Canagliflozin – A SGLT2 Inhibitor: A New Road to Antidiabetic Treatment Harsharan Pal Singh1*, Ishpreet Kaur2 , Gunjan Sharma1 1. Amity Institute of Pharmacy, Amity University, Sector-125, Noida, Uttar Pradesh (India). 2. Delhi Institute of Pharmaceutical Sciences & Research, Pushp Vihar, New Delhi Email.id – harsharanpal.singh@gmail.com Abstract Canagliflozin is a competitive, reversible inhibitor of SGLT2 that lowers the RTG, thus reducing reabsorption of filtered glucose, increasing UGE (Figure), and thereby lowering plasma glucose concentrations in patients with T2DM; this mechanism is independent of insulin secretion. Canagliflozin (Invokana), a novel medication for the treatment of type 2 diabetes, provides an alternative for patients who are not well controlled on current drug therapy or diet and exercise. It works by inhibiting the sodium-glucose co-transporter (SGLT2) in the kidney, thus leading to increased glucose excretion. Canagliflozin is the first FDA- approved SGLT2 inhibitor. It is currently marketed under the trade name of Invokana by Janssen Pharmaceuticals. It is the first of its class approved for use. The kidney has previously been ignored as a potential target organ for pharmacologic mitigation of hyperglycemia, as it was primarily considered an organ of elimination and a regulator of salt and ion balance. The SGLT2 protein, expressed in the renal proximal tubules, is responsible for the majority of the re-absorption of glucose filtered through the glomerulus; expression of SGLT2 is limited to the kidney. By inhibiting SGLT2, canagliflozin lowers Renal threshold for Glucose (RTG), resulting in increased excretion of glucose by the kidney; the increased urinary glucose excretion (UGE) directly lowers plasma-glucose concentrations in patients with elevated glucose levels. Several adverse events have been recorded during Phase II and Phase III clinical studies i.e. diarrhea, upper respiratory tract infection, UTI, hypoglycemia, back pain and headache. Continued assessment of the safety profile of this agent is appropriate, to assure identification of rare events, not observed in the clinical program to date, and to continue to characterize the overall safety and tolerability profile of this agent with longer term treatment. This review deals with the adverse effect study of canagliflozin & to assess its safety & stability in treatment of Type II Diabetes mellitus. Keywords: Canagliflozin, SGLT2 inhibitor, Type 2 Diabetes Mellitus Epidemiology of Diabetes Mellitus Diabetes mellitus is of 3 types :-Type 1 DM, Type 2 DM and Gestational diabetes. 382 million people worldwide have diabetes. Major Complications leading to diabetes are:- Coronary Heart disease, Retinopathy, Nephropathy, Neuropathy & Diabetic foot. Health Expenditure due to diabetes in the world has crossed $ 500 Billions in 2013. Figure: Inhibition of SGLT2 by Canagliflozin Leads to Increased Renal Glucose Excretion and Improved Glucose Homeostasis. Adverse Effects associated with Canagliflozin Canagliflozin is generally well tolerated, with Hypotension, Impairment of renal function, Hyperkalemia, Hypoglycemia, genital mycotic infections, Hypersensitivity reactions, and increases in low-density lipoprotein (LDL) and urinary tract infections (UTIs) being the most commonly experienced adverse effect. Mechanism of Action (SGLT2 Inhibitors) Conclusion In healthy individuals, glucose is freely filtered through the renal glomerulus and then reabsorbed in the proximal tubules. Glucose reabsorption in the renal tubules is largely due to glucose transporters: SGLT2. The SGLT2 is a high-capacity and low-affinity glucose transporter expressed in the proximal renal tubules, and not in other tissues, that is responsible for the majority of the reabsorption into the blood stream of glucose filtered through the glomerulus. Nearly all glucose filtered through the glomerulus is re-absorbed until the transporters reach maximum reabsorptive capacity; the glucose concentration at which this occurs is referred to as renal threshold for glucose (RTG). Above this threshold, urinary excretion of glucose increases in proportion to the plasma glucose concentration. Since the load of filtered glucose is proportional to the glomerular filtration rate (GFR), urinary glucose excretion (UGE) above the RTG also varies with GFR. In patients with T2DM, the RTG is elevated (Figure), leading to increased glucose reabsorption despite hyperglycemia which likely contributes to sustained elevation in serum glucose concentrations. Canagliflozin provides a novel mechanism of action to treat patients with type 2 diabetes who are not currently controlled. Recent studies demonstrate that it is safe and effective for treatment as monotherapy or as add-on therapy to other oral antihyperglycemic agents or insulin. Canagliflozin demonstrates significant reductions in A1C but also provides reductions in body weight and systolic blood pressure. The most common adverse effect is risk of UTIs and mycotic genital infections. Further studies are being conducted to delineate the drug’s impact on cardiovascular outcomes. Introduction With the progressive nature of diabetes, there is a need of additional methods to maintain glucose control. Canagliflozin (Invokana), a novel medication for treatment of type 2 diabetes, provides an alternative for patients who are not well controlled on current drug therapy or diet and exercise. It works by inhibiting the sodium-glucose co-transporter 2 (SGLT2) in the kidney, thus leading to increased glucose excretion. Canagliflozin is the first FDA-approved SGLT2 inhibitor. References John R. White; SGLT2 Inhibitors: A Review of Canagliflozin; US Pharm. 2013;38(10):HS13-HS20. Invokana. Janssen Pharmaceuticals Inc. www.invokana.com. Accessed September 17, 2013. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes. Am J Health Syst Pharm. 2013;70:311-319. White J. Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition. Clin Diabetes. 2010;28:5-10.