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Canagliflozin (Invokana) is a sodium/glucose co-transporter (SGLT-2) inhibitor indicated to improve glycemic control in adults with type 2 diabetes in combination with diet and exercise. It was approved by the FDA in March 2013 for use as monotherapy or in combination therapy with other anti-diabetic agents. Canagliflozin works by blocking the reabsorption of glucose by the kidney and thereby causing increased glucose excretion and reduced blood glucose levels.1 The glycemic control algorithm by American Association of Clinical Endocrinologists suggests the use of SGLT-2 inhibitor as a monotherapy in patients with A1C <7.5% or in combination along with other anti-hyperglycemic agents.2 A position statement by the American Diabetes Association and the European Association for the study of diabetes recommends tailoring treatment according to each patient’s needs. These guidelines further add that treatments with complementary mechanism of action should be included in triple therapy combinations if a patient’s A1C is not controlled with dual therapy.3 Stenlof and colleagues conducted a randomized, double blind, active controlled study comparing canagliflozin with placebo and found significant decrease in A1C levels with canagliflozin 100mg or 300mg compared to placebo (-0.77, -1.03 and 0.14%, respectively; p < 0.001 for both).4

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To evaluate canagliflozin as add-on therapy, Schernthaner and colleagues conducted a 52-week, randomized, double-blind, active controlled multicenter, phase 3 study that evaluated the efficacy and safety of canagliflozin 300 mg compared to sitagliptin 100 mg daily as add-on therapy in patients with Type 2 diabetes inadequately controlled with metformin and a sulfonylurea. Type 2 diabetics using metformin and a sulfonylurea with an A1C of 7.0-10.5% were eligible for inclusion. Exclusion criteria included fasting glucose ≥ 300 mg/dl during pretreatment, history of Type 1 diabetes, cardiovascular disease or uncontrolled hypertension, as well as treatment with PPARγ agonist, insulin, SGLT2 inhibitor or any other anti-diabetic agent within 12 weeks of screening. No rescue therapy was allowed and patients were discontinued in the study if they met specific glycemic criteria at various points of time during the study. The primary objective of the study was change in A1C from baseline through week 52 and the safety outcomes were adverse events. This was a non-inferiority trial; if the pre-specified margin of 0.3% for the upper limit of the two-sided 95% confidence interval was found, then a superiority assessment was planned.5

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Of the 755 patients who started the trial, 464 (61%) completed the 52 weeks. The sitaglipitin group had more discontinue the study than canagliflozin (44.4% vs. 32.6%, respectively). The main reason for withdrawal was glycemic control exceeding the glycemic criteria with 88% of those diabetics stopping the trial by week 26. Canagliflozin demonstrated non-inferiority and superiority compared to sitaglipitin. Canagliflozin had a greater reduction in A1C over 52 weeks compared to sitaglipitin (-1.03% versus -0.66%; 95% CI -0.50 to -0.25), as well as greater reductions in fasting and post-prandial glucose and systolic blood pressure. A greater proportion of patients achieved an A1C <7% and < 6.5% with canagliflozin  (47.6 % versus 35.3% and 22.5% versus 18.9% for canagliflozin vs. sitagliptin, respectively). Canagliflozin showed a significant reduction in body weight compared to sitagliptin (-2.3kg versus 0.1kg; p<0.001). It resulted in increased HDL, but also increased LDL more than sitagliptin, and TG increased similarly in both groups. Overall adverse events and discontinuation of the treatment due to adverse events was similar in both groups. Canagliflozin group had increased incidence of genital mycotic infections (males 9.2% versus 0.5%; females 15.3% versus 4.3% with sitagliptin). Urinary tract infections and hypoglycemic events were similar between two groups.5

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The authors concluded that canagliflozin significantly improved glycemic control and reduced body weight and ...

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