САХАРНЫЙ ДИАБЕТ 2 ТИПА И СЕРДЕЧНО-СОСУДИСТЫЕ ОСЛОЖНЕНИЯ: МОЖНО ЛИ УЛУЧШИТЬ ПРОГНОЗ НАЗНАЧЕНИЕМ САХАРОСНИЖАЮЩИХ ПРЕПАРАТОВ

Несмотря на то, что с сахарным диабетом 2 типа (СД 2 типа) связан высокий риск развития сердечно-сосудистых заболеваний (ССЗ) и их осложнений, в т.ч. сердечной недостаточности (СН), применение большинства сахароснижающих препаратов (ССП) не только не улучшает прогноз жизни этих пациентов, но может повышать риск развития СН. Ингибиторы SGLT2 (глифлозины), новая группа ССП с уникальным неинсулинзависимым механизмом действия, в ряде крупных рандомизированных клинических исследований (РКИ) выдержали не только обязательный тест на сердечно-сосудистую безопасность, но и продемонстрировали способность существенно снижать риск развития комбинированной конечной точки (сердечно-сосудистая смерть, нефатальные ИМ и инсульты) и вероятность госпитализации по поводу СН. Выводы РКИ убедительно подтверждены реальной клинической практикой лечения больных с СД 2 типа, проанализированной в крупнейших многоцентровых исследованиях CVD-REAL и CVD-REAL-2. В них впервые назначенные ингибиторы SGLT2 (в Европе в подавляющем большинстве случаев дапаглифлозин) имели достоверные преимущества перед впервые назначенными ССП других классов по отношению рисков госпитализации по поводу СН и смерти от любой причины. Однако, совокупный период применения глифлозинов является непродолжительным, поэтому ответ на вопрос о стабильности их эффектов в более глубокой перспективе ожидается получить по завершении продолжающихся РКИ как у больных с высоким сердечно-сосудистым риском, так и у больных с СН, в т.ч. не имеющих СД.

1. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241(19):2035-8.

2. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose сoncentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-22. doi:10.1016/S0140-6736(10)60484-9.

3. Di Angelantonio E, Kaptoge S, Wormser D, et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314:52-60. doi:10.1001/JAMA.2015.7008.

4. IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF diabetes atlas: estimates for the year 2013. Diabetes Res Clin Pract. 2015;109(3):461-5. doi:10.1016/j.diabres.2015.05.037.

5. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387:1513-30. doi:10.1016/S0140-6736(16)00618-8.

6. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373:1720-32. doi:10.1056/NEJMoa1504347.

7. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360. doi:10.1161/CIR.0000000000000350.

8. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2015;132:691-718. doi:10.1161/CIR.0000000000000230.

9. Cavender MA, Steg G, Smith SC, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death. Outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) registry. Circulation. 2015;132:923-31. doi:10.1161/CIRCULATIONAHA.114.014796.

10. Fitchett D, Zinman B, Wanner C, et al. 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;37:1526-34. doi:10.1093/EURHEARTJ/EHV728.

11. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-42. doi:10.1056/NEJMOA1501352.

12. Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27:699-703.

13. 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.

14. Lopaschuk GD, Ussher JR, Folmes CD, et al. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-58. doi:10.1152/PHYSREV.00015.2009.

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

16. Drosatos K, Schulze PC. Cardiac lipotoxicity: molecular pathways and therapeutic implications. Curr Heart Fail Rep. 2013;10:109-21. doi:10.1007/s11897-013-0133-0.

17. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 2004;18:1692-700. doi:10.1096/ fj.04-2263com.

18. Saunders J, Mathewkutty S, Drazner MH, McGuire DK. Cardiomyopathy in type 2 diabetes: Update on pathophysiological mechanisms. Herz. 2008;33:184. doi:10.1007/ S00059-008-3115-3.

19. Rijzewijk LJ, van der Meer RW, Smit JW, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52:1793-9. doi:10.1016/J.JACC.2008.07.062.

20. Korosoglou G, Humpert PM, Ahrens J, et al. Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve. J Magn Reson Imaging. 2012;35:804-11. doi:10.1002/JMRI.22879.

21. Metra M, Cotter G, Gheorghiade M, et al. The role of the kidney in heart failure. Eur Heart J. 2012;33:2135-42. doi:10.1093/eurheartj/ehs205.

22. Solini A, Penno G, Bonora E, et al. Renal Insufficiency And Cardiovascular Events (RIACE) Study Group. Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: the Renal Insufficiency and Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care. 2012;35:143-9. doi:10.2337/DC11-1380.

23. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalised with heart failure. J Am Coll Cardiol. 2004;43:61-7.

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

25. 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.

26. 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.

27. Gerstein HCJr, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-59. doi:10.1056/NEJMoa0802743.

28. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. NEngl JMed. 2008;358:2560-72. doi:10.1056/ NEJMoa0802987.

29. Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818-28. doi:10.1056/NEJMoa1006524.

30. 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.

31. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J. 2005;149:168-74.

32. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843-51. doi:10.1016/S2213-8587(14)70031-2.

33. Food and Drug Administration: Guidance for industry: diabetes mellitusevaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://ww.fda. gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/ ucm071627.pdf.

34. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus. Available from: http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.

35. Kristensen SL, Preiss D, Jhund PS, et al. PARADIGM-HF Investigators and Committees. 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;Jan;9(1).pii: e002560. doi:10.1161/CIRCHEARTFAILURE.115.002560.

36. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-26. doi:10.1056/NEJMoa1307684.

37. McGuire DK, Van de Werf F, Armstrong PW, 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 Cardiol. 2016;1(2):126-35. doi:10.1001/jamacardio.2016.0103.

38. Pfeffer MA, Claggett В, 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.

39. 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.

40. 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.

41. Holman RR, Bethel MA, Mentz RJ, et al.; EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Sep 28;377(13):1228-39. doi:10.1056/NEJMoa1612917.

42. Oyama J, Node K. Incretin therapy and heart failure. Circ J. 2014;78(4):819-24. doi:10.1253/circj.CJ-13-1561.

43. Zheng SL, Roddick AJ, Aghar-Jaffar R, 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. doi:10.1001/jama.2018.3024.

44. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32(4):515-31. doi:10.1210/er.2010-0029.

45. Wilding JP, Blonde L, Leiter LA, et al. Efficacy and safety of canagliflozin by baseline HbAlc and known duration of type 2 diabetes mellitus. J Diabetes Complications. 2015;29(3):438-44. doi:10.1016/j.jdiacomp.2014.

46. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, doubleblind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217-24. doi:10.2337/dc10-0612.

47. Barnett AH, Mithal A, Manassie J, et al.; investigators E-RRt. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-84. doi:10.1016/S2213-8587(13)70208-0.

48. Avogaro A, Giaccari A, Fioretto P, et al. A consensus statement for the clinical use of the renal sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes mellitus. Expert Rev Clin Pharmacol. 2017;10(7):763-72. doi:10.1080/1751243 3.2017.1322507.

49. Stein P, Berg JK, Morrow L, et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial. Metabolism. 2014;63(10):1296-303. doi:10.1016/j.metabol.2014.07.003.

50. Stenlof К, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: Findings from the 52-Week CANTATA-M study. Curr Med Res Opin. 2014;30(2):163-75. doi: 10.1185/03007995.2013.850066.

51. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebocontrolled 102-week trial. BMC Medicine. 2013:11:43. doi:10.1186/1741-7015-11-43.

52. Rosenstock J, Chuck L, Gonzalez-Ortiz M, et al. Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naive type 2 diabetes. Diabetes Care. 2016;39(3):353-62. doi:10.2337/dc15-1736.

53. Nauck MA, Del Prato S, Duran-Garcia S, et al. Durability of glycaemic efficacy over 2years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab. 2014;16(11):1111-20. doi:10.1111/dom.12327.

54. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17(6):581-90. doi:10.1111/dom.12459.

55. Kovacs CS, Scshiah V, Swallow R, et al; EMPA-REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebocontrolled trial. Diabetes Obes Metab. 2014:16(2):147-58. doi:10.1111/dom.12188.

56. Rosenstock J, Jelaska A, Zeller C, et al; EMPA-REG BASALTM trial investigators. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2015;17(10):936-48. doi:10.1111/dom.12503.

57. Wilding JP, Woo V, Rohwedder K, et al; Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014;16(2):124-36. doi:10.1111/dom.12187.

58. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016 Feb 19;15:37. doi:10.1186/s12933-016-0356-y.

59. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015:373:2117-28. doi:10.1056/NEJMoa1504720.

60. US Food and Drug Administration (FDA). Guidance for Industry: Non-Inferiority Clinical Trials. FDA. Silver Spring. MD. 2010.

61. Kaul S. Is the mortality benefit with empagliflozin in type 2 diabetes mellitus too good to be true? Circulation. 2016;134:94-6. doi:10.1161/CIRCULATIONAHA.116.022537.

62. 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 Heart J. 2016;37:2129-200. doi:10.1093/eurheartj/ehw128.

63. Butler J, Kalogeropoulos A, Georgiopoulou V, et al. Incident heart failure prediction in the elderly: the health ABC heart failure score. Circ Heart Fail. 2008;1:125-33. doi:10.1161/ CIRCHEARTFAILURE.108.768457.

64. 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. 2017;0:1-8. doi:10.1093/eurheartj/ehx511.

65. Fitchett D, Zinman B, Wanner Ch, et al. the 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.

66. Neal B, Perkovic V, Mahaffey KW, et al. on behalf of the CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57. doi:10.1056/NEJMoa1611925.

67. Packer M. Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure. Circulation. 2017;136(16):1548-59. doi:10.1161/CIRCULATIONAHA.117.030418.

68. Kosiborod M, Cavender MA, Fu AZ, et al. and on behalf of the CVD-REAL Investigators and Study Group. Lower Risk of Heart Failure and Death in Patients Initiated on SodiumGlucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs.The CVDREAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-59. doi:10.1161/CIRCULATIONAHA.117.029190.

69. Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci. 2010;25:1-21. doi:10.1214/09-STS313.

70. Birkeland KI, Jørgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5(9):709-17. doi:10.1016/S2213-8587(17)30258-9.

71. Norhammar A, Bodegard J, Nystrom Th, et al. Dapagliflozin is Associated With Lower Risk of Hospitalization for Heart Failure, Major Adverse Cardiovascular Events and All-Cause Death Compared to DPP-4i in T2D Patients: CVD-REAL Nordic. Canadian Journal of Diabetes. 2017;41(5): Suppl, P51.

72. FDA Briefing Document Endocrine and Metabolic Drug Advisory Committee Meeting June 28, 2016. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/EndocrinologicandMetabolic rugsAdvisoryCommittee/UCM508422.pdf.

73. Kosiborod M, Lam C, Kohsaka S, et al. Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018;71(23):2628-39. doi:10.1016/j.jacc.2018.03.009.

74. DECLARE-TIMI 58: Dapagliflozin Effects on Cardiovascular Events. https://www. clinicaltrials.gov/ct2/show/NCT01730534.

75. Singh JS, Fathi A, Vickneson K, et al. Research into the effect of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Cardiovasc Diabetol. 2016;15:97. doi:10.1186/s12933-016-0419-0.

76. Dapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients With Heart Failure (DEFINE-HF). NCT02653482. https://clinicaltrials.gov/ct2/show/NCT02653482.

77. Dapagliflozin in Type 2 Diabetes or Pre-diabetes, and PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF). NCT03030235. https://clinicaltrials.gov/ct2/show/NCT03030235.

78. Tanaka A, Node K. Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology. Journal of Cardiology. 2017;69:501-7. doi:10.1016/j.jjcc.2016.10.019.

79. Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752-72. doi:10.1161/CIRCULATIONAHA.116.021887.

80. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium–glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney. Int 2016;89:524-6. doi:10.1016/j.kint.2015.12.038.

81. Baker WL, Smyth LR, Riche DM, et al. Effects of sodium–glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262-75.e9. doi:10.1016/j.jash.2014.01.007.

82. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180-93. doi:10.1111/dom.12572.

83. De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis. 2014;64:16-24. doi:10.1053/j.ajkd.2014.02.010.

84. Gilbert RE. Sodium–glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int. 2014;86:693-700. doi:10.1038/ki.2013.451.

85. Cherney DZ, Perkins BA, Soleymanlou, et al. Renal hemodynamic effect of sodium– glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587-97. doi:10.1161/CIRCULATIONAHA.113.005081.

86. Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306:F194-204. doi:10.1152/ajprenal.00520.2013.

87. Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59:1860-70. doi:10.1007/s00125-016-4008-2.

88. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-34. doi:10.1056/NEJMoa1515920.

89. Bolinder J, Ljunggren OЁ, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159-69. doi:10.1111/dom.12189.

90. Neeland IJ, McGuire DK, Chilton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diabetes Vasc Dis Res. 2016;13:119-26. doi:10.1177/1479164115616901.

91. Dapa-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). https:// clinicaltrials.gov/ct2/show/results/NCT03036124.

92. EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction). https://clinicaltrials.gov/ct2/show/NCT03057977.