SGLT-2 inhibitors: the glucosuric antidiabetics
Keywords:
Canagliflozin, Glucosuric antidiabetics, Phlorizin, SGLT-2 inhibitorsAbstract
Despite availability of a number of oral antidiabetics, a sizeable population of diabetics remains uncontrolled. Thus there is growing need of new group of drugs for diabetic control. Understanding renal conservation of glucose by efficient reabsorption through sodium glucose cotransporter-2 (SGLT-2) has paved way for development of an entirely new group of drugs, the SGLT-2 inhibitors. These glucosuric antidiabetic agents have shown promise in early clinical studies. Canagliflozin is recently approved for use in diabetes alone or along with other antidiabetics. Other highly selective inhibitors undergoing various stages of clinical developments are dapagliflozin, sergliflozin, remogliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin and desoxyrhaponticin. KGA-2727 (pyrazole-O-glucoside) is the first selective SGLT-1 inhibitor undergoing intense preclinical testing. There are safety issues associated with this group like urogenital infections (fungal), weight loss, initial osmotic diuresis and increased incidence of cardiovascular events. The long term safety remains to be established. Despite these limitations, SGLT-2 inhibition offers a unique target for achieving adequate control of diabetes in adults.
References
Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch 2004;447 (5):510-8.
Wood IS, Trayhum P. Glucose transporters (GLUT and SGLT): Expanded families of sugar transport proteins. Br J Nutr 2003;89:3-9.
Freitas HS, Ahne GF, Melo MM, Okamoto M, oliviera-Souza M, Bordin S. Na+-Glucose transporter-2 messanger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels. Involvement of hepatocute nuclear factor-1a expression and activity. Endocrinol 2008;149:
-24.
Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev. 2005;21:31-8.
Basile J. New approach to glucose control in type 2 diabetes: the role of kidney sodium-glucose co-transporter 2 inhibition. Postgrad Med. 2011; 123:38-45.
Raskin P. Sodium-glucose cotransporter inhibition: Therapeutic potential for the treatment of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2013 Mar 5. doi: 10.1002/dmrr.2403. [Epub ahead of print].
Chao EC, Henry RR. SGLT2 inhibition--a novel strategy for diabetes treatment Nat Rev Drug Discov. 2010 Jul;9(7):551-9.
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.
Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012 Oct 18;2(5). pii: e001007. doi: 10.1136/bmjopen-2012-001007. Print 2012.
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 Sep;34:2015-22.
Nauck M, Del Prato S. SGLT-2-inhibitor dapagliflozin: new treatment approach for diabetes type 2 - new achievements, but also new questions!. Dtsch Med Wochenschr. 2013;138 Suppl 1:S4-6.
Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin. Dtsch Med Wochenschr. 2013;138 Suppl 1:S27-39.
Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride. Dtsch Med Wochenschr. 2013;138 Suppl 1:S16-27.
Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013 Feb 20;11:43.
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, exhibit antidiabetic efficacy in rodent models. J Pharmacol Exp Ther. 2008 ;327:268-76.
Kurosaki E, Ogasawara H. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical data. Pharmacol Ther. 2013 Apr 4. pii: S0163-7258(13)00082-X.
Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L, Woerle HJ. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozinonce daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013 Jan 28. doi: 10.1111/dom.12073. [Epub ahead of print].
Macha S, Mattheus M, Pinnetti S, Woerle HJ, Broedl UC. Effect of Empagliflozin on the Steady-State Pharmacokinetics of Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers. Clin Drug Investig. 2013 Mar 20. [Epub ahead of print].
Macha S, Sennewald R, Rose P, Schoene K, Pinnetti S, Woerle HJ, Broedl UC. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin
in healthy volunteers. Clin Ther. 2013 Mar;35:226-35.
Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, et al. Effects of SGLT2 Inhibition in Human Kidney Proximal Tubular Cells—Renoprotection in Diabetic Nephropathy? PLoS ONE 8(2): e54442.
Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem. 2010 Sep 9;53:6355-60.
Lamos EM, Younk LM, Davis SN. Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013 Apr 17. [Epub ahead of print].
Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G. 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 Apr 5. [Epub ahead of print] PMID:23564919).
Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, Farrell K, Rothenberg P, Henry RR.Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition toIncreasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013 Feb 14. [Epub ahead of print].
Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15:463-73.
