DIABETOLOGY SGLT2 Inhibitors: a Novel Therapy for Type 2 Diabetes Mellitus
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2016 DIABETOLOGY SGLT2 Inhibitors: A Novel Therapy for Type 2 Diabetes Mellitus PG RAMAN ABSTRACT Sodium-linked glucose transporter (SGLT)2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They increase urinary glucose excretion without inducing hypoglycemia, thereby promoting body weight reduction due to loss of ~300 kcal/day. Several drug candidates have been developed or are currently undergoing clinical trials, including - dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate and ertugliflozin. Of these dapagliflozin and canagliflozin have been launched in India recently. Keywords: SGLT2 inhibitors, insulin-independent mechanism, dapagliflozin, canagliflozin odium-linked glucose transporter (SGLT)2 an unique feature of renal tubules, but also exists in inhibitors are new antidiabetic drugs with an other organs, such as the intestine. Whereas in the Sinsulin-independent mechanism of action. They gastrointestinal tract especially SGLT1 is expressed, increase urinary glucose excretion without inducing renal tubules express SGLT2.5 hypoglycemia, thereby promoting body weight Both transporters are able to reabsorb glucose. reduction due to loss of ~300 kcal/day.1 However, they show significant differences in Several drug candidates have been developed or affinities and transport capacity: SGLT2 has a are currently undergoing clinical trials, including - greater transport capacity and reabsorbs glucose in dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, combination with sodium in the ratio 1:1. SGLT1 has empagliflozin, remogliflozin etabonate and a higher affinity for glucose and reabsorbs glucose ertugliflozin.2 in combination with sodium in the ratio 1:2. These REGULATION OF GLUCOSE HOMEOSTASIS BY THE different transport properties are used by the kidneys KIDNEYS3 to reabsorb all energy, leading to glucose-free urine. SGLT2 is localized mainly in the first two segments The kidneys regulate the homeostasis of numerous of the proximal tubular system (S1 and S2 segment). substances of the body. The role of the kidneys Owing to its high transport capacity, it is capable of in glucose metabolism is important and includes, reabsorbing about 90% of glucose from the urine. gluconeogenesis, glucose utilization, glucose filtration Ten percent of initially filtered glucose is recovered in and reabsorption.4 Daily 180 g is filtered and recovered the third section of the proximal tubule (S3 segment) by afterwards. This mechanism was important for survival SGLT1 because of its high affinity. in times of food scarcity. Glucose recovery is mediated Both transporters are secondarily active owing to their by a tubular transport system that can reabsorb glucose dependence on the activity of the Na+/K+-ATPase in the in combination with sodium. This mechanism is not basolateral membrane for the active removal of sodium. Glucose transporters (GLUT2 and GLUT1) facilitate glucose transport across the basolateral membrane in the early and more distal regions of the proximal Ex-Professor and HOD 6 MGM Medical College, Indore, Madhya Pradesh tubule. Inhibition of the SGLT transport system results Address for correspondence in increased urinary glucose excretion due to reduced Dr PG Raman 72, Dhar Kothi, Indore - 452 001, Madhya Pradesh glucose reabsorption. As a consequence plasma glucose E-mail: [email protected] levels are lowered, resulting in loss of calories. 128 Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016 DIABETOLOGY Table 1. The Salient Features of SGLT2 Inhibitors, Canagliflozin and Dapagliflozin Canagliflozin Dapagliflozin Indication T2DM T2DM Dose 100-300 mg 5-10 mg Renal impairment Contraindicated in end-stage renal disease Contraindicated in end-stage renal disease Hepatic disorders Not to be used Not to be used Drug interaction With digoxin No significant interaction Oral administration Prior to first meal Morning with/without food Pharmacokinetics Onset of action within 24 hours Onset of action within 24 hours 90% protein bound 91% protein bound Oral bioavailability 65% Oral bioavailability 78% Half-life 13.1 hours Half-life 12 hours Adverse reactions Hyperkalemia UTI and genital infection UTI UTI = Urinary tract infection. Table 2. SGLT2 Inhibitors the glomerulus depends not only on plasma glucose levels, but also on the glomerular filtration rate (GFR). Advantages Disadvantages Therefore, it can be expected that with decreasing renal Acts by noninsulin pathway Genital infection function a decrease of activity is paralleled. Unlike Weight loss UTI with other antidiabetic drugs, such as metformin or BP reduction Hypotension glimepiride, with impaired renal function there is no No hypoglycemia Hyperkalemia risk to the patient, but the treatment becomes gradually ineffective. As a consequence, canagliflozin therapy should not be initiated in patients with end-stage renal SGLT2 INHIBITION disease, on dialysis or with renal impairment at an In type 2 diabetes mellitus (T2DM), renal glucose estimated GFR 60 mL/min/1.73 m2. handling and transport is increased, likely due to upregulation of SGLT2. As a result, glucose excretion in PHARMACOLOGY OF CANAGLIFLOZIN—EFFECTS the urine occurs only at higher plasma glucose levels, ON GLUCOSE METABOLISM, BODY WEIGHT AND 10,11 causing conservation of glucose and prolongation of THE CARDIOVASCULAR SYSTEM hyperglycemia. Inhibition of SGLT2 activity reduces Canagliflozin is a competitive, reversible, highly reabsorption of filtered glucose and lowers the selective SGLT2 inhibitor with a 250-fold selectivity blood glucose concentration at which glucose is no towards SGLT2 over SGLT1. Inhibition of SGLT2 longer reabsorbed from the proximal tubule but is by canagliflozin leads to a reduction of glucose instead excreted. This concentration is known as the reabsorption. The induced glucosuria of ~70 g/day renal threshold for glucose.7-9 The salient features results in a loss of glucose and optimized plasma glucose of canagliflozin and dapagliflozin, the two SGLT2 inhibitors are summarized in Table 1. The advantages control. Canagliflozin is indicated in patients with and disadvantages of SGLT2 inhibitors are given in T2DM to improve glycemic control as monotherapy Table 2. and in patients for whom the use of metformin is considered inappropriate owing to intolerance or PHARMACOKINETICS OF CANAGLIFLOZIN8 contraindications. It is indicated as add-on therapy with other antihyperglycemic medicinal products including Canagliflozin has an oral bioavailability of 65% insulin. In poorly controlled diabetic patients even a with a maximum effect after 30-120 minutes. Its reduction of up to - 2.42% was achieved. pharmacokinetic profile is independent of age, body weight, gender, ethnicity and administration with The favorable effect on glycosylated hemoglobin food. Importantly, the amount of glucose filtered in (HbA1C) values was consistent with an improvement Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016 129 DIABETOLOGY of secondary endpoints such as fasting plasma glucose. 2. Wright EM, Loo DD, Hirayama BA. Biology of human The efficacy of canagliflozin was reduced in patients sodium glucose transporters. Physiol Rev. 2011;91(2): with moderate renal impairment. The weight loss is 733-94. caused by loss of fat mass and not osmotic diuresis. 3. Mather A, Pollock C. Glucose handling by the kidney. The weight reducing characteristics of SGLT2 inhibitors Kidney Int Suppl. 2011;(120):S1-6. in T2DM patients also might be effective in nondiabetic 4. Gerich JE. Role of the kidney in normal glucose overweight subjects. This creates the option to widen homeostasis and in the hyperglycaemia of diabetes the indication for the use of SGLT2 inhibitors as mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-42. antiobesity drugs. 5. Wright EM, Hirayama BA, Loo DF. Active sugar transport SAFETY OF CANAGLIFLOZIN12,13 in health and disease. J Intern Med. 2007;261(1):32-43. 6. Oliva RV, Bakris GL. 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