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Published in: Current Diabetes Reports 3/2012

01-06-2012 | Pharmacologic Treatment of Type 2 Diabetes and Obesity (D Wexler, Section Editor)

Efficacy and Safety of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

Authors: Muhammad A. Abdul-Ghani, Luke Norton, Ralph A. DeFronzo

Published in: Current Diabetes Reports | Issue 3/2012

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Abstract

In addition to its central role in the development of microvascular complications, hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) by means of glucotoxicity. Thus, effective glycemic control not only reduces the incidence of microvascular complications but also corrects the metabolic abnormalities that contribute to the progression of the disease. Progressive β-cell failure and multiple side effects, including hypoglycemia and weight gain, associated with many current therapies present obstacles to the achievement of optimal and durable glycemic control in subjects with T2DM. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to reduce the plasma glucose concentration by producing glucosuria. Because the mechanism of action of these oral antidiabetic agents is independent of β-cell function and tissue sensitivity to insulin, they improve glycemic control while avoiding hypoglycemia and promoting weight loss. In this review, we summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic class of therapeutic agents.
Literature
1.
go back to reference 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;329:977–86.CrossRef 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;329:977–86.CrossRef
2.
go back to reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.CrossRef UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.CrossRef
3.
go back to reference DeFronzo RA. Banting lecture: from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.PubMedCrossRef DeFronzo RA. Banting lecture: from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.PubMedCrossRef
5.
go back to reference The American Diabetes Association. Standards of medical care in diabetes-2007. Diabetes Care. 2007;30(Supp I):S4–41.CrossRef The American Diabetes Association. Standards of medical care in diabetes-2007. Diabetes Care. 2007;30(Supp I):S4–41.CrossRef
6.
go back to reference Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81–6.PubMedCrossRef Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81–6.PubMedCrossRef
7.
go back to reference •• Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–31. This is a recent comprehensive review that summarizes the molecular basis of renal glucose reuptake and the clinical and pathophysiological implications of SGLT2 inhibitors..PubMedCrossRef •• Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–31. This is a recent comprehensive review that summarizes the molecular basis of renal glucose reuptake and the clinical and pathophysiological implications of SGLT2 inhibitors..PubMedCrossRef
8.
go back to reference Valtin H. Tubular reabsorption. In renal function. Boston: Little, Brown and Company; 1983. Valtin H. Tubular reabsorption. In renal function. Boston: Little, Brown and Company; 1983.
9.
go back to reference Kamran M, Peterson RG, Dominguez JH. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J Am Soc Nephrol. 1997;8:943–8.PubMed Kamran M, Peterson RG, Dominguez JH. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J Am Soc Nephrol. 1997;8:943–8.PubMed
10.
go back to reference Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest. 1951;30:125–9.PubMedCrossRef Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest. 1951;30:125–9.PubMedCrossRef
11.
go back to reference Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302:R75–83.PubMedCrossRef Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302:R75–83.PubMedCrossRef
12.
go back to reference Chassis H, Jolliffe N, Smith H. The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine, and urea by man. J Clin Invest. 1933;12:1083–9.CrossRef Chassis H, Jolliffe N, Smith H. The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine, and urea by man. J Clin Invest. 1933;12:1083–9.CrossRef
13.
go back to reference Vick HD, Deidrich DF. Reevaluation of renal tubular glucose transport inhibition by phlorizin analogs. Am J Physiol. 1973;224:552–7.PubMed Vick HD, Deidrich DF. Reevaluation of renal tubular glucose transport inhibition by phlorizin analogs. Am J Physiol. 1973;224:552–7.PubMed
14.
go back to reference Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21:31–8.PubMedCrossRef Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21:31–8.PubMedCrossRef
15.
go back to reference Li A, Zhang J, Greenberg J, Lee T, Liu J. Discovery of non-glucoside SGLT2 inhibitors. Bioorg Med Chem Lett. 2011;21:2472–5.PubMedCrossRef Li A, Zhang J, Greenberg J, Lee T, Liu J. Discovery of non-glucoside SGLT2 inhibitors. Bioorg Med Chem Lett. 2011;21:2472–5.PubMedCrossRef
16.
go back to reference Bhanot S, Murray SF, Booten SL, Chakravarty K, Zanardi T, Henry S, Watts LM, Wancewicz EV, Siwkows A. ISIS 388626, an SGLT2 antisense drug, causes robust and sustained glucosuria in multiple species and is safe and well-tolerated. Diabetes. 2009;58(suppl1):A328. Bhanot S, Murray SF, Booten SL, Chakravarty K, Zanardi T, Henry S, Watts LM, Wancewicz EV, Siwkows A. ISIS 388626, an SGLT2 antisense drug, causes robust and sustained glucosuria in multiple species and is safe and well-tolerated. Diabetes. 2009;58(suppl1):A328.
17.
go back to reference Kahn BB, DeFronzo RA, Cushman SW, Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest. 1999;87:561–70.CrossRef Kahn BB, DeFronzo RA, Cushman SW, Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest. 1999;87:561–70.CrossRef
18.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
19.
go back to reference Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80:1037–44.PubMedCrossRef Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80:1037–44.PubMedCrossRef
20.
go back to reference Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14:2873–82.PubMedCrossRef Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14:2873–82.PubMedCrossRef
21.
go back to reference Oku A, Ueta K, Nawano M, Arakawa K, Kano-Ishihara T, Matsumoto M, Saito A, Tsujihara K, Anai M, Asano T. Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats. Eur J Pharmacol. 2000;391:183–92.PubMedCrossRef Oku A, Ueta K, Nawano M, Arakawa K, Kano-Ishihara T, Matsumoto M, Saito A, Tsujihara K, Anai M, Asano T. Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats. Eur J Pharmacol. 2000;391:183–92.PubMedCrossRef
22.
go back to reference Katsuno K, Fujimori Y, Takemura Y, Hiratochi M, Itoh F, Komatsu Y, Fujikura H, Isaji M. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J Pharmacol Exp Ther. 2007;320:323–30.PubMedCrossRef Katsuno K, Fujimori Y, Takemura Y, Hiratochi M, Itoh F, Komatsu Y, Fujikura H, Isaji M. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J Pharmacol Exp Ther. 2007;320:323–30.PubMedCrossRef
23.
go back to reference Hussey E, Clark R, Amin D, Kipnes M, Semmes R, Odriscoll E, Leong J, Murphy S, Dobbins R, Nunez D. Early clinical studies to assess safety, tolerability, pharmacokinetics and pharmacodynamics of single dose of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy volunteers and subjects with type 2 diabetes mellitus. Diabetes. 2007;56(Suppl1):A189. Hussey E, Clark R, Amin D, Kipnes M, Semmes R, Odriscoll E, Leong J, Murphy S, Dobbins R, Nunez D. Early clinical studies to assess safety, tolerability, pharmacokinetics and pharmacodynamics of single dose of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy volunteers and subjects with type 2 diabetes mellitus. Diabetes. 2007;56(Suppl1):A189.
24.
go back to reference Hussey E, Dobbins R, Stolz R, Stockman N, Semmes R, Murray S, Nunez D. A double-blind randomized repeat dose study to assess safety, tolerability, pharmacokineticks and pharmacodynamics of three times daily dosing of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy overweight and obese subjects. Diabetes. 2007;56(Suppl1):A491. Hussey E, Dobbins R, Stolz R, Stockman N, Semmes R, Murray S, Nunez D. A double-blind randomized repeat dose study to assess safety, tolerability, pharmacokineticks and pharmacodynamics of three times daily dosing of sergliflozin, a novel inhibitor of renal glucose reabsorption in healthy overweight and obese subjects. Diabetes. 2007;56(Suppl1):A491.
25.
go back to reference Fujimori Y, Katsuno K, Nakashima I, Ishikawa-Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther. 2008;327:268–76.PubMedCrossRef Fujimori Y, Katsuno K, Nakashima I, Ishikawa-Takemura Y, Fujikura H, Isaji M. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther. 2008;327:268–76.PubMedCrossRef
26.
go back to reference Dobbins RL, Kapur A, Kapitza C, O’connor-Semmes RL, Tao W, Hussey EK. Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2) reduces serum glucose in type 2 diabetes mellitus (T2DM) patients. Diabetes. 2009;58 suppl 1:A573. Dobbins RL, Kapur A, Kapitza C, O’connor-Semmes RL, Tao W, Hussey EK. Remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2) reduces serum glucose in type 2 diabetes mellitus (T2DM) patients. Diabetes. 2009;58 suppl 1:A573.
29.
go back to reference 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 Pharm Ther. 2009;85:513.CrossRef 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 Pharm Ther. 2009;85:513.CrossRef
30.
go back to reference Obermeier M, Yao M, Khanna A, Koplowitz B, Zhu M, Li W, Komoroski B, Kasichayanula S, Discenza L, Washburn W, Meng W, Ellsworth BA, Whaley JM, Humphreys WG. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Am Soc Pharmacol Exp Therapeut. 2010;38:405–14. Obermeier M, Yao M, Khanna A, Koplowitz B, Zhu M, Li W, Komoroski B, Kasichayanula S, Discenza L, Washburn W, Meng W, Ellsworth BA, Whaley JM, Humphreys WG. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Am Soc Pharmacol Exp Therapeut. 2010;38:405–14.
31.
go back to reference List J, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–7.PubMedCrossRef List J, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–7.PubMedCrossRef
32.
go back to reference Ferrannini E, Ramos SJ, Tang W, Salsali A, List JF. Dapagliflozin monotherapy in T2DM patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, multicenter phase III trial. Diabetes Care. 2010;33:2217–24.PubMedCrossRef Ferrannini E, Ramos SJ, Tang W, Salsali A, List JF. Dapagliflozin monotherapy in T2DM patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, multicenter phase III trial. Diabetes Care. 2010;33:2217–24.PubMedCrossRef
33.
go back to reference Wilding JPH, Norwood P, Tjoen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers. Applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656–62.PubMedCrossRef Wilding JPH, Norwood P, Tjoen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers. Applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656–62.PubMedCrossRef
34.
go back to reference Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metabol. 2010;12:510–6.CrossRef Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metabol. 2010;12:510–6.CrossRef
35.
go back to reference Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–22.PubMedCrossRef Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–22.PubMedCrossRef
36.
go back to reference Baily CJ, Gross JI, Yadav M, Iqbal N, Mansfield TA, List JF. Sustained efficacy of dapagliflozin when added to metformin in type 2 diabetes inadequately controlled by metformin monotherapy. Diabetologia. 2011;54(Suppl1):A146. Baily CJ, Gross JI, Yadav M, Iqbal N, Mansfield TA, List JF. Sustained efficacy of dapagliflozin when added to metformin in type 2 diabetes inadequately controlled by metformin monotherapy. Diabetologia. 2011;54(Suppl1):A146.
37.
go back to reference Del Prato S, Nauck M, Rohwedder K, Theuerkauf A, Langkilde AM, Parikh S. Long term efficacy and safety of ass-on dapagliflozin vs add-on glipizide in patients with type 2 diabetes mellitus inadequately controlled with metformin: 2 year results. Diabetologia. 2011;54(Suppl1):A852. Del Prato S, Nauck M, Rohwedder K, Theuerkauf A, Langkilde AM, Parikh S. Long term efficacy and safety of ass-on dapagliflozin vs add-on glipizide in patients with type 2 diabetes mellitus inadequately controlled with metformin: 2 year results. Diabetologia. 2011;54(Suppl1):A852.
38.
go back to reference Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, Shalayda K, Demarest K. Rothenberg PCanagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13:669–72.PubMedCrossRef Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, Shalayda K, Demarest K. Rothenberg PCanagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 2011;13:669–72.PubMedCrossRef
39.
go back to reference Inagaki N, Kondo K, Iwasaki T, Maruyama N, Susuta Y, Sakai M, Kuki H. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes Mellitus (T2DM). Diabetes. 2011;60(suppl):A999. Inagaki N, Kondo K, Iwasaki T, Maruyama N, Susuta Y, Sakai M, Kuki H. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes Mellitus (T2DM). Diabetes. 2011;60(suppl):A999.
40.
go back to reference Rosensotck J, Arbit D, Usiskin K, Capuano G, Canovatchel W. Canagliflozin an inhibitor of sodium glucose co-transporter 2 (SGLT2), improves glycemic control and lowers body weight in subjects with type 2 diabetes (T2D) on metformin. Diabetes. 2010;59 suppl 1:A21. Rosensotck J, Arbit D, Usiskin K, Capuano G, Canovatchel W. Canagliflozin an inhibitor of sodium glucose co-transporter 2 (SGLT2), improves glycemic control and lowers body weight in subjects with type 2 diabetes (T2D) on metformin. Diabetes. 2010;59 suppl 1:A21.
41.
go back to reference Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, Ways K, Schwartz S. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012[ahead of print]. Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, Ways K, Schwartz S. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012[ahead of print].
42.
go back to reference Polidori D, Zhao Y, Sha S, Canovatchel W. Canagliflozin treatment improves beta cell function in subject with type 2 diabetes. Diabetes. 2010;59 suppl 1:A176. Polidori D, Zhao Y, Sha S, Canovatchel W. Canagliflozin treatment improves beta cell function in subject with type 2 diabetes. Diabetes. 2010;59 suppl 1:A176.
43.
go back to reference Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.PubMedCrossRef Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14:83–90.PubMedCrossRef
44.
go back to reference Koiwai K, Seman L, Yamamura N, Macha S, Taniguchi A, Negishi T, Sesoko S, Dugi KA. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of BI 10773, a sodium-glucose co-transporter inhibitor (SGLT2), in Japanese healthy volunteers. Diabetes. 2010;59 suppl 1:2175PO. Koiwai K, Seman L, Yamamura N, Macha S, Taniguchi A, Negishi T, Sesoko S, Dugi KA. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of BI 10773, a sodium-glucose co-transporter inhibitor (SGLT2), in Japanese healthy volunteers. Diabetes. 2010;59 suppl 1:2175PO.
45.
go back to reference Heise T, Seewaldt-Becker E, Macha S, Hantel S, Huber K, Pinnetti S, Seman L, Hans-Juergen W. BI 10773, a sodium-glucose co-transporter inhibitor (SGLT-2), is safe and efficacious following 4-week treatment in patients with type 2 diabetes. Diabetes. 2010;59(suppl):629P. Heise T, Seewaldt-Becker E, Macha S, Hantel S, Huber K, Pinnetti S, Seman L, Hans-Juergen W. BI 10773, a sodium-glucose co-transporter inhibitor (SGLT-2), is safe and efficacious following 4-week treatment in patients with type 2 diabetes. Diabetes. 2010;59(suppl):629P.
46.
go back to reference Rosenstock J, Jelaska A, Seman L, Pinnetti S, Hantel S, Woerle HJ. Efficacy and safety of BI 10773, a new sodium glucose cotransporter-2 (SGLT-2) inhibitor, in type 2 diabetes inadequately controlled on metformin. Diabetes. 2011;60(suppl):989P. Rosenstock J, Jelaska A, Seman L, Pinnetti S, Hantel S, Woerle HJ. Efficacy and safety of BI 10773, a new sodium glucose cotransporter-2 (SGLT-2) inhibitor, in type 2 diabetes inadequately controlled on metformin. Diabetes. 2011;60(suppl):989P.
47.
go back to reference Kashiwagi A, Utsuno A, Kazuta K, Yoshida S, Kageyama S. ASP1941, a novel, selective SGLT2 inhibitor, was effective and safe in Japanese healthy volunteers and patients with type 2 diabetes mellitus. Diabetes. 2010;59 suppl 1:A21. Kashiwagi A, Utsuno A, Kazuta K, Yoshida S, Kageyama S. ASP1941, a novel, selective SGLT2 inhibitor, was effective and safe in Japanese healthy volunteers and patients with type 2 diabetes mellitus. Diabetes. 2010;59 suppl 1:A21.
48.
go back to reference Takinami A, Takinami Y, Kazuta K, Yoshida S, Utsuno A, Nagase I, Kashiwagi A. Ipragliflozin improved glycemic control with additional benefit of reduction of body weight and blood pressure in Japanese patients with type 2 diabetes mellitus BRIGHTEN Study. Diabetologia. 2011;54(suppl):A149. Takinami A, Takinami Y, Kazuta K, Yoshida S, Utsuno A, Nagase I, Kashiwagi A. Ipragliflozin improved glycemic control with additional benefit of reduction of body weight and blood pressure in Japanese patients with type 2 diabetes mellitus BRIGHTEN Study. Diabetologia. 2011;54(suppl):A149.
49.
go back to reference Freiman J, Ruff DA, Frazier KS, Combs K, Turnage A, Shadoan M, Powell D, Zambrowicz B, Brown P. LX4211, a dual SGLT2/SGLT1 inhibtor, shows rapid and significant improvements in glycemic control over 28 days in patients with type 2 diabetes (T2DM). Diabetes 2010;59(suppl 1), (late breaking abstract). Freiman J, Ruff DA, Frazier KS, Combs K, Turnage A, Shadoan M, Powell D, Zambrowicz B, Brown P. LX4211, a dual SGLT2/SGLT1 inhibtor, shows rapid and significant improvements in glycemic control over 28 days in patients with type 2 diabetes (T2DM). Diabetes 2010;59(suppl 1), (late breaking abstract).
50.
go back to reference Seino Y, Sasaki T, Fukatsu A, Samukawa Y, Sakai S, Watanabe T. TS-071, a novel and selective SGLT2 inhibitor, improved glycemic control and decreased body weight in 12-week study of Japanese patients with type 2 diabetes mellitus. Diabetes. 2011;60(suppl):P998. Seino Y, Sasaki T, Fukatsu A, Samukawa Y, Sakai S, Watanabe T. TS-071, a novel and selective SGLT2 inhibitor, improved glycemic control and decreased body weight in 12-week study of Japanese patients with type 2 diabetes mellitus. Diabetes. 2011;60(suppl):P998.
51.
go back to reference Nucci G, Amin NB, Wang X, Lee DS, Rusnak JM. The sodium glucose co-transported PF04971729, provides multifaced improvement in diabetic patients inadequately controlled on metformin. Diabetologia. 2011;54(suppl):A850. Nucci G, Amin NB, Wang X, Lee DS, Rusnak JM. The sodium glucose co-transported PF04971729, provides multifaced improvement in diabetic patients inadequately controlled on metformin. Diabetologia. 2011;54(suppl):A850.
52.
go back to reference Kadokura T, Ishikawa H, Nakajo I, Yoshida S, Utsuno A, Smulders RA, Morozumi K. The effect of renal impairment on the pharmacokinetics and urinary glucose excretion of the SGLT2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus patients. Diabetologia. 2011;54(suppl):A847. Kadokura T, Ishikawa H, Nakajo I, Yoshida S, Utsuno A, Smulders RA, Morozumi K. The effect of renal impairment on the pharmacokinetics and urinary glucose excretion of the SGLT2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus patients. Diabetologia. 2011;54(suppl):A847.
53.
go back to reference 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;10:2569–76.PubMed 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;10:2569–76.PubMed
54.
go back to reference Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol. 2004;286:F8–18. Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol. 2004;286:F8–18.
55.
go back to reference Noonan WT, Shapiro VM, Banks RO. Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci. 2001;68:2967–77.PubMedCrossRef Noonan WT, Shapiro VM, Banks RO. Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci. 2001;68:2967–77.PubMedCrossRef
56.
go back to reference Dominguez JH, Camp K, Maianu L, Feister H, Garvey WT. Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. Am J Physiol. 1994;266:F283–90.PubMed Dominguez JH, Camp K, Maianu L, Feister H, Garvey WT. Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. Am J Physiol. 1994;266:F283–90.PubMed
57.
go back to reference Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med. 1996;335:1636–42.PubMedCrossRef Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med. 1996;335:1636–42.PubMedCrossRef
58.
go back to reference Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, DeFronzo RA. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med. 1991;324:1626–32.PubMedCrossRef Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, DeFronzo RA. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med. 1991;324:1626–32.PubMedCrossRef
59.
go back to reference Arakawa K, Ishihara T, Oku A, Nawano M, Ueta K, Kitamura K, Matsumoto M, Saito A. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095. Br J Pharmacol. 2001;132:578–86.PubMedCrossRef Arakawa K, Ishihara T, Oku A, Nawano M, Ueta K, Kitamura K, Matsumoto M, Saito A. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095. Br J Pharmacol. 2001;132:578–86.PubMedCrossRef
60.
go back to reference Parikh S, Johnsson K, Ptaszynska A, Schmitz B, Sugg J, List JF. Characterization of urinary tract infection in the setting of pharmacologically induced glucosuria. Diabetologia. 2011;54(suppl):A841. Parikh S, Johnsson K, Ptaszynska A, Schmitz B, Sugg J, List JF. Characterization of urinary tract infection in the setting of pharmacologically induced glucosuria. Diabetologia. 2011;54(suppl):A841.
Metadata
Title
Efficacy and Safety of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes Mellitus
Authors
Muhammad A. Abdul-Ghani
Luke Norton
Ralph A. DeFronzo
Publication date
01-06-2012
Publisher
Current Science Inc.
Published in
Current Diabetes Reports / Issue 3/2012
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-012-0275-6

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