Journal List > J Korean Diabetes > v.15(3) > 1054923

Lee: The Non-glycemic Effects of SGLT2 Inhibitor

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been introduced as a new class of antidiabetic agents. In addition to their glycemic action, SGLT2 inhibitors also have a number of non-glycemic effects that may contribute to renal and/or cardiovascular benefits. These include effects on tubuloglomerular feedback in the kidney, body weight, blood pressure, and serum uric acid. Other non-glycemic effects of SGLT2 inhibitors that need to be further studied include the effects on lipid profiles, food intake, and secretion of hormones such as leptin, incretins, and aldosterone. Also, the exact mechanisms of various non-glycemic actions should be further studied. Additionally, SGLT2 inhibitor therapy in combination with other drugs may have beneficial glycemic and non-glycemic effects.

REFERENCES

2. Freitas HS, Anhê GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S, Machado UF. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008; 149:717–24.
2. 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; 54:3427–34.
crossref
3. Beloto-Silva O, Machado UF, Oliveira-Souza M. Glucose-induced regulation of NHEs activity and SGLTs expression involves the PKA signaling pathway. J Membr Biol. 2011; 239:157–65.
crossref
4. Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol. 2011; 300:R1009–22.
crossref
5. Kitada K, Nakano D, Ohsaki H, Hitomi H, Minamino T, Yatabe J, Felder RA, Mori H, Masaki T, Kobori H, Nishiyama A. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. J Diabetes Complications 2014 Jun 4 [Epub].http://dx.doi.org/10.1016/j.jdiacomp.2014.05.010.
6. 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; 29:406–12.
crossref
7. 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.
crossref
8. 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:F194–204.
crossref
9. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis. 2014; 64:16–24.
crossref
10. 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 sodiumglucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014; 129:587–97.
crossref
11. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009; 52:691–7.
crossref
12. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G. GFR Study Investigators. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012; 35:2061–8.
crossref
13. 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:e100777.
crossref
14. Gembardt F, Bartaun C, Jarzebska N, Mayoux E, Todorov VT, Hohenstein B, Hugo C. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014; 307:F317–25.
crossref
15. 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.
crossref
16. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G. 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 noninferiority trial. Lancet. 2013; 382:941–50.
crossref
17. Yamout H, Perkovic V, Davies M, Woo V, de Zeeuw D, Mayer C, Vijapurkar U, Kline I, Usiskin K, Meininger G, Bakris G. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol. 2014; 40:64–74.
crossref
18. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, Wajs E, Figueroa K, Jiang J, Law G, Usiskin K, Meininger G. on behalf of the DIA3004 Study Group. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 2014 Jun 25 [Epub].http://dx.doi.org/10.1111/dom.12348.
19. 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; 159:262–74.
20. Oliva RV, Bakris GL. Blood pressure effects of sodiumglucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014; 8:330–9.
crossref
21. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S. 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.
crossref
22. Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, Zhao X, Moeckel GW, Samuel VT, Whaley JM, Shulman GI, Kibbey RG. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes. 2011; 60:890–8.
23. Kojima N, Williams JM, Takahashi T, Miyata N, Roman RJ. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther. 2013; 345:464–72.
crossref
24. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014; 124:509–14.
crossref
25. 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.
crossref
26. Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, Sica D, Rothenberg P, Plum-Mörschel L. Effect of the sodium glucose cotransporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2014 Jun 17 [Epub].http://dx.doi.org/10.1111/dom.12322.
27. Osorio H, Bautista R, Rios A, Franco M, Santamaría J, Escalante B. Effect of treatment with losartan on salt sensitivity and SGLT2 expression in hypertensive diabetic rats. Diabetes Res Clin Pract. 2009; 86:e46–9.
crossref
28. 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.
crossref
29. Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012; 72:2289–312.
30. Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi JI, 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 Jul 7.http://dx.doi.org/10.1002/bdd.1909.
31. So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010; 120:1791–9.
crossref
32. Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M, Bonora E. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care. 2009; 32:1716–20.
crossref
33. Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, Capuano G, Canovatchel W. Canagliflozin DIA 2001 Study Group. Dose-ranging effects of canagliflozin, a sodiumglucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012; 35:1232–8.
crossref
34. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, Ruff D, Shadoan M, Banks P, Mseeh F, Rawlins DB, Goodwin NC, Mabon R, Harrison BA, Wilson A, Sands A, Powell DR. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012; 92:158–69.
crossref

Fig. 1.
Potential role of sodium glucose cotransporter 2 (SGLT2) inhibitor in renoprotection for patients with type 2 diabetes. PKCβ, protein kinase C β; ODC, ornithine decarboxylase; TGFβ, transforming growth factor β; CDK, cyclin-dependent kinase.
jkd-15-151f1.tif
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