпаглифлозина на переносимость нагрузки и диастолическую функцию левого желудочка у пациентов с сердечной недостаточностью с сохранённой фракцией выброса и сахарным диабетом типа 2: проспективное одноцентровое пилотное исследование

Цель. Оценить влияние ингибитора натрийзависимого переносчика глюкозы 2 типа эмпаглифлозина на переносимость нагрузки и диастолическую функцию левого желудочка у больных с сердечной недостаточностью с сохранённой фракцией выброса (СНсФВ) и сахарным диабетом типа 2 (СД2).

Материал и методы. В настоящее проспективное одноцентровое открытое исследование было включено 60 пациентов с СНсФВ и СД2, которые были распределены в группы приёма эмпаглифлозина 10 мг/сут. или ранее принимаемой гипогликемической терапии (контрольная группа); период наблюдения составил 24 нед. Всем пациентам исходно и в конце исследования выполнили 6-минутный тест ходьбы и эхокардиографию в покое и при нагрузке.

Результаты. Через 24 нед. в группе эмпаглифлозина отмечалось увеличение дистанции 6-минутного теста ходьбы на 20 м (95% доверительный интервал (ДИ) от 7 до 33 м), уменьшение митрального соотношения E/e’ на 1,8 (95% ДИ от -2,4 до -1,2) и максимального объёма левого предсердия на 2,6 (95% ДИ от -4,4 до -0,8) мл/м2 и увеличение диастолического резерва (степени прироста митральной скорости e’ при нагрузке с 2,2 (95% ДИ от 1,7 до 2,7) до 3,4 (95% ДИ от 2,4 до 4,2) см/с; во всех случаях Р<0,01). В контрольной группе значимые изменения отсутствовали.

Заключение. У пациентов с СНсФВ и СД2 эмпаглифлозин улучшает переносимость физической нагрузки и диастолическую функцию левого желудочка. Для подтверждения этих данных требуется проведение крупных плацебо-контролируемых рандомизированных испытаний.

1. 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.

2. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17(9):559-73. doi:10.1038/s41569-020-0363-2.

3. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-71. doi:10.1016/j.jacc.2013.02.092.

4. Dhingra A, Garg A, Kaur S, et al. Epidemiology of heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2014;11(4):354-65. doi:10.1007/s11897-014-0223-7.

5. Saunders J, Mathewkutty S, Drazner M, McGuire D. Cardiomyopathy in type 2 diabetes: Update on pathophysiological mechanisms. Herz. 2008;33(3):184-90. doi:10.1007/s00059-008-3115-3.

6. 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.

7. van Melle J, Bot M, de Jonge P, et al. Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease: data from the heart and soul study. Diabetes Care. 2010;33(9):2084-9. doi:10.2337/dc10-0286.

8. MacDonald M, Petrie M, Varyani F, 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(11):1377-85. doi:10.1093/eurheartj/ehn153.

9. Butler J, Hamo CE, Filippatos G, et al., EMPEROR Trials Program. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19(11):1390-400. doi:10.1002/ejhf.933.

10. Hammoudi N, Jeong D, Singh R, et al. Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther. 2017;31(3):233-46. doi:10.1007/s10557-017-6734-1.

11. Kusaka H, Koibuchi N, Hasegawa Y, et al. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol. 2016;15(1):157. doi:10.1186/s12933-016-0473-7.

12. Joubert M, Jagu B, Montaigne D, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66(4):1030-40. doi:10.2337/db16-0733.

13. Habibi J, Aroor A, Sowers J, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9. doi:10.1186/s12933-016-0489-z.

14. Zimlichman R. Treatment of hypertension and metabolic syndrome: lowering blood pressure is not enough for organ protection, new approach-arterial destiffening. Curr Hypertens Rep. 2014;16(10):479. doi:10.1007/s11906-014-0479-z.

15. Mudaliar S, Alloju S, Henry R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG outcome study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-22. doi:10.2337/dc16-0542.

16. Green J, Bethel M, Armstrong P, 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.

17. Hirakawa Y, Arima H, Zoungas S, et al. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care. 2014;37(8):2359-65. doi:10.2337/dc14-0199.

18. Dormandy J, Charbonnel B, Eckland D, 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. doi:10.1016/S0140-6736(05)67528-9.

19. Cavender M, Scirica B, Raz I, et al. Cardiovascular outcomes of patients in SAVOR-TIMI 53 by baseline hemoglobin A1c. Am J Med. 2016;129(3):340.e1-8. doi:10.1016/j.amjmed.2015.09.022.

20. Fitchett D, Zinman B, Wanner C, et al.; EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J. 2016;37(19):1526-34. doi:10.1093/eurheartj/ehv728.

21. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. doi:10.1002/ejhf.592.

22. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol. 2012;110(6):870-6. doi:10.1016/j.amjcard.2012.05.014.

23. Buckley LF, Canada JM, Del Buono MG, et al. Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction. ESC Heart Fail. 2018;5(2):372-8. doi:10.1002/ehf2.12235.

24. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39.e14. doi:10.1016/j.echo.2014.10.003.

25. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277-314. doi:10.1016/j.echo.2016.01.011.

26. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713. doi:10.1016/j.echo.2010.05.010.

27. Овчинников А. Г., Агеев Ф. Т., Алёхин М. Н. и др. Диастолическая трансторакальная стресс-эхокардиография с дозированной физической нагрузкой в диагностике сердечной недостаточности с сохранённой фракцией выброса: показания, методология, интерпретация результатов. Ультразвуковая и функциональная диагностика. 2020;2:60-90. doi:10.24835/1607-0771-2020-2-60-90.

28. Pieske B, Tschope C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297-317. doi:10.1093/eurheartj/ehz641.

29. Redfield MM, Chen HH, Borlaug BA, et al.; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-77. doi:10.1001/jama.2013.2024.

30. O’Keeffe ST, Lye M, Donnellan C, Carmichael DN. Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients. Heart. 1998;80(4):377-82. doi:10.1136/hrt.80.4.377.

31. Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J. 2020;ehaa943. doi:10.1093/eurheartj/ehaa943.

32. Овчинников А. Г., Потехина А. В., Ибрагимова Н. М. и др. Механизмы плохой переносимости физической нагрузки у больных с СНсФВ. Часть I: роль нарушений со стороны левых камер сердца. Кардиология 2019;59(6S):4-16. doi:10.18087/cardio.n394.

33. Madamanchi C, Alhosaini H, Sumida A, Runge MS. Obesity and natriuretic peptides, BNP and NT-proBNP: mechanisms and diagnostic implications for heart failure. International Journal of Cardiology. 2014;176(3):611-7. doi:10.1016/j.ijcard.2014.08.007.

34. Januzzi JL Jr, Butler J, Jarolim P, et al. Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes. J Am Coll Cardiol. 2017;70(6):704-12. doi:10.1016/j.jacc.2017.06.016.

35. Dekkers CCJ, Sjostrom CD, Greasley PJ, et al. Effects of the sodium glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(12):2667-73. doi:10.1111/dom.13855.

36. Matsutani D, Sakamoto M, Kayama Y, et al. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):73. doi:10.1186/s12933-018-0717-9.

37. Ferrannini G, Hach T, Crowe S, et al. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730-5. doi:10.2337/dc15-0355.

38. Packer M. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: a paradigm shift in understanding their mechanism of action. Diabetes Care. 2020;43(3):508-11. doi:10.2337/dci19-0074.

39. Kalra S, Jain A, Ved J, Unnikrishnan AG. Sodiumglucose cotransporter 2 inhibition and health benefits: the Robin Hood effect. Indian J Endocrinol Metab. 2016;20(5):725-9. doi:10.4103/2230-8210.183826.

40. Pabel S, Wagner S, Bollenberg H, et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 2018;20(12):1690-700. doi:10.1002/ejhf.1328.

41. Kolijn D, Pabel S, Tian Y, et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Ga oxidation. Cardiovasc Res. 2020;cvaa123. doi:10.1093/cvr/cvaa123.

42. Baartscheer A, Schumacher C, Wust 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. doi:10.1007/s00125-016-4134-x.

43. Packer M, Anker SD, Butler J, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action JAMA Cardiol. 2017;2(9):1025-9. doi:10.1001/jamacardio.2017.2275.

44. Verma S, Mazer CD, Yan AT, et al. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019;140(21):1693-702. doi:10.1161/CIRCULATIONAHA.119.042375.

45. Bami K, Gandhi S, Leong-Poi H, et al. Effects of Empagliflozin on Left Ventricular Remodeling in Patients with Type 2 Diabetes and Coronary Artery Disease: Echocardiographic Substudy of the EMPA-HEART CardioLink-6 Randomized Clinical Trial. J Am Soc Echocardiogr. 2020;33(5):644-6. doi:10.1016/j.echo.2020.02.005.

46. Ovchinnikov AG, Potekhina AV, Borisov AA, et al. The contribution of left atrial dysfunction to exercise intolerance in early heart failure with preserved left ventricular ejection fraction. Eur Heart J Cardiovasc Imag. 2019;21(Suppl 1):1743. doi:10.1093/ehjci/jez320.

47. Melenovsky V, Hwang SJ, Lin G, et al. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J. 2014;35(48):3452-62. doi:10.1093/eurheartj/ehu193.

48. Gorter TM, van Veldhuisen DJ, Bauersachs J, et al. Right heart dysfunction and failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(1):16-37. doi:10.1002/ejhf.1029.

49. Phan TT, Shivu GN, Abozguia K, et al. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail 2010;3(1):29-34. doi:10.1161/CIRCHEARTFAILURE.109.877720.

50. Pandey A, Khera R, Park B, et al. Relative impairments in hemodynamic exercise reserve parameters in heart failure with preserved ejection fraction: a study-level pooled analysis. JACC Heart Fail. 2018;6(2):117-26. doi:10.1016/j.jchf.2017.10.014.

51. Huang PH, Leu HB, Chen JW, et al. Comparison of endothelial vasodilator function, inflammatory markers, and N-terminal pro-brain natriuretic peptide in patients with or without chronotropic incompetence to exercise test. Heart. 2006;92(5):609-14. doi:10.1136/hrt.2005.064147.

52. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-29. doi:10.1016/S0140-6736(20)31824-9.