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A Role for SGLT-2 Inhibitors in Treating Non-diabetic Chronic Kidney Disease

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Abstract

In recent years, inhibitors of the sodium-glucose co-transporter 2 (SGLT2 inhibitors) have been shown to have significant protective effects on the kidney and the cardiovascular system in patients with diabetes. This effect is also manifested in chronic kidney disease (CKD) patients and is minimally due to improved glycaemic control. Starting from these positive findings, SGLT2 inhibitors have also been tested in patients with non-diabetic CKD or heart failure with reduced ejection fraction. Recently, the DAPA-CKD trial showed a significantly lower risk of CKD progression or death from renal or cardiovascular causes in a mixed population of patients with diabetic and non-diabetic CKD receiving dapagliflozin in comparison with placebo. In patients with heart failure and reduced ejection fraction, two trials (EMPEROR-Reduced and DAPA-HF) also found a significantly lower risk of reaching the secondary renal endpoint in those treated with an SGLT2 inhibitor in comparison with placebo. This also applied to patients with CKD. Apart from their direct mechanism of action, SGLT2 inhibitors have additional effects that could be of particular interest for patients with non-diabetic CKD. Among these, SGLT2 inhibitors reduce blood pressure and serum acid uric levels and can increase hemoglobin levels. Some safety issues should be further explored in the CKD population. SGLT2 inhibitors can minimally increase potassium levels, but this has not been shown by the CREDENCE trial. They also increase magnesium and phosphate reabsorption. These effects could become more significant in patients with advanced CKD and will need monitoring when these agents are used more extensively in the CKD population. Conversely, they do not seem to increase the risk of acute kidney injury.

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References

  1. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–33.

    Article  Google Scholar 

  2. Al-Kibria GM, Crispen R. Prevalence and trends of chronic kidney disease and its risk factors among US adults: an analysis of NHANES 2003–18. Rev Med Rep. 2020;20: 101193.

    Google Scholar 

  3. Liyanage T, Ninomiya T, Jha V. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015;385:1975–82.

    Article  PubMed  Google Scholar 

  4. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.

    Article  CAS  PubMed  Google Scholar 

  5. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–52.

    Article  PubMed  Google Scholar 

  6. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of diet in renal disease study group. N Engl J Med. 1994;330:877–84.

    Article  CAS  PubMed  Google Scholar 

  7. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.

    Article  CAS  Google Scholar 

  8. Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, HALT-PKD Trial Investigators, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371:2255–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Xharleston J, African American Study of Kidney Disease and Hypertension Study Group, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–31.

    Article  CAS  PubMed  Google Scholar 

  10. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. Effects of intensive BP control in CKD. J Am Soc Nephrol. 2017;28:2812–23.

    Article  PubMed  PubMed Central  Google Scholar 

  11. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink Km, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16.

    Article  CAS  Google Scholar 

  12. Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, et al. Renin-angiotensin system inhibitors and kidney and cardiovascular out- comes in patients with CKD: a Bayesian network meta-analysis of randomized clinical trials. Am J Kidney Dis. 2016;67:728–41.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang Y, He D, Zhang W, Xing Y, Guo Y, Wang F, et al. ACE inhibitor benefit to kidney and cardiovascular outcomes for patients with non-dialysis chronic kidney disease stages 3–5: a network meta-analysis of randomised clinical trials. Drugs. 2020;80(8):797–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, AIPRI Study Group, et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-convert- ing enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 2003;139:244–52.

    Article  CAS  PubMed  Google Scholar 

  15. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, et al. effect of inhibitors of the renin-angiotensin system and other antihypertensve drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026–33.

    Article  CAS  PubMed  Google Scholar 

  16. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309–20.

    Article  PubMed  Google Scholar 

  17. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.

    Article  CAS  PubMed  Google Scholar 

  18. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, ALTITUDE Investigators, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.

    Article  CAS  PubMed  Google Scholar 

  19. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, VA NEPHRON-D Investigators, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–903.

    Article  CAS  PubMed  Google Scholar 

  20. Feng Y, Huang R, Kavanagh J, Li L, Zeng X, Li Y, Fu P. Efficacy and safety of dual blockade of analysis. J Cardiovasc Drugs. 2019;19(3):259–86.

    Article  CAS  Google Scholar 

  21. https://www.ema.europa.eu/en/documents/referral/restriction-combined-use-medicines-affecting-renin-angiotensin-system-ras_en.pdf. Accessed 12 June 2021

  22. D’Elia L, Rossi G, di Cola MS, Savino I, Galletti F, Strazzullo P. Meta-analysis of the effect of dietary sodium restriction with or without concomitant renin-angiotensin-aldosterone system-inhibiting treatment on albuminuria. Clin J Am Soc Nephrol. 2015;10(9):1542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qiao Y, Shin JI, Sang Y, Inker LA, Secora A, Luo S, et al. Discontinuation of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic kidney disease. Mayo Clin Proc. 2019;94(11):2220–9.

    Article  CAS  PubMed  Google Scholar 

  24. Joost HG, Thorens B. The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol. 2001;18:247–56.

    Article  CAS  PubMed  Google Scholar 

  25. Wright EM. Renal Na(+)-glucose co-transporters. Am J Physiol Renal Physiol. 2001;280:F10–8.

    Article  CAS  PubMed  Google Scholar 

  26. Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. J Parenter Enteral Nutr. 2004;28:364–71.

    Article  CAS  Google Scholar 

  27. Hirayama BA, Wong HC, Smith CD, Hagenbuch BA, Hediger MA, Wright EM. Intestinal and renal Na+/glucose co-transporters share common structures. Am J Physiol. 1991;261:C296-304.

    Article  CAS  PubMed  Google Scholar 

  28. Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF. The Na(+)/glucose co-transporters: from genes to therapy. Braz J Med Biol Res. 2010;43:1019–26.

    Article  CAS  PubMed  Google Scholar 

  29. Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol. 2010;5:133–41.

    Article  CAS  PubMed  Google Scholar 

  30. Shepard BD, Cheval L, Peterlin Z, Firestein S, Koepsell H, Doucet A, et al. A renal olfactory receptor aids in kidney glucose handling. Sci Rep. 2016;6:35215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sopjani M, Bhavsar SK, Fraser S, Kemp BE, Föller M, Lang F. Regulation of Na+-coupled glucose carrier SGLT1 by AMP-activated protein kinase. Mol Membr Biol. 2010;27:137–44.

    Article  CAS  PubMed  Google Scholar 

  32. Birnir B, Lee HS, Hediger MA, Wright EM. Expression and characterization of the intestinal Na+/glucose co-transporter in COS-7 cells. Biochim Biophys Acta. 1990;1048:100–4.

    Article  CAS  PubMed  Google Scholar 

  33. Tabatabai NM, Sharma M, Blumenthal SS, Petering DH. Enhanced expressions of sodium-glucose co-transporters in the kidneys of diabetic Zucker rats. Diabetes Res Clin Pract. 2009;83:e27-30.

    Article  CAS  PubMed  Google Scholar 

  34. Augustin R. The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life. 2010;62:315–33.

    CAS  PubMed  Google Scholar 

  35. Chintalapati C, Keller T, Mueller TD, Gorboulev V, Schäfer N, Zilkowski I, et al. Protein RS1 (RSC1A1) downregulates the exocytotic pathway of glucose transporter SGLT1 at low intracellular glucose via inhibition of ornithine decarboxylase. Mol Pharmacol. 2016;90:508–21.

    Article  CAS  PubMed  Google Scholar 

  36. Veyhl M, Keller T, Gorboulev V, Vernaleken A, Koepsell H. RS1 (RSC1A1) regulates the exocytotic pathway of Na+-d-glucose co-transporter SGLT1. Am J Physiol Renal Physiol. 2006;291:F1213–23.

    Article  CAS  PubMed  Google Scholar 

  37. Balen D, Ljubojevic M, Breljak D, Brzica H, Zlender V, Koepsell H, et al. Revised immunolocalization of the Na+-d-glucose co-transporter SGLT1 in rat organs with an improved antibody. Am J Physiol Cell Physiol. 2008;295:C475–89.

    Article  CAS  PubMed  Google Scholar 

  38. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, et al. Na(+)-d-glucose co-transporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61:187–96.

    Article  CAS  PubMed  Google Scholar 

  40. Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306:F188–93.

    Article  CAS  PubMed  Google Scholar 

  41. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62:3324–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, et al. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012;35:2061–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose co-transporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752–72.

    Article  CAS  PubMed  Google Scholar 

  44. Pollock CA, Lawrence JR, Field MJ. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am J Physiol Renal Physiol. 1991;260:946-F952.

    Article  Google Scholar 

  45. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10:2569–76.

    Article  CAS  PubMed  Google Scholar 

  46. Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140:303–15.

    Article  CAS  PubMed  Google Scholar 

  47. Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose co-transporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    Article  CAS  PubMed  Google Scholar 

  48. Thomson SC, Vallon V. Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats. Am J Physiol Renal Physiol. 2021;320:F761–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Osorio H, Coronel I, Arellano A, Pacheco U, Bautista R, Franco M, et al. Sodium-glucose co-transporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev. 2012;2012: 542042.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Tanaka S, Sugiura Y, Saito H, Sugahara M, Higashijima Y, Yamaguchi J, et al. Sodium–glucose co-transporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice. Kidney Int. 2018;94:912–25.

    Article  CAS  PubMed  Google Scholar 

  51. van Bommel EJM, Muskiet MHA, van Baar MJB, Tonneijck L, Smits MM, Emanuel AL, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int. 2020;97:202–12.

    Article  PubMed  CAS  Google Scholar 

  52. 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;373:2117–28.

    Article  CAS  PubMed  Google Scholar 

  53. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.

    Article  PubMed  Google Scholar 

  54. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    Article  CAS  PubMed  Google Scholar 

  55. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, VERTIS CV Investigators, et al. Ertugliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2020;383:1425–35.

    Article  CAS  PubMed  Google Scholar 

  56. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, DECLARE–TIMI 58 Investigators, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.

    Article  CAS  PubMed  Google Scholar 

  57. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, 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. 2019;393(10166):31–9.

    Article  CAS  PubMed  Google Scholar 

  58. Tang H, Fang Z, Wang T, Cui W, Zhai S, Song Y. Meta-analysis of effects of sodium-glucose co-transporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118(11):1774–80.

    Article  CAS  PubMed  Google Scholar 

  59. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, et al. Cardiovascular outcomes with sodium- glucose co-transporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol. 2017;228:352–8.

    Article  PubMed  Google Scholar 

  60. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al. Effects of sodium- glucose co-transporter- 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.

    Article  CAS  PubMed  Google Scholar 

  61. Savarese G, D’Amore C, Federici M, De Martino F, Delle Srottaglie S, Marciano C, et al. Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked co-transporter-2 Inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta- analysis. Int J Cardiol. 2016;220:595–601.

    Article  PubMed  Google Scholar 

  62. Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol. 2017;54(1):19–36.

    Article  CAS  PubMed  Google Scholar 

  63. 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;15:37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S. Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analsis of data from randomized placebo-controlled trials. Diabetes Obes Metab. 2016;18(10):1034–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, SCORED Investigators, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129–39.

    Article  CAS  PubMed  Google Scholar 

  66. Schork A, Saynisch J, Vosseler A, Jaghutriz BA, Heyne N, Peter A, et al. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol. 2019;18(1):46.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sarzani R, Giulietti F, Di Pentima C, Spannella F. Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events. Nutr Metab Cardiovasc Dis. 2020;30(10):1622–32.

    Article  CAS  PubMed  Google Scholar 

  68. Masuda T, Muto S, Fukuda K, Watanabe M, Ohara K, Koepsell H, et al. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol Rep. 2020;8(2): e14360.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kario K, Okada K, Kato M, Nishizawa M, Yoshida T, Asano T, 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;139(18):2089–97.

    Article  PubMed Central  CAS  Google Scholar 

  70. Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21:70.

    Article  PubMed  Google Scholar 

  71. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose co-transporter 2. J Hypertens. 2017;35:2059–68.

    Article  CAS  PubMed  Google Scholar 

  72. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. A meta-analysis. JAMA Cardiol. 2021;6(2):148–58.

    Article  PubMed  Google Scholar 

  73. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, EMPA-REG OUTCOME Investigators, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.

    Article  CAS  PubMed  Google Scholar 

  74. Seidu S, Kunutsor SK, Cos X, Gillani S, Khunti K, For and on behalf of Primary Care Diabetes Europe, et al. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: a systematic review and meta-analysis. Prim Care Diabetes. 2018;12(3):265–83.

    Article  PubMed  Google Scholar 

  75. Zhang XL, Zhu QQ, Chen YH, Li XL, Chen F, Huang JA, et al. Cardiovascular safety, long- term non cardiovascular safety, and efficacy of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc. 2018;7(2): e007165.

    PubMed  PubMed Central  Google Scholar 

  76. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14:2873–82.

    Article  CAS  PubMed  Google Scholar 

  77. Nespoux J, Patel R, Zhang H, Huang W, Freeman B, Sanders PW, et al. Gene knockout of the Na+-glucose co-transporter SGLT2i in a murine model of acute kidney injury induced by ischemia-reperfusion. Am J Physiol Renal Physiol. 2020;318(5):F1100–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Pirklbauer M, Bernd M. Empagliflozin inhibits basal and IL-1β-mediated MCP-1/CCL2 and endothelin-1 expression in human proximal tubular cells. Int J Mol Sci. 2020;21:8189.

    Article  CAS  PubMed Central  Google Scholar 

  79. Castoldi G, Carletti R, Ippolito S, Colzani M, Barzaghi F, Stella A, et al. Renal anti-fibrotic effect of sodium glucose co-transporter 2 inhibition in angiotensin II-dependent hypertension. Am J Nephrol. 2020;51:119–29.

    Article  CAS  PubMed  Google Scholar 

  80. Jaikumkao K, Pongchaidecha A, Chueakula N, Thongnak LO, Wanchai K, Chatsudthipong V, et al. Dapagliflozin, a sodium- glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats. Diabetes Obes Metab. 2018;20:2617–26.

    Article  CAS  PubMed  Google Scholar 

  81. Yamato M, Kato N, Kakino A, Yamada KI, Inoguchi T. Low dose of sodium-glucose transporter 2 inhibitor ipragliflozin attenuated renal dysfunction and interstitial fibrosis in adenine-induced chronic kidney disease in mice without diabetes. Metabol Open. 2020;7: 100049.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Takagi S, Li J, Takagaki Y, Kitada M, Nitta K, Takasu T, et al. Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high-fat diet. J Diabetes Investig. 2018;9:1025–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang Y, Nakano D, Guan Y, Hitomi H, Uemura A, Masaki T, et al. A sodium-glucose co-transporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018;94:524–35.

    Article  CAS  PubMed  Google Scholar 

  84. Kong KH, Oh HJ, Lim BJ, Kim M, Han KH, Choi YH, et al. Selective tubular activation of hypoxia-inducible factor-2alpha has dual effects on renal fibrosis. Sci Rep. 2017;7(1):11351.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Cassis P, Locatelli M, Cerullo D, Corna D, Buelli S, Zanchi C, et al. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI Insight. 2018;3(15): e98720.

    Article  PubMed Central  Google Scholar 

  86. Wakisaka M, Nagao T, Yoshinari M. Sodium glucose cotransporter 2 (SGLT2) plays as a physiological glucose sensor and regulates cellular contractility in rat mesangial cells. PLoS ONE. 2016;11(3): e0151585.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Paccosi S, Giachi M, Di Gennaro P, Guglielmotti A, Parenti A. The chemokine (C-C motif) ligand protein synthesis inhibitor bindarit prevents cytoskeletal rearrangement and contraction of human mesangial cells. Cytokine. 2016;85:92–100.

    Article  CAS  PubMed  Google Scholar 

  88. Mohamed DI, Khairy E, Saad SST, Habib EK, Hamouda MA. Potential protective effects of dapagliflozin in gentamicin induced nephrotoxicity rat model via modulation of apoptosis associated miRNAs. Gene. 2019;707:198–204.

    Article  CAS  PubMed  Google Scholar 

  89. Hasan R, Lasker S, Hasan A, Zerin F, Zamila M, Parvez F, et al. Canagliflozin ameliorates renal oxidative stress and inflammation by stimulating AMPK-Akt-eNOS pathway in the isoprenaline-induced oxidative stress model. Sci Rep. 2020;10(1):14659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M, Huang W, et al. A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Renal Physiol. 2020;319(4):F712–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mannon EC, O’Connor PM. Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection? Am J Physiol Renal Physiol. 2020;319(6):F1090–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang Y, Thai K, Kepecs DM, Gilbert RE. Sodium-glucose linked co-transporter-2 inhibition does not attenuate disease progression in the rat remnant kidney model of chronic kidney disease. PLoS ONE. 2016;11(1): e0144640.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Ma Q, Steiger S, Anders HJ. Sodium glucose transporter-2 inhibition has no renoprotective effects on non-diabetic chronic kidney disease. Physiol Rep. 2017;5: e13228.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Wheeler DC, Stefansson BV, Batiushin M, Bilchenko O, Cherney DZI, Chertow GM, et al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics. Nephrol Dial Transplant. 2020;35(10):1700–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, DAPA-CKD Trial Committees and Investigators, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.

    Article  CAS  PubMed  Google Scholar 

  96. Locatelli F, Del Vecchio L, Pozzoni P, D’Amico M, Andrulli S. Is it the agent or the blood pressure level that matters for renal and vascular protection in chronic nephropathies? Kidney Int. 2005;67(suppl 93):S15-19.

    Article  Google Scholar 

  97. Wheeler DC, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, DAPA-CKD Trial Committees and Investigators, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22–31.

    Article  CAS  PubMed  Google Scholar 

  98. Wheeler DC, Toto RD, Stefansson BV, Jongs N, Chertow GM, Greene T, for the DAPA-CKD Trial Committees and Investigators, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021. https://doi.org/10.1016/j.kint.2021.03.033 (S0085-2538(21)00396-3; Online ahead of print).

    Article  PubMed  Google Scholar 

  99. McMurray JJV, Wheeler DC, Stefánsson BV, Jongs N, Postmus D, Correa-Rotter R, DAPA-CKD Trial Committees and Investigators, et al. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease. Circulation. 2021;143(5):438–48.

    Article  CAS  PubMed  Google Scholar 

  100. Cherney DZI, Dekkers CCJ, Barbour SJ, Cattran D, Gafor AHA, Greasley PJ, DIAMOND investigators, et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 2020;8(7):582–93.

    Article  CAS  PubMed  Google Scholar 

  101. Rajasekeran H, Reich HN, Hladunewich MA, Cattran D, Lovshin JA, Lytvyn Y, et al. Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. Am J Physiol Renal Physiol. 2018;314(3):F412–22.

    Article  PubMed  CAS  Google Scholar 

  102. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24.

    Article  CAS  PubMed  Google Scholar 

  103. Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Bělohlávek J, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA. 2020;323:1353–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zannad F, Ferreira JP, Pocock SJ, Zeller C, Anker SD, Butler J, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation. 2021;143(4):310–21.

    Article  CAS  PubMed  Google Scholar 

  105. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, 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;396:819–29.

    Article  PubMed  Google Scholar 

  106. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2020;384:117–28.

    Article  PubMed  Google Scholar 

  107. Kimura G. Importance of inhibiting sodium-glucose co-transporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens. 2016;10(3):271–8.

    Article  CAS  PubMed  Google Scholar 

  108. Sanidas EA, Papadopoulos DP, Hatziagelaki E, Grassos C, Velliou M, Barbetseas J. Sodium glucose co-transporter 2 (SGLT2) inhibitors across the spectrum of hypertension. Am J Hypertens. 2020;33(3):207–13.

    CAS  PubMed  Google Scholar 

  109. Tian B, Deng Y, Cai Y, Han M, Xu G. Efficacy and safety of combination therapy with sodium-glucose transporter 2 inhibitors and renin-angiotensin system blockers in patients with type 2 diabetes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2021 (Online ahead of print)

  110. Ye N, Jardine MJ, Oshima M, Hockham C, Heerspink HJL, Agarwal R, et al. Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease: insights from the CREDENCE Trial. Circulation. 2021;143(18):1735–49.

  111. Chambergo-Michilot D, Tauma-Arrué A, Loli-Guevara S. Effects and safety of SGLT2 inhibitors compared to placebo in patients with heart failure: a systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020;32: 100690.

    PubMed  PubMed Central  Google Scholar 

  112. Feig DI, Kang D-H, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lytvyn Y, Škrtić M, Yang GK, Yip PM, Perkins BM, Cherney DZI. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015;308(2):F77-83.

    Article  CAS  PubMed  Google Scholar 

  114. Novikov A, Fu Y, Huang W, Freeman B, Patel R, van Ginkel C, et al. SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Renal Physiol. 2019;316(1):F173–85.

    Article  CAS  PubMed  Google Scholar 

  115. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2018;20(2):458–62.

    Article  CAS  PubMed  Google Scholar 

  116. Verma S, Ji Q, Bhatt DL, Mazer CD, Al-Omran M, Inzucchi SE, et al. Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA-REG OUTCOME. Diabetes Obes Metab. 2020;22(7):1207–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stack AG, Han D, Goldwater R, Johansson S, Dronamraju N, Oscarsson J, et al. Dapagliflozin added to verinurad plus febuxostat further reduces serum uric acid in hyperuricemia: the QUARTZ Study. J Clin Endocrinol Metab. 2021;106(5):e2347–56.

  118. Cosentino C, Dicembrini I, Nreu B, Mannucci E, Monami M. Nephrolithiasis and sodium-glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2019;155: 107808.

    Article  CAS  PubMed  Google Scholar 

  119. Stefánsson BV, Heerspink HJL, Wheeler DC, Sjöström CD, Greasley PJ, Sartipy P, et al. Correction of anemia by dapagliflozin in patients with type 2 diabetes. J Diabetes Complicat. 2020;34(12): 107729.

    Article  Google Scholar 

  120. Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, et al. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol. 2020;8(11):903–14.

    Article  CAS  PubMed  Google Scholar 

  121. Maruyama T, Takashima H, Oguma H, Nakamura Y, Ohno M, Utsunomiya K, et al. Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol Ther. 2019;21(12):713–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Marathias KP, Lambadiari VA, Markakis KP, Vlahakos VD, Bacharaki D, Raptis AE, et al. Competing effects of renin angiotensin system blockade and sodium-glucose co-transporter-2 inhibitors on erythropoietin secretion in diabetes. Am J Nephrol. 2020;51(5):349–56.

    Article  CAS  PubMed  Google Scholar 

  123. Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS ONE. 2013;8(2): e54442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Packer M. Mutual antagonism of hypoxia-inducible factor isoforms in cardiac, vascular, and renal disorders. JACC Basic Transl Sci. 2020;5(9):961–8.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Krishan P, Singh G, Bedi O. Carbohydrate restriction ameliorates nephropathy by reducing oxidative stress and upregulating HIF-1a levels in type-1 diabetic rats. J Diabetes Metab Disord. 2017;16:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Bessho R, Takiyama Y, Takiyama T, et al. Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci Rep. 2019;9:14754.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, et al. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab. 2020;105(4): dgaa057.

    Article  PubMed  Google Scholar 

  128. Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2020;141:704–7.

    Article  PubMed  Google Scholar 

  129. Sowton AP, Griffin JL, Murray AJ. Metabolic profiling of the diabetic heart: toward a richer picture. Front Physiol. 2019;10:639.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Selvaraj S, Kelly DP, Margulies KB. Implications of altered ketone metabolism and therapeutic ketosis in heart failure. Circulation. 2020;141(22):1800–12.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Cavaiola TS, Pettus J. Cardiovascular effects of sodium glucose co-transporter 2 inhibitors. Diabetes Metab Syndr Obes. 2018;11:133–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Inagaki N, Kazuoki Kondo K, Yoshinari T, Kuki H. Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52-week open-label study. J Diabetes Investig. 2015;6(2):210–8.

    Article  CAS  PubMed  Google Scholar 

  133. Tomita I, Kume S, Sugahara S, Osawa N, Yamahara Y, Yasuda-Yamahara M, et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 2020;32(3):404–19.

    Article  CAS  PubMed  Google Scholar 

  134. Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, Mayoux E, et al. SGLT2 Inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Jones BJ, Tan T, Bloom SR. Minireview: glucagon in stress and energy homeostasis. Endocrinology. 2012;153(3):1049–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium- glucose co-transporter 2 inhibition in ty pe 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–7.

    Article  CAS  PubMed  Google Scholar 

  138. Hattori Y. Beneficial effects on kidney during treatment with sodium-glucose co-transporter 2 inhibitors: proposed role of ketone utilization. Heart Fail Rev. 2021;26(4):947–52.

    Article  CAS  PubMed  Google Scholar 

  139. Oelze M, Kröller-Schön S, Welschof P, Ansen T, Hausding M, Mikhed Y, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE. 2014;9(11): e112394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Yaribeygi H, Atkin SL, Butler AE, Sahebkar A. Sodium–glucose co-transporter inhibitors and oxidative stress: an update. J Cell Physiol. 2019;234(4):3231–7.

    Article  CAS  PubMed  Google Scholar 

  141. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    Article  PubMed  CAS  Google Scholar 

  142. Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Hear Fail. 2018;6:489–98.

    Article  Google Scholar 

  143. Ruggenenti P, Remuzzi G. Combined neprilysin and RAS inhibition for the failing heart: Straining the kidney to help the heart? Eur J Heart Fail. 2015;17:468–71.

    Article  CAS  PubMed  Google Scholar 

  144. Solomon SD, Jhund PS, Claggett BL, Dewan P, Køber L, Kosiborod MN, et al. Effect of dapagliflozin in patients with hfref treated with sacubitril/valsartan: the DAPA-HF trial. JACC Heart Fail. 2020;8:811–8.

    Article  PubMed  Google Scholar 

  145. Sarafidis PA, Memmos E, Alexandrou ME, Papagianni A. Mineralocorticoid receptor antagonists for nephroprotection: current evidence and future perspectives. Curr Pharm Des. 2018;24(46):5528–36.

    Article  CAS  PubMed  Google Scholar 

  146. Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int. 2019;96(2):302–19.

    Article  CAS  PubMed  Google Scholar 

  147. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, FIDELIO-DKD Investigators, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219–29.

    Article  CAS  PubMed  Google Scholar 

  148. Sawamura T, Karashima S, Nagase S, Nambo H, Shimizu E, Higashitani T, et al. Effect of sodium-glucose co-transporter-2 inhibitors on aldosterone-to-renin ratio in diabetic patients with hypertension: a retrospective observational study. BMC Endocr Disord. 2020;20(1):177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shen L, Kristensen SL, Bengtsson O, Böhm M, de Boer RA, Docherty KF, et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail. 2021;S2213–1779(20):30704–6.

    Google Scholar 

  150. Ortiz A, Ferro CJ, Balafa O, Burnier M, Ekart R, Halimi JM, et al. Mineralocorticoid receptors antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association—European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and Kidney working group of the European Society of Hypertension (ESH). Nephrol Dial Transplant. 2021. https://doi.org/10.1093/ndt/gfab167 (Online ahead of print).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Pelletier R, Ng K, Alkabbani W, Labib Y, Mourad N, Gamble JM. Adverse events associated with sodium glucose co-transporter 2 inhibitors: an overview of quantitative systematic reviews. Ther Adv Drug Saf. 2021;12:2042098621989134.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Zhao M, Sun S, Huang Z, Wang T, Tang H. Network meta-analysis of novel glucose-lowering drugs on risk of acute kidney injury. Clin J Am Soc Nephrol. 2020;16(1):70–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Rampersad C, Kraut E, Whitlock RH, Komenda P, Woo V, Rigatto C, et al. Acute kidney injury events in patients with type 2 diabetes using SGLT2 inhibitors versus other glucose-lowering drugs: a retrospective cohort study. Am J Kidney Dis. 2020;76(4):471–9.

    Article  CAS  PubMed  Google Scholar 

  154. Jardine MJ, Zhou Z, Mahaffey KW, Oshima M, Agarwal R, Bakris G, CREDENCE Study Investigators, et al. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial. J Am Soc Nephrol. 2020;31(5):1128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Oshima M, Jardine MJ, Agarwal R, Bakris G, Cannon CP, Charytan DM, et al. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int. 2021;99(4):999–1009.

    Article  CAS  PubMed  Google Scholar 

  156. Ryan R, Choo S, Willows J, Walker J, Prasad K, Tez D. Acute interstitial nephritis due to sodium-glucose co-transporter 2 inhibitor empagliflozin. Clin Kidney J. 2020;14(3):1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Cianciolo G, De Pascalis A, Gasperoni L, Tondolo F, Zappulo F, Capelli I, et al. The off-target effects, electrolyte and mineral disorders of SGLT2i. Molecules. 2020;25(12):2757.

    Article  CAS  PubMed Central  Google Scholar 

  158. Barrett PQ, Aronson PS. Glucose and alanine inhibition of phosphate transport in renal microvillus membrane vesicles. Am J Physiol. 1982;242:126–31.

    Google Scholar 

  159. Lang F. Osmotic diuresis. Renal Physiol. 1987;10:160–73.

    CAS  PubMed  Google Scholar 

  160. Blau JE, Bauman V, Conway EM, Piaggi P, Walter MF, Wright EC, et al. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight. 2018;3: e99123.

    Article  PubMed Central  Google Scholar 

  161. de Jong MA, Petrykiv SI, Laverman GD, van Herwaarden AE, de Zeeuw D, Bakker SJL, et al. Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol. 2019;14(1):66–73.

    Article  PubMed  Google Scholar 

  162. Li X, Li T, Cheng Y, Lu Y, Xue M, Xu L, et al. Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: an updated meta-analysis. Diabetes Metab Res Rev. 2019;35(7): e3170.

    Article  PubMed  Google Scholar 

  163. Tang H, Zhang X, Zhang J, Li Y, Del Gobbo LC, Zhai S, et al. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials. Diabetologia. 2016;59(12):2546–51.

    Article  CAS  PubMed  Google Scholar 

  164. Weir MR, Kline I, Xie J, Edwards R, Usiskin K. Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin. 2014;30(9):1759–68.

    Article  CAS  PubMed  Google Scholar 

  165. Gilbert RE, Mende C, Vijapurkar U, Sha S, Davies MJ, Desai M. Effects of canagliflozin on serum magnesium in patients with type 2 diabetes mellitus: a post hoc analysis of randomized controlled trials. Diabetes Ther. 2017;8(2):451–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Filippatos TD, Tsimihodimos V, Liamis G, Elisaf MS. SGLT2 inhibitors-induced electrolyte abnormalities: an analysis of the associated mechanisms. Diabetes Metab Syndr. 2018;12(1):59–63.

    Article  CAS  PubMed  Google Scholar 

  167. Wang KM, Li JW, Bhalla V, Jardine MJ, Neal B, de Zeeuw D. Canagliflozin, serum magnesium and cardiovascular outcomes—analysis from the CANVAS Program. Endocrinol Diab Metab. 2021. https://doi.org/10.1002/edm2.247.

    Article  Google Scholar 

  168. van de Wal-Visscher ER, Kooman JP, van der Sande FM. Magnesium in chronic kidney disease: should we care? Blood Purif. 2018;45(1–3):173–8.

    Article  PubMed  CAS  Google Scholar 

  169. Ter Braake AD, Vervloet MG, de Baaij JHF, Hoenderop JGJ. Magnesium to prevent kidney disease-associated vascular calcification: crystal clear? Nephrol Dial Transplant. 2020 (Online ahead of print).

  170. Leenders NHJ, Vermeulen EA, van Ballegooijen AJ, Hoekstra T, de Vries R, Beulens JW, Vervloet MG. The association between circulating magnesium and clinically relevant outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Clin Nutr. 2021;40(5):3133–47.

    Article  PubMed  Google Scholar 

  171. Xiong J, He T, Wang M, Nie L, Zhang Y, Wang Y, et al. Serum magnesium, mortality, and cardiovascular disease in chronic kidney disease and end-stage renal disease patients: a systematic review and meta-analysis. J Nephrol. 2019;32(5):791–802.

    Article  CAS  PubMed  Google Scholar 

  172. Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348–55.

    Article  CAS  PubMed  Google Scholar 

  173. Bakris G, Oshima M, Mahaffey KW, Agarwal R, Cannon CP, Capuano G, et al. Effects of canagliflozin in patients with baseline eGFR < 30 mL/min per 1.73 m(2): subgroup analysis of the randomized CREDENCE Trial. Clin J Am Soc Nephrol. 2020;15(12):1705–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Yu J, Arnott C, Neuen BL, Heersprink HL, Mahaffey KW, Cannon CP, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program. ESC Heart Fail. 2021;8(2):1482–93.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Griffin M, Riello R, Rao VS, Ivey-Miranda J, Fleming J, Maulion C, et al. Sodium glucose co-transporter 2 inhibitors as diuretic adjuvants in acute decompensated heart failure: a case series. ESC Heart Fail. 2020;7(4):1966–71.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Shentu Y, Li Y, Xie S, Jiang H, Sun S, Lin R, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-beta/Smad signaling. Int Immunopharmacol. 2021;93: 107374.

    Article  CAS  PubMed  Google Scholar 

  177. He Y, Pachori A, Chen P, Ma S, Mendonza AE, Amer A, et al. Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2, in patients with chronic kidney disease: a randomized trial. Diabetes Obes Metab. 2021;23(5):1182–90.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, Como, Italy

    Lucia Del Vecchio, Carlo Jovane & Silvia Peiti

  2. Internal Medicine Unit, Valduce Hospital, 22100, Como, Italy

    Angelo Beretta

  3. School of Medicine and Surgery, Nephrology Clinic, University of Milano, Bicocca, 20100, Milan, Italy

    Silvia Peiti & Simonetta Genovesi

  4. Istituto Auxologico Italiano, IRCCS, 20100, Milan, Italy

    Simonetta Genovesi

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Lucia Del Vecchio received speaker fees from Mundipharma. Simonetta Genovesi received speaker fees from Astra-Zeneca. Angelo Beretta, Carlo Jovane and Silvia Peiti have no conflicts of interest to declare. All the Authors contributed to the writing and revision of the manuscript.

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Del Vecchio, L., Beretta, A., Jovane, C. et al. A Role for SGLT-2 Inhibitors in Treating Non-diabetic Chronic Kidney Disease. Drugs 81, 1491–1511 (2021). https://doi.org/10.1007/s40265-021-01573-3

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