Background: Diabetes is the leading cause of end-stage renal disease (ESRD) and accounts for 40-50% of patients requiring renal replacement therapy. The main pathophysiology of diabetic nephropathy comprises glucose-dependent pathways, hemodynamic pathways, and genetic factors. Summary: Glucose-dependent pathways, known as advanced glycation, polyols, and protein kinase C activation have been implicated in the pathogenesis of diabetic nephropathy. Current studies have indicated that intensified glycemic control retards the rate of development of albuminuria and impairs renal function in both patients with type 1 and 2 diabetes. However, therapeutic options have substantially increased over the last decade, but have not yet been translated to remarkably reduce the incidence of ESRD from diabetic nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents with potential renoprotective effects. Key Message: SGLT2 inhibitors represent a promising therapeutic approach to prevent and improve nephropathy among patients with type 2 diabetes. The current data strongly support that SGLT2 inhibitors have renoprotective properties not only by improving glycemic control but also through hemodynamic and nonhemodynamic renal effects. This review focuses on the latest published data dealing with hypoglycemic agents and SGLT2 inhibitors regarding the progression of kidney disease.

1.
Satirapoj B, Adler SG: Comprehensive approach to diabetic nephropathy. Kidney Res Clin Pract 2014;33:121-131.
2.
Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH: Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24:302-308.
3.
Satirapoj B: Review on pathophysiology and treatment of diabetic kidney disease. J Med Assoc Thai 2010;93(suppl 6):S228-S241.
4.
Satirapoj B, Adler SG: Prevalence and management of diabetic nephropathy in western countries. Kidney Dis (Basel) 2015;1:61-70.
5.
Mishra R, Emancipator SN, Kern T, Simonson MS: High glucose evokes an intrinsic proapoptotic signaling pathway in mesangial cells. Kidney Int 2005;67:82-93.
6.
Heilig CW, Deb DK, Abdul A, Riaz H, James LR, Salameh J, Nahman NS Jr: GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy. Am J Nephrol 2013;38:39-49.
7.
Gurley SB, Coffman TM: The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 2007;27:144-152.
8.
Fan YY, Kobori H, Nakano D, Hitomi H, Mori H, Masaki T, Sun YX, Zhi N, Zhang L, Huang W, et al: Aberrant activation of the intrarenal renin-angiotensin system in the developing kidneys of type 2 diabetic rats. Horm Metab Res 2013;45:338-343.
9.
Durvasula RV, Shankland SJ: Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol 2008;294:F830-F839.
10.
Soulis T, Cooper ME, Vranes D, Bucala R, Jerums G: Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney Int 1996;50:627-634.
11.
Singh AK, Mo W, Dunea G, Arruda JA: Effect of glycated proteins on the matrix of glomerular epithelial cells. J Am Soc Nephrol 1998;9:802-810.
12.
Ha H, Hwang IA, Park JH, Lee HB: Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 2008;82(suppl 1):S42-S45.
13.
Freedman BI, Bostrom M, Daeihagh P, Bowden DW: Genetic factors in diabetic nephropathy. Clin J Am Soc Nephrol 2007;2:1306-1316.
14.
Satirapoj B, Supasyndh O, Dispan R, Punpanich D, Tribanyatkul S, Choovichian P: Apolipoprotein E genetic polymorphisms and the development of nephropathy in type 2 diabetes. J Med Assoc Thai 2013;96:1119-1126.
15.
Kim JH, Shin HD, Park BL, Moon MK, Cho YM, Hwang YH, Oh KW, Kim SY, Lee HK, Ahn C, et al: SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes 2006;55:843-848.
16.
Shimazaki A, Kawamura Y, Kanazawa A, Sekine A, Saito S, Tsunoda T, Koya D, Babazono T, Tanaka Y, Matsuda M, et al: Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 2005;54:1171-1178.
17.
McDonough CW, Palmer ND, Hicks PJ, Roh BH, An SS, Cooke JN, Hester JM, Wing MR, Bostrom MA, Rudock ME, et al: A genome-wide association study for diabetic nephropathy genes in African Americans. Kidney Int 2011;79:563-572.
18.
Kawazu S, Tomono S, Shimizu M, Kato N, Ohno T, Ishii C, Murata K, Watanabe T, Negishi K, Suzuki M, et al: The relationship between early diabetic nephropathy and control of plasma glucose in non-insulin-dependent diabetes mellitus. The effect of glycemic control on the development and progression of diabetic nephropathy in an 8-year follow-up study. J Diabetes Complications 1994;8:13-17.
19.
The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
20.
The Diabetes Control and Complications (DCCT) Research Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995;47:1703-1720.
21.
Shichiri M, Kishikawa H, Ohkubo Y, Wake N: Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(suppl 2):B21-B29.
22.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853.
23.
Group DER, de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Zinman B: Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011;365:2366-2376.
24.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-1589.
25.
Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69-75.
26.
Fioretto P, Sutherland DE, Najafian B, Mauer M: Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int 2006;69:907-912.
27.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, et al: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.
28.
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, et al: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.
29.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, et al: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.
30.
Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, et al: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.
31.
Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR: Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med 2012;172:761-769.
32.
National Kidney Foundation: KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis 2012;60:850-886.
33.
Andrassy KM: Comments on “KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.” Kidney Int 2013;84:622-623.
34.
American Diabetes Association: Standards of medical care in diabetes - 2014. Diabetes Care 2014;37(suppl 1):S14-S80.
35.
Gallo LA, Wright EM, Vallon V: Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res 2015;12:78-89.
36.
DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, Leslie BR, Boulton DW, Ching A, et al: Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 2013;36:3169-3176.
37.
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;54:3427-3434.
38.
Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ: Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc 2014;62:1252-1262.
39.
Bailey CJ, Gross JL, Pieters A, Bastien A, List JF: Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-2233.
40.
Kohan DE, Fioretto P, Tang W, List JF: Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962-971.
41.
Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, Wajs E, Figueroa K, Jiang J, Law G, et al: Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 2014;16:1016-1027.
42.
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;2:369-384.
43.
Lytvyn Y, Skrtic M, Yang GK, Yip PM, Perkins BA, Cherney DZ: Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol 2015;308:F77-F83.
44.
Hovind P, Rossing P, Johnson RJ, Parving HH: Serum uric acid as a new player in the development of diabetic nephropathy. J Ren Nutr 2011;21:124-127.
45.
Satirapoj B, Supasyndh O, Chaiprasert A, Ruangkanchanasetr P, Kanjanakul I, Phulsuksombuti D, Utainam D, Choovichian P: Relationship between serum uric acid levels with chronic kidney disease in a Southeast Asian population. Nephrology (Carlton) 2010;15:253-258.
46.
Heerspink HJ, Johnsson E, Gause-Nilsson I, Cain VA, Sjostrom CD: Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab 2016;18:590-597.
47.
Cherney D, Lund SS, Perkins BA, Groop PH, Cooper ME, Kaspers S, Pfarr E, Woerle HJ, von Eynatten M: The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia 2016;59:1860-1870.
48.
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;28:368-375.
49.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.
50.
Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundstrom J, Neal B: Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2016;4:411-419.
51.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B, et al: Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334.
52.
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;10:2569-2576.
53.
Faulhaber-Walter R, Chen L, Oppermann M, Kim SM, Huang Y, Hiramatsu N, Mizel D, Kajiyama H, Zerfas P, Briggs JP, et al: Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury. J Am Soc Nephrol 2008;19:722-730.
54.
Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T: Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol 2013;304:F156-F167.
55.
Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, et al: Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-597.
56.
Kojima N, Williams JM, Slaughter TN, Kato S, Takahashi T, Miyata N, Roman RJ: Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats. Physiol Rep 2015;3:e12436.
57.
Zhang PL, Mackenzie HS, Troy JL, Brenner BM: Effects of an atrial natriuretic peptide receptor antagonist on glomerular hyperfiltration in diabetic rats. J Am Soc Nephrol 1994;4:1564-1570.
58.
Wang Y, Xu L, Yuan L, Li D, Zhang Y, Zheng R, Liu C, Feng X, Li Q, Li Q, et al: Sodium-glucose co-transporter-2 inhibitors suppress atrial natriuretic peptide secretion in patients with newly diagnosed Type 2 diabetes. Diabet Med 2016;33:1732-1736.
59.
Hills CE, Squires PE: The role of TGF-beta and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev 2011;22:131-139.
60.
Satirapoj B, Aramsaowapak K, Tangwonglert T, Supasyndh O: Novel tubular biomarkers predict renal progression in type 2 diabetes mellitus: a prospective cohort study. J Diabetes Res 2016;2016:3102962.
61.
Maeda S, Matsui T, Takeuchi M, Yamagishi S: Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab Res Rev 2013;29:406-412.
62.
Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, Pollock C, Mather A: Effects of SGLT2 inhibition in human kidney proximal tubular cells - renoprotection in diabetic nephropathy? PLoS One 2013;8:e54442.
63.
Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, Ahn YB, Kim ES, Moon SD, Kim MJ, et al: 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:e0165703.
64.
Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T: SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 2014;306:F194-F204.
65.
Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, Eguchi J, Horiguchi CS, Nishii N, Yamada H, et al: 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:e100777.
66.
Korner A, Eklof AC, Celsi G, Aperia A: Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 1994;43:629-633.
67.
Fine LG, Norman JT: Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008;74:867-872.
68.
Standards of Medical Care in Diabetes - 2017: Summary of Revisions. Diabetes Care 2017;40:S4-S5.
69.
Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A: Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159:262-274.
70.
Nauck MA: Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther 2014;8:1335-1380.
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