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Significance of SGLT2 inhibitors: lessons from renal clinical outcomes in patients with type 2 diabetes and basic researches

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Abstract

Diabetic kidney disease (DKD), a microvascular complication of diabetes, has been the leading cause of end-stage kidney disease (ESKD). Accordingly, patients with type 2 diabetes mellitus (T2DM) develop renal damage due to multiple metabolic and cardiorenal disease-related risk factors, including hyperglycemia, hypertension, dyslipidemia, hyperuricemia, and overnutrition/obesity. Despite multifactorial management including the administration of renin–angiotensin system inhibitors, patients often do not experience sufficient suppression of DKD progression and, thus, remain at risk for ESKD. Recent studies on cardiovascular outcomes among patients with T2DM have clearly shown that sodium–glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, canagliflozin, and dapagliflozin, have cardiorenal protective effects apart from their glucose-lowering effects. In particular, SGLT2 inhibitors have been found to improve renal outcomes, including ESKD, by slowing renal function decline and reducing urinary albumin excretion through their class effect. The proposed mechanisms for the renoprotective effects of SGLT2 inhibitors include the action of tubulo-glomerular feedback system and attenuation of hypoxia and metabolic stress in proximal tubular cells mediated through the inhibition of excessive glucose and sodium reabsorption, increased erythropoiesis, or increased ketone body production.

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References

  1. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–21.

    PubMed  PubMed Central  Google Scholar 

  2. Radcliffe NJ, Seah JM, Clarke M, et al. Clinical predictive factors in diabetic kidney disease progression. J Diabetes Investig. 2017;8:6–18.

    CAS  PubMed  Google Scholar 

  3. Kitada M, Kanasaki K, Koya D. Clinical therapeutic strategies for early stage of diabetic kidney disease. World J Diabetes. 2014;15(5):342–56.

    Google Scholar 

  4. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93.

    PubMed  Google Scholar 

  5. Araki SI. Comprehensive risk management of diabetic kidney disease in patients with type 2 diabetes mellitus. Diabetol Int. 2018;9:100–7.

    PubMed  PubMed Central  Google Scholar 

  6. Yokoyama H, Araki S, Honjo J, et al. Association between remission of macroalbuminuria and preservation of renal function in patients with type 2 diabetes with overt proteinuria. Diabetes Care. 2013;36:3227–333.

    PubMed  PubMed Central  Google Scholar 

  7. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    CAS  PubMed  Google Scholar 

  8. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    CAS  PubMed  Google Scholar 

  9. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

    CAS  PubMed  Google Scholar 

  10. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

    CAS  PubMed  Google Scholar 

  11. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.

    CAS  PubMed  Google Scholar 

  12. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA. 2019;321:69–79.

    CAS  PubMed  Google Scholar 

  13. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.

    CAS  PubMed  Google Scholar 

  15. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–30.

    CAS  PubMed  Google Scholar 

  16. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–288.

    CAS  PubMed  Google Scholar 

  17. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    CAS  PubMed  Google Scholar 

  18. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.

    CAS  PubMed  Google Scholar 

  19. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94.

    CAS  PubMed  Google Scholar 

  20. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    CAS  PubMed  Google Scholar 

  21. Kadowaki T, Nangaku M, Hantel S, et al. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: results from the EMPA-REG OUTCOME® trial. J Diabetes Investig. 2019;10:760–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:610–21.

    CAS  PubMed  Google Scholar 

  23. Neuen BL, 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. 2019;30:2229–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7:606–17.

    CAS  PubMed  Google Scholar 

  25. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    CAS  PubMed  Google Scholar 

  26. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7:845–54.

    CAS  PubMed  Google Scholar 

  27. Heerspink HJL, Karasik A, Thuresson M, et al. Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study. Lancet Diabetes Endocrinol. 2020;8:27–35.

    CAS  PubMed  Google Scholar 

  28. Miyoshi H, Kameda H, Yamashita K, et al. Protective effect of sodium-glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes. J Diabetes Investig. 2019;10:1510–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18:783–94.

    CAS  PubMed  Google Scholar 

  30. Ito Y, Van Schyndle J, Nishimura T, et al. Real-world effectiveness of sodium glucose co-transporter-2 inhibitors in Japanese patients with diabetes mellitus. Diabetes Ther. 2019;10:2219–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28:1023–39.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427–34.

    CAS  PubMed  Google Scholar 

  34. Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol. 2015;308:F1343–F13571357.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kidokoro K, Cherney DZI, Bozovic A, et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140:303–15.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Rajasekeran H, Lytvyn Y, Bozovic A, et al. Urinary adenosine excretion in type 1 diabetes. Am J Physiol Renal Physiol. 2017;313:F184–F191191.

    CAS  PubMed  Google Scholar 

  38. Layton AT, Vallon V, Edwards A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol. 2016;310:F1269–F12831283.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Neill O, Fasching A, Pihl L, et al. Acute SGLT inhibition normalizes oxygen tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015;309:F227–F23434.

    Google Scholar 

  40. Mimura I, Nangaku M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol. 2010;6:667–78.

    CAS  PubMed  Google Scholar 

  41. Hansell P, Welch WJ, Blantz RC, et al. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin Exp Pharmacol Physiol. 2013;40:123–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kamezaki M, Kusaba T, Komaki K, et al. Comprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice. Sci Rep. 2018;8:4029.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  44. Maxwell P. HIF-1: an oxygen response system with special relevance to the kidney. J Am Soc Nephrol. 2003;14:2712–22.

    PubMed  Google Scholar 

  45. Sato Y, Yanagita M. Renal anemia: from incurable to curable. Am J Physiol Renal Physiol. 2013;305:F1239–F12481248.

    CAS  PubMed  Google Scholar 

  46. Inzucchi SE, 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. 2018;41:356–63.

    CAS  PubMed  Google Scholar 

  47. Sano M, Takei M, Shiraishi Y, et al. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8:844–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rieg T, Masuda T, Gerasimova M, 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–F193193.

    CAS  PubMed  Google Scholar 

  49. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:1115–22.

    CAS  PubMed  Google Scholar 

  50. Zhang G, Darshi M, Sharma K. The warburg effect in diabetic kidney disease. Semin Nephrol. 2018;38:111–20.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Srivastava SP, Li J, Kitada M, et al. SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis. Cell Death Dis. 2018;9:997.

    PubMed  PubMed Central  Google Scholar 

  53. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig. 2010;1:77–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Koya D. Diabetic kidney disease: its current trends and future therapeutic perspectives. J Diabetes Investig. 2019;10:1174–6.

    PubMed  PubMed Central  Google Scholar 

  55. van Baar MJB, Scholtes RA, van Raalte DH. SGLT2 inhibitors' interaction with other renoactive drugs in type 2 diabetes patients: still a lot to learn. Kidney Int. 2019;96:283–6.

    PubMed  Google Scholar 

  56. The Committee on the Proper Use of SGLT2 Inhibitors. Recommendations on the Proper Use of SGLT2 Inhibitors. Diabetology Int. 2019;11:1–5.

    Google Scholar 

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Correspondence to Munehiro Kitada.

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Kitada, M., Hirai, T. & Koya, D. Significance of SGLT2 inhibitors: lessons from renal clinical outcomes in patients with type 2 diabetes and basic researches. Diabetol Int 11, 245–251 (2020). https://doi.org/10.1007/s13340-020-00444-8

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