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Protection of the kidney with sodium–glucose cotransporter 2 inhibitors: potential mechanisms raised by the large-scaled randomized control trials

  • Satoru KuriyamaEmail author
Review article

Abstract

This communication provides a current overview on the renal protective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in diabetics. Following the epoch-making publications, the CANVAS Program and the EMPA-REG OUTCOME trial, numerous literature has discussed the mechanisms by which SGLT2 inhibition exerts its cardio-renal protective effects. Some of them reached agreement, while others did not. This review focuses on the hemodynamic aspect and the remaining potential factors relevant to the renal protection which have not been so much taken up by other review papers. Questions unanswered include factors of uric acid, lipids, erythropoiesis and oxidative stress, salt and sympathetic nerve, and the Na–H exchanger in heart and kidney.

Keywords

Sodium–glucose cotransporter 2 inhibitor Diabetic nephropathy Renal protection Uric acid Small dense LDL-cholesterol Erythropoiesis 

Notes

Compliance with ethical standards

Conflict of interest

No conflict of interest is declared.

Human and animal rights

This article does not contain any studies with human participants or animals performed by the authors.

Informed consent

There is no informed consent. This article is a review.

References

  1. 1.
    Law MR1, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. Brit Med J. 2009;338:b1665.PubMedCrossRefGoogle Scholar
  2. 2.
    SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16.CrossRefGoogle Scholar
  3. 3.
    Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.PubMedCrossRefGoogle Scholar
  4. 4.
    Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez-Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL. SAVOR-TIMI 53 Steering Committee and Investigators: heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88.PubMedCrossRefGoogle Scholar
  5. 5.
    Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129–36.PubMedCrossRefGoogle Scholar
  6. 6.
    ACCORD Study Group. Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28.  https://doi.org/10.1056/NEJMoa1006524.CrossRefGoogle Scholar
  7. 7.
    Group ADVANCEC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.  https://doi.org/10.1056/NEJMoa0802987. Epub 2008 Jun 6.CrossRefGoogle Scholar
  8. 8.
    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.PubMedCrossRefGoogle Scholar
  10. 10.
    Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.PubMedCrossRefGoogle Scholar
  11. 11.
    Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017;28:368–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018;94(1):26–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Georgianos PI, Divani M, Eleftheriadis T, Mertens PR, Liakopoulos V. SGLT-2 inhibitors in diabetic kidney disease: what lies behind their renoprotective properties? Curr Med Chem. 2018.  https://doi.org/10.2174/0929867325666180524114033. [Epub ahead of print]. May 23.CrossRefPubMedGoogle Scholar
  14. 14.
    Layton AT. Optimizing SGLT inhibitor treatment for diabetes with chronic kidney diseases. Biol Cybern. 2018;28.  https://doi.org/10.1007/s00422-018-0765-y. [Epub ahead of print].
  15. 15.
    de Albuquerque Rocha N, Neeland IJ, McCullough PA, Toto RD, McGuire DK. Effects of sodium glucose co-transporter 2 inhibitors on the kidney. Diab Vasc Dis Res. 2018;1:1479164118783756.Google Scholar
  16. 16.
    Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–81.CrossRefGoogle Scholar
  17. 17.
    Ito S. Cardiorenal connection in chronic kidney disease. Clin Exp Nephrol. 2012;16(1):8–16.PubMedCrossRefGoogle Scholar
  18. 18.
    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(13):1296–305.PubMedCrossRefGoogle Scholar
  19. 19.
    Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351(13):1285–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8(5):293–300.  https://doi.org/10.1038/nrneph.2012.19.CrossRefPubMedGoogle Scholar
  21. 21.
    Blantz RC, Singh P. Glomerular and tubular function in the diabetic kidney. Adv Chronic Kidney Dis. 2014;21(3):297–303.  https://doi.org/10.1053/j.ackd.2014.03.006.CrossRefPubMedGoogle Scholar
  22. 22.
    Škrtić M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24(1):96–103.PubMedCrossRefGoogle Scholar
  23. 23.
    Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14(6):782–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54(12):3427–34.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang XX, Levi J, Luo Y, Myakala K, Herman-Edelstein M, Qiu L, Wang D, Peng Y, Grenz A, Lucia S, Dobrinskikh E, D’Agati VD, Koepsell H, Kopp JB, Rosenberg AZ, Levi M. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem. 2017;292(13):5335–5348.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Sabatini S, Kurtzman N. Role of Hyperfiltration in the pathogenesis of Diabetic nephropathy; ISBN: 978-1-61122-134-3.Google Scholar
  28. 28.
    Ichikawa L. Will angiotensin II receptor antagonists be renoprotective in humans?. Kidney Int. 1996;50(2):684–92.PubMedCrossRefGoogle Scholar
  29. 29.
    Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney Effects, Potential Mechanisms, and Clinical applications. Circulation. 2016;134(10):752–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24(2):168–75.PubMedCrossRefGoogle Scholar
  31. 31.
    Persson F, Lindhardt M, Rossing P, Parving HH. Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: a systematic review. J Renin Angiotensin Aldosterone Syst. 2016;17(3).Google Scholar
  32. 32.
    Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, Wanner C. 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(8):610–21.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. EMPA-REG RENAL trial investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369–84.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, von Eynatten M, Broedl UC. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Cardoso CR, Ferreira MT, Leite NC, Salles GF. Prognostic impact of aortic stiffness in high-risk type 2 diabetic patients: the Rio de Janeiro Type 2 diabetes cohort study. Diabetes Care. 2013;36(11):3772–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180–93.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House AA, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P. Acute dialysis quality initiative (ADQI) consensus group: Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010;31(6):703–11.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–97.PubMedCrossRefGoogle Scholar
  39. 39.
    Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014;37(3):867–75.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Ahmadieh H, Azar S. Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus. Diabetes Technol Ther. 2017;19(9):507–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ. EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, Chen L. 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.PubMedCrossRefGoogle Scholar
  44. 44.
    Davies MJ, Trujillo A, Vijapurkar U, Damaraju CV, Meininger G. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015 Apr;17(4):426–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wanner C. EMPA-REG OUTCOME. The nephrologist’s point of view. Am J Med. 2017;130(6S):S63–S72.PubMedCrossRefGoogle Scholar
  46. 46.
    Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Kanbay M, Jensen T, Solak Y, Le M, Roncal-Jimenez C, Rivard C, Lanaspa MA, Nakagawa T, Johnson RJ. Uric acid in metabolic syndrome: from an innocent bystander to a central player. Eur J Intern Med. 2016;29:3–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res. 2001;24(6):691–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis. 2004;44(4):642–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhu P, Liu Y, Han L, Xu G, Ran JM. Serum uric acid is associated with incident chronic kidney disease in middle-aged populations: a meta-analysis of 15 cohort studies. PLoS One. 2014;9(6):e100801.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Xu Y, Zhu J, Gao L, Liu Y, Shen J, Shen C, Matfin G, Wu X. Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients: a meta-analysis. PLoS One. 2013;24(10):e78206. 8(.CrossRefGoogle Scholar
  52. 52.
    Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010;123(10):957–61.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chen JH, Lan JL, Cheng CF, Liang WM, Lin HY, Tsay GJ, Yeh WT, Pan WH. Effect of urate-lowering therapy on all-cause and cardiovascular mortality in hyperuricemic patients without gout: a case-matched cohort study. PLoS One. 2015;10(12):e0145193.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kohagura K, Kochi M, Miyagi T, Kinjyo T, Maehara Y, Nagahama K, Sakima A, Iseki K, Ohya Y. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study. Hypertens Res. 2013;36(1):43–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Uedono H, Tsuda A, Ishimura E, Nakatani S, Kurajoh M, Mori K, Uchida J, Emoto M, Nakatani T, Inaba M. U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects. Am J Physiol Renal Physiol. 2017;312(6):F992-F997.PubMedCrossRefGoogle Scholar
  56. 56.
    Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811–21.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Feig DI. Uric acid and hypertension. Semin Nephrol. 2011;31(5):441–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Majewski C, Bakris GL. Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care. 2015;38(3):429–30.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39(5):717–25.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Caulfield MJ, Munroe PB, O’Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P, Shaw-Hawkins S, Dobson RJ, Wallace C, Newhouse SJ, Brown M, Connell JM, Dominiczak A, Farrall M, Lathrop GM, Samani NJ, Kumari M, Marmot M, Brunner E, Chambers J, Elliott P, Kooner J, Laan M, Org E, Veldre G, Viigimaa M, Cappuccio FP, Ji C, Iacone R, Strazzullo P, Moley KH, Cheeseman C. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5(10):e197.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, Tamai I. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35(7):391–404.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Bose B, Badve SV, Hiremath SS, Boudville N, Brown FG, Cass A, de Zoysa JR, Fassett RG, Faull R, Harris DC, Hawley CM, Kanellis J, Palmer SC, Perkovic V, Pascoe EM, Rangan GK, Walker RJ, Walters G, Johnson DW. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2014;29(2):406–13.PubMedCrossRefGoogle Scholar
  63. 63.
    Kanji T, Gandhi M, Clase CM, Yang R. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol. 2015;16:58.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63(5):713–35.PubMedCrossRefGoogle Scholar
  65. 65.
    Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, Pandey R. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricemia: a 6-month, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis. 2015;66(6):945–50.PubMedCrossRefGoogle Scholar
  66. 66.
    Shibagaki Y, Ohno I, Hosoya T, Kimura K. Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction. Hypertens Res. 2014;37(10):919–25.PubMedCrossRefGoogle Scholar
  67. 67.
    Goicoechea M, Garcia de Vinuesa S, Verdalles U, Verde E, Macias N, Santos A, Pérez de Jose A, Cedeño S, Linares T, Luño J. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis. 2015;65(4):543–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Wada T, Hosoya T, Honda D, Sakamoto R, Narita K, Sasaki T, Okui D, Kimura K. Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study). Clin Exp Nephrol. 2018;22(4):860–70.PubMedCrossRefGoogle Scholar
  69. 69.
    Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant. 2013;28(9):2221–8.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Sone H, Tanaka S, Tanaka S, Iimuro S, Oida K, Yamasaki Y, Oikawa S, Ishibashi S, Katayama S, Ohashi Y, Akanuma Y, Yamada N. Japan Diabetes Complications Study Group. Serum level of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab. 2011;96(11):3448–56.PubMedCrossRefGoogle Scholar
  71. 71.
    Ptaszynska A, Hardy E, Johnsson E, Parikh S, List J. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125(3):181–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Hayashi T, Fukui T, Nakanishi N, Yamamoto S, Tomoyasu M, Osamura A, Ohara M, Yamamoto T, Ito Y, Hirano T. Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin. Cardiovasc Diabetol. 2017;16(1):8.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Hirano T. Pathophysiology of Diabetic Dyslipidemia. J Atheroscler Thromb. 2018.  https://doi.org/10.5551/jat.RV17023. [Epub ahead of print]. Jul 12.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hayashi T, Fukui T, Nakanishi N, Yamamoto S, Tomoyasu M, Osamura A, Ohara M, Yamamoto T, Ito Y, Hirano T. Correction to: Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin. Cardiovasc Diabetol. 2017;16(1):149.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Bando Y, Tohyama H, Aoki K, Kanehara H, Hisada A, Okafuji K, Toya D. Ipragliflozin lowers small, dense low-density lipoprotein cholesterol levels in Japanese patients with type 2 diabetes mellitus. J Clin Transl Endocrinol. 2016;6:1–7.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Yagi S, Hirata Y, Ise T, Kusunose K, Yamada H, Fukuda D, Salim HM, Maimaituxun G, Nishio S, Takagawa Y, Hama S, Matsuura T, Yamaguchi K, Tobiume T, Soeki T, Wakatsuki T, Aihara KI, Akaike M, Shimabukuro M, Sata M. Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9:78.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Matsutani D, Sakamoto M, Kayama Y, Takeda N, Horiuchi R, Utsunomiya K. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):73.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006;291(2):F271-81.PubMedCrossRefGoogle Scholar
  79. 79.
    Chang YK, Choi H, Jeong JY, Na KR, Lee KW, Lim BJ, Choi DE. Dapagliflozin, SGLT2 inhibitor, attenuates renal ischemia-reperfusion injury. PLoS One. 2016;11(7):e0158810.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8(12):844–7.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17(1):17–25.PubMedCrossRefGoogle Scholar
  82. 82.
    O’Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 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(3):F227-34.PubMedGoogle Scholar
  83. 83.
    Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, Eguchi J, Horiguchi CS, Nishii N, Yamada H, Takei K, Makino H. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014;9(6):e100777.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How does empagliflozin reduce cardiovascular mortality? insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2):356–63.PubMedCrossRefGoogle Scholar
  86. 86.
    Sousa AG, Cabral JV, El-Feghaly WB, de Sousa LS, Nunes AB. Hyporeninemic hypoaldosteronism and diabetes mellitus: pathophysiology assumptions, clinical aspects and implications for management. World J Diabetes. 2016;10(5):101–11. 7(.CrossRefGoogle Scholar
  87. 87.
    Carlson SH, Roysomutti S, Peng N, Wyss JM. The role of the central nervous system in NaCl-sensitive hypertension in spontaneously hypertensive rats. Am J Hypertens. 2001;14(6 Pt 2):155S–162S.PubMedCrossRefGoogle Scholar
  88. 88.
    Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009;54(6):1195–201.PubMedCrossRefGoogle Scholar
  89. 89.
    Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, Roveda F, de Matos LN, Braga AM, Middlekauff HR, Negrão CE. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol. 2009;10(3):302–7. 135(.CrossRefGoogle Scholar
  90. 90.
    Hillis GS, Hata J, Woodward M, Perkovic V, Arima H, Chow CK, Zoungas S, Patel A, Poulter NR, Mancia G, Williams B, Chalmers J. Resting heart rate and the risk of microvascular complications in patients with type 2 diabetes mellitus. J Am Heart Assoc. 2012;1(5):e002832.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Cherney DZ, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M, Burns KD. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86(5):1057–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Yoshimoto T, Furuki T, Kobori H, Miyakawa M, Imachi H, Murao K, Nishiyama A. Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. J Investig Med. 2017;65(7):1057–61.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, Ahn YB, Kim ES, Moon SD, Kim MJ, Ko SH. Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PLoS One. 2016;11(11):e0165703.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sano M, Chen S, Imazeki H, Ochiai H, Seino Y. Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Subanalysis of placebo-controlled, double-blind clinical trials. J Diabetes Investig. 2018;9(3):638–41.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Wan N, Rahman A, Hitomi H, Nishiyama A. The Effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol (Lausanne). 2018;26:9:421.CrossRefGoogle Scholar
  96. 96.
    Packer M. Activation and inhibition of sodium–hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation. 2017;136(16):1548–1559.PubMedCrossRefGoogle Scholar
  97. 97.
    Padan E, Landau M. Sodium-proton (Na(+)/H(+)) antiporters: properties and roles in health and disease. Met Ions Life Sci. 2016;16:391–458.PubMedCrossRefGoogle Scholar
  98. 98.
    Wakabayashi S, Hisamitsu T, Nakamura TY. Regulation of the cardiac Na+/Ha+ exchanger in health and disease. J Mol Cell Cardiol. 2013;61:68–76.PubMedCrossRefGoogle Scholar
  99. 99.
    Liu T, Takimoto E, Dimaano VL, DeMazumder D, Kettlewell S, Smith G, Sidor A, Abraham TP, O’Rourke B. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115(1):44–54.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Böhm M, O’Rourke B, Maack C. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010;121(14):1606–13.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Lütken SC, Kim SW, Jonassen T, Marples D, Knepper MA, Kwon TH, Frøkiaer J, Nielsen S. Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT1 receptor blockade. Am J Physiol Renal Physiol. 2009;297(6):F1678-88.PubMedCrossRefGoogle Scholar
  102. 102.
    Xiao XH, Allen DG. The role of endogenous angiotensin II in ischaemia, reperfusion and preconditioning of the isolated rat heart. Pflugers Arch. 2003;445(6):643–50.PubMedCrossRefGoogle Scholar
  103. 103.
    Cingolani HE, Pérez NG, Cingolani OH, Ennis IL. The Anrep effect: 100 years later. Am J Physiol Heart Circ Physiol. 2013;304(2):H175-82.PubMedCrossRefGoogle Scholar
  104. 104.
    Liu G, Hitomi H, Rahman A, Nakano D, Mori H, Masaki T, Ma H, Iwamoto T, Kobori H, Nishiyama A. High sodium augments angiotensin II-induced vascular smooth muscle cell proliferation through the ERK 1/2-dependent pathway. Hypertens Res. 2014;37(1):13–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Girardi AC, Knauf F, Demuth HU, Aronson PS. Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells. Am J Physiol Cell Physiol. 2004;287(5):C1238-45.PubMedCrossRefGoogle Scholar
  106. 106.
    Carraro-Lacroix LR, Malnic G, Girardi AC.. Carraro-Lacroix LR, Malnic G, Girardi AC. Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol. 2009;297(6):F1647-55.PubMedCrossRefGoogle Scholar
  107. 107.
    Farah LX, Valentini V, Pessoa TD, Malnic G, McDonough AA, Girardi AC. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am J Physiol Renal Physiol. 2016;310(2):F123-7.PubMedCrossRefGoogle Scholar
  108. 108.
    Crajoinas RO, Oricchio FT, Pessoa TD, Pacheco BP, Lessa LM, Malnic G, Girardi AC. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol. 2011;301(2):F355-63.PubMedCrossRefGoogle Scholar
  109. 109.
    Kawase H, Bando YK, Nishimura K, Aoyama M, Monji A, Murohara T. A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis. J Mol Cell Cardiol. 2016;98:37–47.PubMedCrossRefGoogle Scholar
  110. 110.
    Baartscheer A, Schumacher CA, Wüst RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–73.PubMedCrossRefGoogle Scholar
  111. 111.
    Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na + and vasodilation. Diabetologia. 2018;61(3):722–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, Rosenthal N, Jardine MJ, Bakris G, Perkovic V. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function: data from the CANVAS program. Circulation. 2018;138(15):1537–50.  https://doi.org/10.1161/CIRCULATIONAHA.118.035901.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, Bull S, Cannon CP, Charytan DM, de Zeeuw D, Edwards R, Greene T, Heerspink HJL, Levin A, Pollock C, Wheeler DC, Xie J, Zhang H, Zinman B, Desai M, Perkovic V. CREDENCE study investigators. the canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462–72.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20(3):479–87.  https://doi.org/10.1111/dom.13126. Epub 2017 Nov 15.CrossRefPubMedGoogle Scholar
  115. 115.
    Ryan PB, Buse JB, Schuemie MJ, DeFalco F, Yuan Z, Stang PE, Berlin JA, Rosenthal N. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab. 2018;20:2585–2597.  https://doi.org/10.1111/dom.13424.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Zelniker TA, 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. 2018;72(15):1845–55.  https://doi.org/10.1016/j.jacc.2018.06.040.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2018

Authors and Affiliations

  1. 1.Miho Clinic, Jikei University School of MedicineTokyoJapan

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