DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20150852

Sodium-glucose co-transporter-2 inhibitors as anti-diabetic agents: a review

Chirag B. Mistry, Radhika A. Vaishnav, Mona H. Shah

Abstract


The incidence and prevalence of Type 2 diabetes mellitus (T2DM) have been increasing worldwide. However, existing therapeutic classes of anti-diabetic drugs are not adequately effective in achieving and maintaining long-term glycemic control in the most patients. The majority of the drugs control blood sugar without addressing the basic pathology of insulin resistance and relative deficiency. Moreover, side effects such as hypoglycemia and weight gain, of both new and established drugs need to be considered prior to treating a patient. An emerging anti-hyperglycemic intervention, the sodium glucose co-transporter 2 (SGLT2) inhibitor acts by a novel mechanism. Under physiological conditions, SGLT2 accounts for 90% of the glucose re-absorption in the kidney, while the SGLT2 inhibitors result in an increase in urinary excretion of glucose and lower plasma glucose levels. Here, the pros and cons of SGLT2 inhibitors are considered, while approaching a patient with T2DM. The basic biochemistry and physiology underlying the mechanisms of SGLT2 inhibitors are discussed alongside its clinical pharmacology, with a focus on metabolic changes associated with urinary glucose loss. Finally, a consideration of Food and Drug Administration safety concerns associated with acidosis due to SGLT2 inhibitor usage is presented, to allow a complete understanding of the utility of these molecules in the light of existing T2DM therapies.


Keywords


Anti-hyperglycemic drugs, Cardiovascular safety, Food and Drug Administration, Hyperglycemia, Renal function, Sodium-glucose co-transporter-2 inhibitors, Type 2 diabetes mellitus

Full Text:

PDF

References


Abdul-Ghani MA, DeFronzo RA. Dapagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2013;14(12):1695-703.

Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl. 2011:S1-6.

Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-42.

Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261(1):32-43.

Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733-94.

Barfuss DW, Schafer JA. Differences in active and passive glucose transport along the proximal nephron. Am J Physiol. 1981;241(3):F322-32.

Coolen JC, Verhaeghe J. Physiology and clinical value of glycosuria after a glucose challenge during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2010;150(2):132-6.

Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14(11):2873-82.

Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008;23(12):3874-9.

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(2):125-9.

Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest. 1971;28(1):101-9.

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(12):3427-34.

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(3):e46-9.

Freitas HS, Anhê GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S, et al. 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(2):717-24.

Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus. J Clin Pharmacol. 2012;52(4):457-63.

Chao EC, Henry RR. SGLT2 inhibition – a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551-9.

Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31-8.

Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44(4):375-93.

Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract. 2013;41(2):72-84.

Burki TK. FDA rejects novel diabetes drug over safety fears. Lancet. 2012;379(9815):507.

European Medicins Agency 2014. Available at http://www.ema.europa.eu/ema/. Accessed 11 August 2015.

Haslam DW, James WP. Obesity. Lancet. 2005;366(9492):1197-209.

Committee for Medicinal Products for Human Use. European Public Assessment Report (EPAR) Canagliflozin. European Medicines Agency; 2013: EMA/374133/2013.

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(9896):941-50.

Luippold G, Klein T, Mark M, Grempler R. Empagliflozin, a novel potent and selective SGLT-2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin-induced diabetic rats, a model of type 1 diabetes mellitus. Diabetes Obes Metab. 2012;14(7):601-7.

Lamos EM, Younk LM, Davis SN. Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of type 1 diabetes. Expert Opin Investig Drugs. 2014;23(6):875-82.

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333-46.

Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 2003;46(1):3-19.

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(15):1577-89.

Control Group, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288-98.

Liday C. Overview of the guidelines and evidence for the pharmacologic management of type 2 diabetes mellitus. Pharmacotherapy. 2011;31 12 Suppl:37S-43.

Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med. 2014;371(16):1547-8.

Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106-18.

Groop LC. Sulfonylureas in NIDDM. Diabetes Care. 1992;15(6):737-54.

Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194-206.

Mitka M. More patients get good diabetes control, but only a minority meet all goals. JAMA. 2013;309(13):1335-6.

Lawrence DB, Ragucci KR, Long LB, Parris BS, Helfer LA. Relationship of oral antihyperglycemic (sulfonylurea or metformin) medication adherence and hemoglobin A1c goal attainment for HMO patients enrolled in a diabetes disease management program. J Manag Care Pharm. 2006;12(6):466-71.

Nicolle LE, Capuano G, Fung A, Usiskin K. Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med. 2014;126(1):7-17.

Elmore LK, Baggett S, Kyle JA, Skelley JW. A review of the efficacy and safety of canagliflozin in elderly patients with type 2 diabetes. Consult Pharm. 2014;29(5):335-46.

Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. BMC Endocr Disord. 2014;14:37.

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(1):16-24.

Reilly TP, Graziano MJ, Janovitz EB, Dorr TE, Fairchild C, Lee F, et al. Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. Diabetes Ther. 2014;5(1):73-96.

Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (canvas) – a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-223.e11.

FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015. Available at http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed 11 August 2015.

Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015;3(1):8-10.

Kalra S, Baruah MP, Sahay R. Medication counselling with sodium glucose transporter 2 inhibitor therapy. Indian J Endocrinol Metab. 2014;18(5):597-9.

US Food and Drug Administaration 2014. Available at http://www.fda.gov/. Accessed 11 August 2015.

Pharmaceuticals and Medical Devices Agency, Japan 2014. Available at http://www.pmda.go.jp/. Accessed 11 August 2015.