Статья
Выбор сахароснижающих препаратов у больных сахарным диабетом 2‑го типа очень высокого сердечно-сосудистого риска (часть 2)
Во второй части обзора у больных сахарным диабетом 2‑го типа очень высокого сердечно-сосудистого риска представлены особенности выбора и назначения сахароснижающей терапии из групп тиазолидиндионов, ингибиторов дипептидилпептидазы‑4, агонистов рецепторов и аналогов глюкагонподобного пептида (ГПП) 1‑го типа, селективных ингибиторов натрий-глюкозного котранспортера 2‑го типа. Оценка клинических исследований, метаанализов опубликованных исследований по кардиоваскулярной безопасности сахароснижающих препаратов показала, что наряду с метформином, препаратами первой линии в лечении больных очень высокого сердечно-сосудистого риска, как в монотерапии, так и в комбинации, являются селективные ингибиторы натрий- глюкозного котранспортера 2‑го типа (эмпаглифлозин) и аналоги ГПП 1‑го типа (лираглютид) как лекарственные средства, которые снижают риск развития сердечно-сосудистых событий. Кардиоваскулярная безопасность доказана для агонистов рецепторов ГПП 1‑го типа (ликсисенатид), иДПП‑4 (алоглиптин). При использовании саксаглиптина и ситаглиптина, по данным метаанализов, выявлено увеличение риска сердечной недостаточности. Препараты тиазолидиндионы не рекомендуются для лечения больных сахарным диабетом 2‑го типа очень высокого сердечно-сосудистого риска, особенно при наличии признаков хронической сердечной недостаточности или высокого риска ее развития. С учетом данных первой части статьи в обзоре представлен проект алгоритма выбора инициирующей сахароснижающей терапии у больных очень высокого сердечно-сосудистого риска в зависимости от исходного уровня гликированного гемоглобина.
1. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD — summary. Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC); European Association for the Study of Diabetes (EASD). Diab Vasc Dis Res. 2014;11(3):133–73. doi: 10.1177/1479164114525548
2. Дедов И. И., Шестакова М. В., Галстян Г. Р., Григорян О. Р., Есаян М. Р., Калашников В. Ю. и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / под ред. И. И. Дедова, М. В. Шестаковой. Сахарный диабет. 2015;18(1S):1–112..
3. Gruneir A, Markle-Reid M, Fisher K, Reimer H, Ma X, Ploeg J et al. Comorbidity Burden and Health Services Use in Community-Living Older Adults with Diabetes Mellitus: A Retrospective Cohort Study. Can J Diabetes. 2016;40(1):35–42. doi: 10.1016/j.jcjd.2015.09.002
4. Gao N, Yuan Z, Tang X, Zhou X, Zhao M, Liu L et al. Prevalence of CHD-related metabolic comorbidity of diabetes mellitus in Northern Chinese adults: the REACTION study. J Diabetes Complications. 2016;30(2):199–205. doi: 10.1016/j.jdiacomp.2015.11.018
5. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81. doi: 10.1093/eurheartj/ehw106
6. Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217(1):3–46. PMID:21882396
7. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации. V пересмотр. Атеросклероз и дислипидемии. 2012;4:4–53..
8. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934. doi: 10.1016/j.jacc.2013.11.002
9. Козиолова Н. А., Чернявина А. И., Полянская Е. А. Выбор сахароснижающих препаратов у больных сахарным диабетом 2‑го типа очень высокого сердечно-сосудистого риска (часть 1). Артериальная гипертензия. 2016;22(4):330–348..
10. Nesto RW, Bell D, Bonow RO, Fonseca V, Fonseca V, Grundy SM et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation. 2003;108(23):2941–8. doi: 10.1161/01.CIR.0000103683.99399.7E
11. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med. 2001;134(1):61–71. PMID:11187421
12. Khan MA, St Peter JV, Xue JL. A prospective, randomizedcomparison of the metabolic effects -of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care. 2003;25(4):708–11. PMID:11919129
13. Horita S, Nakamura M, Satoh N, Suzuki M, Seki G. Thiazolidinediones and edema: recent advances in the pathogenesis of thiazolidinediones-induced renal sodium retention. PPAR Res. 2015;2015:646423. doi: 10.1155/2015/646423
14. Rudnicki M, Tripodi GL, Ferrer R, Boscá L, Pitta MG, Pitta IR et al. New thiazolidinediones affect endothelial cell activation and angiogenesis. Eur J Pharmacol. 2016;782:98–106. doi: 10.1016/j.ejphar.2016.04.038
15. Roughead EE, Chan EW, Choi NK, Kimura M, Kimura T, Kubota K et al. Variation in association between thiazolidinediones and heart failure across ethnic groups: retrospective analysis of large healthcare claims databases in six countries. Drug Saf. 2015;38 (9):823–31. doi: 10.1007/s40264– 015–0318–4
16. 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. Lancet. 2005;366(9493):1279–89. doi:10.1016/S0140–6736(05)67528–9
17. Inzucchi SE, Viscoli CM, Young LH, Inzucchi SE, Viscoli CM, Young LH et al. Pioglitazone prevents diabetes in insulin-resistant patients with cerebrovascular disease. Diabetes Care. 2016. 9(10):1684–92. pii: dc160798. doi:10.2337/dc16–0798
18. 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. J Am Med Assoc. 2007;298(10):1180–8. doi:10.1001/jama.298.10.1180
19. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71. doi:10.1056/NEJMoa072761
20. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71. doi:10.1056/NEJMoa072761
21. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP et al. Rosiglitazone evaluated for cardiovascular outcomes an interim analysis.N Engl J Med. 2007;357(1): 28–38. doi:10.1056/NEJMoa073394
22. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. J Am Med Assoc. 2007;298 (10):1189–95. doi:10.1001/jama.298.10.1189
23. . URL: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm242588.htm
24. Bach RG, Brooks MM, Lombardero M, Genuth S, Donner TW, Garber A et al. Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2013;128(8):785–94. doi: 10.1161/CIRCULATIONAHA.112.000678
25. Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(2):240–249. doi: 10.1016/j.ahj.2013.05.004
26. . URL: http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm
27. Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. Br Med J. 2016;354: i3477. doi: 10.1136/bmj.i3477
28. Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18(3):266–73. doi: 10.1111/dom.12608
29. Khodeer DM, Zaitone SA, Farag NE, Moustafa YM. Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis. Can J Physiol Pharmacol. 2016;94(5):463–76. doi: 10.1139/cjpp‑2015–0135
30. Wei WY, Ma ZG, Xu SC, Zhang N, Tang QZ. Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3β and MAPK Signaling Pathways. PPAR Res. 2016;2016:9174190. doi: 10.1155/2016/9174190
31. Мареев В. Ю., Агеев Ф. Т., Арутюнов Г. П., Коротеев А. В., Мареев Ю. В., Овчинников А. Г. Национальные рекомендации ОССН, РКО и РНМОТ по диагностике и лечению ХСН (четвертый пересмотр). Сердечная недостаточность. 2013;14 (7):379–472..
32. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ 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(27):2129–200. doi: 10.1093/eurheartj/ehw128
33. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM et al. 2016 ACC/AHA/HFSA Focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476–88. pii: S0735–1097(16)33024–8. doi: 10.1016/j.jacc.2016.05.011
34. . URL: http://www.vidal.ru/drugs/avandia__3575
35. . URL: http://www.vidal.kz/poisk_preparatov/actos.htm
36. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase‑4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta- analysis. Br Med J. 2012;344: e1369. doi: 10.1136/bmj.e1369
37. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2‑drug combinations. Ann Intern Med. 2011;154(9):602–13. doi: 10.7326/0003–4819–154–9-201105030–00336
38. Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58(1):69–73. PMID: 21206136
39. Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122(3):16–27. doi: 10.3810/pgm.2010.05.2138
40. Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3. doi: 10.1186/1475–2840– 11–3
41. Engel SS, Golm GT, Shapiro D, Davies MJ, Kaufman KD, Goldstein BJ. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol. 2013;12:3. doi: 10.1186/1475–2840–12–3
42. Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol. 2014;13:33. doi: 10.1186/1475–2840–13–33
43. Keating GM. Alogliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2015;75(7):777–96. doi: 10.1007/s40265–015–0385‑y
44. 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(14):1327–35. doi: 10.1056/NEJMoa1305889
45. 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. Lancet. 2015;385 (9982):2067–76. doi: 10.1016/S0140– 6736 (14)62225‑X
46. 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 (14):1317–26. doi: 10.1056/NEJMoa1307684
47. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88. doi: 10.1161/CIRCULATIONAHA.114.010389
48. 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(3):232–42. doi: 10.1056/NEJMoa1501352
49. Weir DL, McAlister FA, Senthilselvan A, Minhas-Sandhu JK, Eurich DT. Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study. JACC Heart Fail. 2014;2(6):573–82. doi: 10.1016/j.jchf.2014.04.005
50. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase‑4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24 (7):689–97. doi: 10.1016/j.numecd.2014.01.017
51. Marney A, Kunchakarra S, Byrne L, Brown N. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. J Hypertension. 2010;56(4):728–33. doi: 10.1161/ HYPERTENSIONAHA.110.156554
52. Desouza CV, Gupta N, Patel A. Cardiometabolic effects of a new class of antidiabetic agents. Clin Ther. 2015;37(6):1178–94. doi: 10.1016/j.clinthera.2015.02.016
53. . URL: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm494252.htm
54. Raschi E, Poluzzi E, Koci A, Antonazzo IC, Marchesini G, De Ponti F. Dipeptidyl peptidase‑4 inhibitors and heart failure: analysis of spontaneous reports submitted to the FDA adverse event reporting system. Nutr Metab Cardiovasc Dis. 2016;26 (5):380–6. doi: 10.1016/j.numecd.2016.02.006
55. Fava S. Glucagon-like peptide 1 and the cardiovascular system. Curr Diabetes Rev. 2014;10(5):302–10. PMID:25360712
56. Katout M, Zhu H, Rutsky J, Shah P, Shah P, Brook RD et al. Effect of GLP‑1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic metaanalysis and meta-regression. Am J Hypertens. 2014;27(1):130–9. doi: 10.1093/ajh/hpt196
57. Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP‑1) receptor agonist exenatide twice daily or other glucoselowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care. 2011;34(1):90–5. doi: 10.2337/dc10– 1393
58. Monami M, Cremasco F, Lamanna C, Colombi C, Desideri CM, Iacomelli I et al. Glucagon-like peptide‑1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res. 2011;2011:215764. doi: 10.1155/2011/215764
59. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide‑1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(1):38–47. doi: 10.1111/dom.12175
60. Wu S, Sun F, Zhang Y, Yang Z, Hong T, Chen Y et al. The cardiovascular effects of glucagon-like peptide‑1 receptor agonists: a trial sequential analysis of randomized controlled trials. J Clin Pharm Ther. 2014;39(1):7–13. doi: 10.1111/jcpt.12102
61. Fisher M, Petrie MC, Ambery PD, Donaldson J, Ye J, McMurray JJ. Cardiovascular safety of albiglutide in the Harmony programme: a meta-analysis. Lancet Diabetes Endocrinol. 2015;3 (9):697–703. doi: 10.1016/S2213–8587(15)00233–8
62. 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. N Engl J Med. 2015;373 (23):2247–57. doi: 10.1056/NEJMoa1509225
63. 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(4):311–22. doi: 10.1056/NEJMoa1603827
64. 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. doi: 10.1186/s12872–016–0260–0
65. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L et al. Recombinant glucagon-like peptide‑1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110(8):955–61. doi:10.1161/01.CIR.0000139339.85840.DD
66. Ravassa S, Zudaire A, Díez J. GLP‑1 and cardioprotection: from bench to bedside. Cardiovasc Res. 2012;94(2):316–23. doi: 10.1093/cvr/cvs123
67. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117(18):2340–50. doi: 10.1161/CIRCULATIONAHA.107.739938
68. Yu M, Moreno C, Hoagland KM, Dahly A, Dahly A, Ditter K et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003;21(6):1125–35. doi:10.1097/01.hjh.0000059046.65882.49
69. Sun F, Wu S, Guo S, Yu K, Yang Z, Li L et al. Impact of GLP‑1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26–37. doi: 10.1016/j.diabres.2015.07.015
70. Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z et al. Effect of glucagon-like peptide‑1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network metaanalysis. Clin Ther. 2015;37(1):225–241.e8. doi: 10.1016/j.clinthera.2014.11.008
71. . URL: https://clinicaltrials.gov
72. Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37(7):1815–23. doi: 10.2337/dc13–3055
73. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38 (3):420–8. doi: 10.2337/dc14–1096
74. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 2016; 42(4):224–33. pii: S1262–3636(16)30409– 8. doi: 10.1016/j.diabet.2016.05.006
75. Dziuba J, Alperin P, Racketa J, Iloeje U, Goswami D, Hardy E et al. Modeling effects of SGLT‑2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab. 2014;16(7):628–35. doi: 10.1111/dom.12261
76. 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(22):2117–28. doi: 10.1056/NEJMoa1504720
77. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J et al. Effects of sodium-glucose cotransporter‑2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–9. doi: 10.1016/S2213–8587 (16)00052–8
78. Savarese G, D’Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C et al. Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter‑2 inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol. 2016;220:595–601. doi: 10.1016/j.ijcard.2016.06.208
79. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A 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 (19):1526–34. doi: 10.1093/eurheartj/ehv728
80. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375 (4):323–34. doi: 10.1056/NEJMoa1515920
81. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39 Suppl 2: S165–71. doi: 10.2337/dcS15–3006