Correction (Journal of the American College of Cardiology (2020) 75(4) (422–434), (S0735109719385134), (10.1016/j.jacc.2019.11.031));Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review

Journal of the American College of Cardiology

Volumn 75, Issue 4, 2020, Pages 422-434

  Zelniker, Thomas A ^a   Braunwald, Eugene ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

diabetes; heart failure; renal function; SGLT2 inhibitor

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; GLIMEPIRIDE; GLUCOSE; INSULIN; SODIUM GLUCOSE COTRANSPORTER 1; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; ANTIDIABETIC AGENT; SLC5A2 PROTEIN, HUMAN;

ANTIINFLAMMATORY ACTIVITY; CARDIOVASCULAR SYSTEM; CHRONIC KIDNEY FAILURE; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DIABETIC NEPHROPATHY; DRUG MECHANISM; HEART FAILURE; HEART MUSCLE METABOLISM; HEART PROTECTION; HUMAN; HYPERGLYCEMIA; NATRIURESIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RENAL PROTECTION; REVIEW; RISK FACTOR; ADRENERGIC SYSTEM; ANIMAL; BLOOD; CLINICAL TRIAL (TOPIC); DRUG EFFECT; FIBROSIS; GLUCOSE BLOOD LEVEL; HEART; HYPERTENSION; INFLAMMATION; KIDNEY; MOUSE; OXIDATIVE STRESS; PHARMACOLOGY;

ANIMALS; BLOOD GLUCOSE; CARDIOVASCULAR SYSTEM; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; FIBROSIS; HEART; HEART FAILURE; HUMANS; HYPERTENSION; HYPOGLYCEMIC AGENTS; INFLAMMATION; KIDNEY; MICE; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; RENAL INSUFFICIENCY, CHRONIC; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; SYMPATHETIC NERVOUS SYSTEM;

EID: 85078069803     PISSN: 07351097     EISSN: 15583597     Source Type: Journal    
DOI: 10.1016/j.jacc.2020.08.010     Document Type: Erratum

References (106)

1. Dabelea, D., Mayer-Davis, E.J., Saydah, S., Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 311 (2014), 1778–1786.
2. Menke, A., Casagrande, S., Cowie, C.C., Prevalence of diabetes in adolescents aged 12 to 19 Years in the United States, 2005-2014. JAMA 316 (2016), 344–345.
3. Cho, N.H., Shaw, J.E., Karuranga, S., et al. IDF Diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 138 (2018), 271–281.
4. Benjamin, E.J., Muntner, P., Alonso, A., et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 139 (2019), e56–e528.
5. Vecchio, I., Tornali, C., Bragazzi, N.L., Martini, M., The discovery of insulin: an important milestone in the history of medicine. Front Endocrinol (Lausanne), 9, 2018, 613.
6. Nissen, S.E., Wolski, K., Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356 (2007), 2457–2471.
7. U.S. Food and Drug Administration. FDA background document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Available at: https://www.fda.gov/media/121272/download, 2018. (Accessed 27 September 2019)
8. U.S. Food and Drug Administration. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf, 2008. (Accessed 27 September 2019)
9. European Medical Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. Available at: https://www.ema.europa.eu/documents/scientific-guideline/draft-guideline-clinical-investigation-medicinal-products-treatment-prevention-diabetes-mellitus_en.pdf, 2018. (Accessed 27 September 2019)
10. Zelniker, T.A., Wiviott, S.D., Raz, I., 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. Lancet 393 (2019), 31–39.
11. Kristensen, S.L., Rorth, R., Jhund, P.S., et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 7 (2019), 776–785.
12. McMurray, J.J.V., Solomon, S.D., Inzucchi, S.E., et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381 (2019), 1995–2008.
13. Zelniker, T.A., Braunwald, E., Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol 72 (2018), 1845–1855.
14. Wright, E.M., Turk, E., The sodium/glucose cotransport family SLC5. Pflugers Arch 447 (2004), 510–518.
15. Kanai, Y., Lee, W.S., You, G., Brown, D., Hediger, M.A., The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93 (1994), 397–404.
16. Alicic, R.Z., Neumiller, J.J., Johnson, E.J., Dieter, B., Tuttle, K.R., Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes 68 (2019), 248–257.
17. 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 136 (2017), 1548–1559.
18. Santer, R., Kinner, M., Lassen, C.L., et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 14 (2003), 2873–2882.
19. Santer, R., Calado, J., Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 5 (2010), 133–141.
20. Cherney, D.Z.I., Cooper, M.E., Tikkanen, I., et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 93 (2018), 231–244.
21. Horie, I., Abiru, N., Hongo, R., et al. Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment. Diabetes Res Clin Pract 135 (2018), 178–184.
22. Osataphan, S., Macchi, C., Singhal, G., et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight, 4, 2019, 123130.
23. Sato, T., Aizawa, Y., Yuasa, S., et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol, 17, 2018, 6.
24. Miyachi, Y., Tsuchiya, K., Shiba, K., et al. A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition. Sci Rep, 8, 2018, 16113.
25. Braunwald, E., Diabetes, heart failure, and renal dysfunction: The vicious circles. Prog Cardiovasc Dis 62 (2019), 298–302.
26. Kenny, H.C., Abel, E.D., Heart failure in type 2 diabetes mellitus. Circ Res 124 (2019), 121–141.
27. Jia, G., Hill, M.A., Sowers, J.R., Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res 122 (2018), 624–638.
28. Dunlay, S.M., Givertz, M.M., 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 140 (2019), e294–e324.
29. Marwick, T.H., Ritchie, R., Shaw, J.E., Kaye, D., Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol 71 (2018), 339–351.
30. Dillmann, W.H., Diabetic cardiomyopathy. Circ Res 124 (2019), 1160–1162.
31. Zelniker, T.A., Braunwald, E., Clinical benefit of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol 75 (2020), 436–448.
32. Tanaka, H., Takano, K., Iijima, H., et al. Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther 34 (2017), 436–451.
33. Sha, S., Polidori, D., Heise, T., et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab 16 (2014), 1087–1095.
34. Hallow, K.M., Helmlinger, G., Greasley, P.J., McMurray, J.J.V., Boulton, D.W., Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 20 (2018), 479–487.
35. Karg, M.V., Bosch, A., Kannenkeril, D., et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol, 17, 2018, 5.
36. Schneider, M.P., Raff, U., Kopp, C., et al. Skin Sodium concentration correlates with left ventricular hypertrophy in CKD. J Am Soc Nephrol 28 (2017), 1867–1876.
37. Kario, K., Okada, K., Kato, M., et al. 24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: Results from the randomized, placebo-controlled SACRA study. Circulation, 2018 Nov 29 [E-pub ahead of print].
38. Wiviott, S.D., Raz, I., Bonaca, M.P., et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380 (2019), 347–357.
39. Scheen, A.J., Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep, 21, 2019, 70.
40. Matthews, V.B., Elliot, R.H., Rudnicka, C., et al. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens 35 (2017), 2059–2068.
41. Tran, D.H., Wang, Z.V., Glucose metabolism in cardiac hypertrophy and heart failure. J Am Heart Assoc, 8, 2019, e012673.
42. Sowton, A.P., Griffin, J.L., Murray, A.J., Metabolic profiling of the diabetic heart: Toward a richer picture. Front Physiol, 10, 2019, 639.
43. Ferrannini, E., Baldi, S., Frascerra, S., et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65 (2016), 1190–1195.
44. Horton, J.L., Davidson, M.T., Kurishima, C., et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight, 4, 2019, 12407.
45. Youm, Y.H., Nguyen, K.Y., Grant, R.W., et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21 (2015), 263–269.
46. Santos-Gallego, C.G., Requena-Ibanez, J.A., San Antonio, R., et al. Empagliflozin ameliorates adverse left ventricular remodeling in nonndiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 73 (2019), 1931–1944.
47. Lehrke, M., SGLT2 inhibition: Changing what fuels the heart. J Am Coll Cardiol 73 (2019), 1945–1947.
48. Verma, S., Rawat, S., Ho, K.L., et al. Empagliflozin increases cardiac energy production in diabetes: Novel translational insights into the heart failure benefits of SGLT2 inhibitors. J Am Coll Cardiol Basic Transl Sci 3 (2018), 575–587.
49. Abdurrachim, D., Teo, X.Q., Woo, C.C., et al. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: A hyperpolarized (13) C magnetic resonance spectroscopy study. Diabetes Obes Metab 21 (2019), 357–365.
50. Nakamura, M., Sadoshima, J., Ketone body can be a fuel substrate for failing heart. Cardiovasc Res 115 (2019), 1567–1569.
51. Lim, V.G., Bell, R.M., Arjun, S., et al. SGLT2 Inhibitor, canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart. J Am Coll Cardiol Basic Transl Sci 4 (2019), 15–26.
52. Maruyama, T., Takashima, H., Oguma, H., et al. Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol Ther 21 (2019), 713–720.
53. Toto, R.D., Goldenberg, R., Chertow, G.M., et al. Correction of hypomagnesemia by dapagliflozin in patients with type 2 diabetes: a post hoc analysis of 10 randomized, placebo-controlled trials. J Diabetes Complications, 2019, 107402.
54. Montaigne, D., Marechal, X., Coisne, A., et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130 (2014), 554–564.
55. Uthman, L., Baartscheer, A., Schumacher, C.A., et al. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol, 9, 2018, 1575.
56. Zelniker, T.A., Jarolim, P., Scirica, B.M., et al. Biomarker of collagen turnover (C-terminal telopeptide) and prognosis in patients with non- ST -elevation acute coronary syndromes. J Am Heart Assoc, 8, 2019, e011444.
57. Ye, Y., Bajaj, M., Yang, H.C., Perez-Polo, J.R., Birnbaum, Y., SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther 31 (2017), 119–132.
58. El-Daly, M., Pulakazhi Venu, V.K., et al. Hyperglycaemic impairment of PAR2-mediated vasodilation: prevention by inhibition of aortic endothelial sodium-glucose-co-transporter-2 and minimizing oxidative stress. Vascul Pharmacol 109 (2018), 56–71.
59. Mustroph, J., Wagemann, O., Lucht, C.M., et al. Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes. ESC Heart Fail 5 (2018), 642–648.
60. Uthman, L., Baartscheer, A., Bleijlevens, B., et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia 61 (2018), 722–726.
61. Uthman, L., Nederlof, R., Eerbeek, O., et al. Delayed ischemic contracture onset by Empagliflozin associates with NHE-1 inhibition and is dependent on insulin in isolated mouse hearts. Cardiovasc Res 115 (2019), 1533–1545.
62. Packer, M., Reconceptualization of the molecular mechanism by which sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure events. Circulation 140 (2019), 443–445.
63. Connelly, K.A., Zhang, Y., Visram, A., et al. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. J Am Coll Cardiol Basic Transl Sci 4 (2019), 27–37.
64. Zhang, N., Feng, B., Ma, X., Sun, K., Xu, G., Zhou, Y., Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovasc Diabetol, 18, 2019, 107.
65. Solini, A., Seghieri, M., Giannini, L., et al. The effects of dapagliflozin on systemic and renal vascular function display an epigenetic signature. J Clin Endocrinol Metab 104 (2019), 4253–4263.
66. Pabel, S., Wagner, S., Bollenberg, H., et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail 20 (2018), 1690–1700.
67. Matsutani, D., Sakamoto, M., Kayama, Y., et al. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol, 17, 2018, 73.
68. Soga, F., Tanaka, H., Tatsumi, K., et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol, 17, 2018, 132.
69. Oh, C.M., Cho, S., Jang, J.Y., et al. Cardioprotective potential of an SGLT2 inhibitor against doxorubicin-induced heart failure. Korean Circ J 49 (2019), 1183–1195.
70. Verma, S., McMurray, J.J.V., SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 61 (2018), 2108–2117.
71. Cherney, D.Z., Perkins, B.A., Soleymanlou, N., et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol, 13, 2014, 28.
72. Bonnet, F., Scheen, A.J., Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab 44 (2018), 457–464.
73. Mancini, S.J., Boyd, D., Katwan, O.J., et al. Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep, 8, 2018, 5276.
74. Hess, D.A., Terenzi, D.C., Trac, J.Z., et al. SGLT2 Inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metab 30 (2019), 609–613.
75. Adingupu, D.D., Gopel, S.O., Gronros, J., et al. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob(-/-) mice. Cardiovasc Diabetol, 18, 2019, 16.
76. Stahl, E.P., Dhindsa, D.S., Lee, S.K., et al. Nonalcoholic fatty liver disease and the heart: JACC State-of-the-Art Review. J Am Coll Cardiol 73 (2019), 948–963.
77. Younossi, Z.M., Koenig, A.B., Abdelatif, D., et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (2016), 73–84.
78. Omori, K., Nakamura, A., Miyoshi, H., et al. Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice. Metabolism 98 (2019), 27–36.
79. Latva-Rasku, A., Honka, M.J., Kullberg, J., et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care 42 (2019), 931–937.
80. Basu, D., Huggins, L.A., Scerbo, D., et al. Mechanism of increased LDL (low-Density lipoprotein) and decreased triglycerides with SGLT2 (sodium-glucose cotransporter 2) inhibition. Arterioscler Thromb Vasc Biol 38 (2018), 2207–2216.
81. Chagnac, A., Zingerman, B., Rozen-Zvi, B., Herman-Edelstein, M., Consequences of glomerular hyperfiltration: the role of physical forces in the pathogenesis of chronic kidney disease in diabetes and obesity. Nephron 143 (2019), 38–42.
82. Lowen, J., Grone, E., Grone, H.J., Kriz, W., Herniation of the tuft with outgrowth of vessels through the glomerular entrance in diabetic nephropathy damages the juxta-glomerular- apparatus. Am J Physiol Renal Physiol 317 (2019), F399–F410.
83. Heerspink, H.J., Perkins, B.A., Fitchett, D.H., Husain, M., Cherney, D.Z., Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134 (2016), 752–772.
84. Kidokoro, K., Cherney, D.Z.I., Bozovic, A., et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation 140 (2019), 303–315.
85. Wanner, C., Sodium glucose cotransporter 2 inhibition and the visualization of kidney hemodynamics. Circulation 140 (2019), 316–318.
86. Mayer, G.J., Wanner, C., Weir, M.R., et al. Analysis from the EMPA-REG OUTCOME((R)) trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int 96 (2019), 489–504.
87. Wanner, C., Heerspink, H.J.L., Zinman, B., et al. Empagliflozin and kidney function decline in patients with type 2 diabetes: a slope analysis from the EMPA-REG OUTCOME trial. J Am Soc Nephrol 29 (2018), 2755–2769.
88. Neuen, B.L., Ohkuma, T., Neal, B., et al. Effect of canagliflozin on renal and cardiovascular outcomes across different levels of albuminuria: data from the CANVAS program. J Am Soc Nephrol 30 (2019), 2229–2242.
89. Inzucchi, S.E., Zinman, B., Fitchett, D., et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41 (2018), 356–363.
90. Sano, M., Goto, S., Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139 (2019), 1985–1987.
91. Novikov, A., Fu, Y., Huang, W., et al. SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Renal Physiol 316 (2019), F173–F185.
92. Wilcox, C.S., Shen, W., Boulton, D.W., Leslie, B.R., Griffen, S.C., Interaction between the sodium-glucose-linked transporter 2 inhibitor dapagliflozin and the loop diuretic bumetanide in normal human subjects. J Am Heart Assoc, 7, 2018, e007046.
93. Lytvyn, Y., Perkins, B.A., Cherney, D.Z., Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes 39 (2015), 239–246.
94. Alicic, R.Z., Rooney, M.T., Tuttle, K.R., Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol 12 (2017), 2032–2045.
95. Woods, T.C., Satou, R., Miyata, K., et al. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol 49 (2019), 331–342.
96. Yaribeygi, H., Atkin, S.L., Butler, A.E., Sahebkar, A., Sodium-glucose cotransporter inhibitors and oxidative stress: an update. J Cell Physiol 234 (2019), 3231–3237.
97. Birnbaum, Y., Bajaj, M., Yang, H.C., Ye, Y., Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes. Cardiovasc Drugs Ther 32 (2018), 135–145.
98. Masters, S.L., Dunne, A., Subramanian, S.L., et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11 (2010), 897–904.
99. Heerspink, H.J.L., Perco, P., Mulder, S., et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia 62 (2019), 1154–1166.
100. Lee, Y.H., Kim, S.H., Kang, J.M., et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Renal Physiol 317 (2019), F767–F780.
101. Mulder, S., Heerspink, H.J.L., Darshi, M., et al. Effects of dapagliflozin on urinary metabolites in patients with type 2 diabetes. Diabetes Obes Metab 21 (2019), 2422–2428.
102. Shibusawa, R., Yamada, E., Okada, S., et al. Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death. Sci Rep, 9, 2019, 9887.
103. Cooper, M.E., Inzucchi, S.E., Zinman, B., et al. Glucose control and the effect of empagliflozin on kidney outcomes in type 2 diabetes: An analysis from the EMPA-REG OUTCOME Trial. Am J Kidney Dis 74 (2019), 713–715.
104. Heerspink, H.J., Desai, M., Jardine, M., et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol 28 (2017), 368–375.
105. Evans, M., Morgan, A.R., Yousef, Z., What next after metformin? Thinking beyond glycaemia: are SGLT2 inhibitors the answer?. Diabetes Ther 10 (2019), 1719–1731.
106. Vergara, A., Jacobs-Cacha, C., Soler, M.J., Sodium-glucose cotransporter inhibitors: beyond glycaemic control. Clin Kidney J 12 (2019), 322–325.