New Diabetes Therapies and Diabetic Kidney Disease Progression: the Role of SGLT-2 Inhibitors

Current Diabetes Reports

Volumn 18, Issue 5, 2018, Pages

  Dekkers, Claire C J ^a   Gansevoort, Ron T ^a   Heerspink, Hiddo J L ^a  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

Author keywords

Chronic kidney disease; Clinical trials; Pharmacology; Sodium glucose co trasporter 2 inhibitor; Type 2 diabetes

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; ERTUGLIFLOZIN; GLUCOSE; HEMOGLOBIN A1C; IPRAGLIFLOZIN; LUSEOGLIFLOZIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SOTAGLIFLOZIN; TOFOGLIFLOZIN; SODIUM GLUCOSE COTRANSPORTER 2;

ALBUMINURIA; AMPUTATION; BLOOD PRESSURE; BODY WEIGHT LOSS; DIABETIC NEPHROPATHY; DISEASE EXACERBATION; DRUG EFFECT; DRUG INDICATION; DRUG SAFETY; FEEDBACK SYSTEM; GLOMERULAR DYSFUNCTION; GLOMERULAR HYPERFILTRATION; GLYCEMIC CONTROL; HEART PROTECTION; HUMAN; HYPOGLYCEMIA; KIDNEY DISEASE; METABOLISM; NATRIURESIS; NEPHRITIS; NON DIABETIC KIDNEY DISEASE; OXYGENATION; RENAL OXYGENATION; RENAL PROTECTION; REVIEW; RISK; RISK REDUCTION; TUBULOGLOMERULAR FEEDBACK; CHEMISTRY; CLINICAL TRIAL (TOPIC); PATHOLOGY; PATHOPHYSIOLOGY; TREATMENT OUTCOME;

BLOOD PRESSURE; CLINICAL TRIALS AS TOPIC; DIABETIC NEPHROPATHIES; DISEASE PROGRESSION; HUMANS; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TREATMENT OUTCOME;

EID: 85044732899     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-018-0992-6     Document Type: Review

References (81)

1. International Diabetes Federation. IDF Diabetes Atlas. 7th ed. Brussels: International Diabetes Federation; 2015. http://www.diabetesatlas.org
2. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(Suppl 1):S14–80. https://doi.org/10.2337/dc14-S014.
3. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–21. https://doi.org/10.1681/ASN.2008121270.
4. Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24:302–8. https://doi.org/10.1681/ASN.2012070718.
5. Quaresma M, Coleman MP, Rachet B. 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: a population-based study. Lancet. 2015;385:1206–18. https://doi.org/10.1016/S0140-6736(14)61396-9.
6. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93. https://doi.org/10.1056/NEJMoa021778.
7. Oellgaard J, Gaede P, Rossing P, Persson F, Parving HH, Pedersen O. Intensified multifactorial intervention in type 2 diabetics with microalbuminuria leads to long-term renal benefits. Kidney Int. 2017;91:982–8.
8. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72. https://doi.org/10.1056/NEJMoa0802987.
9. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39. https://doi.org/10.1056/NEJMoa0808431.
10. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59. https://doi.org/10.1056/NEJMoa0802743.
11. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42. https://doi.org/10.1056/NEJMoa1501352.
12. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26. https://doi.org/10.1056/NEJMoa1307684.
13. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35. https://doi.org/10.1056/NEJMoa1305889.
14. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39. https://doi.org/10.1056/NEJMoa1612917.
15. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22. https://doi.org/10.1056/NEJMoa1603827.
16. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44. https://doi.org/10.1056/NEJMoa1607141.
17. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57. https://doi.org/10.1056/NEJMoa1509225.
18. •• 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. https://doi.org/10.1056/NEJMoa1504720. This large clinical trial shows the beneficial cardiovascular and renoprotective effects of SGLT-2 inhibitors.
19. •• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34. https://doi.org/10.1056/NEJMoa1515920. This large clinical trial shows the beneficial cardiovascular and renoprotective effects of SGLT-2 inhibitors.
20. •• Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925. This large clinical trial shows the beneficial cardiovascular and renoprotective effects of SGLT-2 inhibitors.
21. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism. 2014;63:1228–37. https://doi.org/10.1016/j.metabol.2014.06.018.
22. Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int. 2009;75:1272–7. https://doi.org/10.1038/ki.2009.87.
23. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32–43.
24. Ghezzi C, Yu AS, Hirayama BA, Kepe V, Liu J, Scafoglio C, et al. Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule. J Am Soc Nephrol. 2017;28:802–10. https://doi.org/10.1681/ASN.2016050510.
25. Blondel O, Bailbe D, Portha B. Insulin resistance in rats with non-insulin-dependent diabetes induced by neonatal (5 days) streptozotocin: evidence for reversal following phlorizin treatment. Metabolism. 1990;39:787–93.
26. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987;79:1510–5. https://doi.org/10.1172/JCI112981.
27. Starke A, Grundy S, McGarry JD, Unger RH. Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes. Proc Natl Acad Sci U S A. 1985;82:1544–6.
28. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Efficacy DMJ. 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. https://doi.org/10.1111/dom.12670.
29. Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2:691–700. https://doi.org/10.1016/S2213-8587(14)70120-2.
30. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508–15. https://doi.org/10.2337/dc12-2491.
31. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–50. https://doi.org/10.1016/S0140-6736(13)60683-2.
32. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217–24. https://doi.org/10.2337/dc10-0612.
33. Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–82. https://doi.org/10.1111/dom.12054.
34. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–14. https://doi.org/10.1172/JCI70704.
35. Liu JJ, Lee T, DeFronzo RA. Why do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes. 2012;61:2199–204. https://doi.org/10.2337/db12-0052.
36. Blonde L, Stenlof K, Fung A, Xie J, Canovatchel W, Meininger G. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks. Postgrad Med. 2016;128:371–80. https://doi.org/10.1080/00325481.2016.1169894.
37. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31. https://doi.org/10.1210/jc.2011-2260.
38. Liu J, Fox CS, Hickson DA, May WD, Hairston KG, Carr JJ, et al. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson heart study. J Clin Endocrinol Metab. 2010;95:5419–26. https://doi.org/10.1210/jc.2010-1378.
39. Heerspink HJ, List J, Boulton D, Liu X, Ying L, de Zeeuw D. The SGLT2 inhibitor dapagliflozin, a proximal tubular diuretic with antihypertensive properties? Presented at the World Congress of Nephrology, 8–12 April 2011;Vancouver, Canada. 2011. Abstract SU183.
40. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009;85:513–9. https://doi.org/10.1038/clpt.2008.250.
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;15:853–62. https://doi.org/10.1111/dom.12127.
42. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–75.e9. https://doi.org/10.1016/j.jash.2014.01.007.
43. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435–43. https://doi.org/10.1016/S0140-6736(15)00805-3.
44. Lv J, Ehteshami P, Sarnak MJ, Tighiouart H, Jun M, Ninomiya T, et al. Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis. CMAJ. 2013;185:949–57. https://doi.org/10.1503/cmaj.121468.
45. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–8. https://doi.org/10.2337/dc14-1096.
46. Rahman A, Hitomi H, Nishiyama A. Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. Hypertens Res. 2017;40:535–40. https://doi.org/10.1038/hr.2016.193.
47. Muskiet MH, van Bommel EJ, van Raalte DH. Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes. Lancet Diabetes Endocrinol. 2016;4:188–9. https://doi.org/10.1016/S2213-8587(15)00457-X.
48. Schneider MP, Raff U, Kopp C, Scheppach JB, Toncar S, Wanner C, et al. Skin sodium concentration correlates with left ventricular hypertrophy in CKD. J Am Soc Nephrol. 2017;28:1867–76. https://doi.org/10.1681/ASN.2016060662.
49. Karg MV, Bosch A, Kannenkeril D, Striepe K, Ott C, Schneider MP, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol. 2018;17:5. https://doi.org/10.1186/s12933-017-0654-z.
50. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28. https://doi.org/10.1186/1475-2840-13-28.
51. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8:293–300. https://doi.org/10.1038/nrneph.2012.19.
52. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97. https://doi.org/10.1161/CIRCULATIONAHA.113.005081.
53. Gilbert RE. SGLT2 inhibitors: beta blockers for the kidney? Lancet Diabetes Endocrinol. 2016;4:814. https://doi.org/10.1016/S2213-8587(16)30237-6.
54. 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;8:844–7. https://doi.org/10.14740/jocmr2760w.
55. O’Neill J, Fasching A, Pihl L, Patinha D, Franzen 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:F227–34. https://doi.org/10.1152/ajprenal.00689.2014.
56. Wolkow PP, Niewczas MA, Perkins B, Ficociello LH, Lipinski B, Warram JH, et al. Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol. 2008;19:789–97. https://doi.org/10.1681/ASN.2007050556.
57. Sangoi MB, de Carvalho JA, Tatsch E, Hausen BS, Bollick YS, Londero SW, et al. Urinary inflammatory cytokines as indicators of kidney damage in type 2 diabetic patients. Clin Chim Acta. 2016;460:178–83. https://doi.org/10.1016/j.cca.2016.06.028.
58. Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res. 2015;47:686–92. https://doi.org/10.1055/s-0034-1395609.
59. 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:e54442. https://doi.org/10.1371/journal.pone.0054442.
60. Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M. Glycemic control with Ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in Streptozotocin-induced diabetic mouse. Front Cardiovasc Med. 2016;3:43. https://doi.org/10.3389/fcvm.2016.00043.
61. Dekkers CCJ, Petrykiv S, Laverman G, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Oral abstract presentation at the American Society of Nephrology (ASN) kidney week 2017 annual meeting. 2017.
62. Cherney D, Lund SS, Perkins BA, Groop PH, Cooper ME, Kaspers S, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59:1860–70. https://doi.org/10.1007/s00125-016-4008-2.
63. Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, 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.
64. 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;18:590–7. https://doi.org/10.1111/dom.12654.
65. Petrykiv SI, Laverman GD, de Zeeuw D, Heerspink HJL. The albuminuria-lowering response to dapagliflozin is variable and reproducible among individual patients. Diabetes Obes Metab. 2017;19:1363–70. https://doi.org/10.1111/dom.12936.
66. Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, Broedl UC, Lund SS. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93:231–244. https://doi.org/10.1016/j.kint.2017.06.017.
67. Dekkers CCJ, Wheeler DC, Sjostrom CD, Stefansson BV, Cain V, Heerspink HJL. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and stages 3b-4 chronic kidney disease. Nephrol Dial Transplant. 2018; https://doi.org/10.1093/ndt/gfx350.
68. Petrykiv S, Sjostrom CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function. Clin J Am Soc Nephrol. 2017;12:751–9. https://doi.org/10.2215/CJN.10180916.
69. 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. https://doi.org/10.1681/ASN.2016030278.
70. Whaley-Connell A, Sowers JR. Obesity and kidney disease: from population to basic science and the search for new therapeutic targets. Kidney Int. 2017;92:313–23.
71. Hill GS. Hypertensive nephrosclerosis. Curr Opin Nephrol Hypertens. 2008;17:266–70. https://doi.org/10.1097/MNH.0b013e3282f88a1f.
72. Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. https://doi.org/10.1038/nrdp.2016.1.
73. Abdi-Ali A, Mann MC, Hemmelgarn BR, MacRae JM, Turin TC, Benediktsson H, et al. IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin-angiotensin system activity. J Renin-Angiotensin-Aldosterone Syst. 2015;16:521–8. https://doi.org/10.1177/1470320313510586.
74. Pozzi C. Treatment of IgA nephropathy. J Nephrol. 2016;29:21–5. https://doi.org/10.1007/s40620-015-0248-3.
75. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12:502–17. https://doi.org/10.2215/CJN.05960616.
76. Futrakul N, Futrakul P, Siriviriyakul P. Correction of peritubular capillary flow reduction with vasodilators restores function in focal segmental glomerulosclerotic nephrosis. Clin Hemorheol Microcirc. 2004;31:197–205.
77. Komoroski B, Vachharajani N, Boulton D, Kornhauser D, Geraldes M, Li L, et al. dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85:520–6. https://doi.org/10.1038/clpt.2008.251.
78. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes—2018. Diabetes Care. 2018;41:S86–S104. https://doi.org/10.2337/dc18-S009.
79. Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med. 2017;376:2300–2. https://doi.org/10.1056/NEJMc1701990.
80. Jensen ML, Persson F, Andersen GS, Ridderstrale M, Nolan JJ, Carstensen B, et al. Incidence of ketoacidosis in the Danish type 2 diabetes population before and after introduction of sodium-glucose cotransporter 2 inhibitors—a nationwide, retrospective cohort study, 1995-2014. Diabetes Care. 2017;40:e57–8. https://doi.org/10.2337/dc16-2793.
81. Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA adverse event reporting system. Lancet Diabetes Endocrinol. 2017;5:680–1.