AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise.MethodsIn this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study.ResultsAt week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (−0.77, −1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups.ConclusionCanagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.

AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2].MethodsIn this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated.ResultsBoth canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin.ConclusionCanagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.

OBJECTIVETo evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy.RESEARCH DESIGN AND METHODSThis was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed.RESULTSCanagliflozin was associated with significant reductions in A1C from baseline (7.6–8.0%) to week 12: −0.79, −0.76, −0.70, −0.92, and −0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus −0.22% for placebo (all P < 0.001) and −0.74% for sitagliptin. FPG was reduced by −16 to −27 mg/dL, and body weight was reduced by −2.3 to −3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non–dose-dependent increase in symptomatic genital infections with canagliflozin (3–8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3–9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low.CONCLUSIONSCanagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.

AimsCanagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM.MethodsPatients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52).ResultsHbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (–0.85%, –1.06%, and –0.13%; p < 0.001); these reductions were maintained at week 52 (–0.74%, –0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo.ConclusionsCanagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.

Introduction:Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55-80 years) with T2DM inadequately controlled on their current regimen of blood glucose-lowering agents (any approved oral or injectable treatment). Methods: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA 1c ) levels $ 7.0% to # 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA 1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA 1c levels , 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study. Results: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA 1c levels compared with placebo (−0.60%, −0.73%, −0.03%, respectively; P , 0.001); more subjects achieved HbA 1c levels , 7.0% with both canagliflozin doses compared with placebo (P , 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P , 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%, 72.2%, 73.4%, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose-lowering agents. pendent ethics committees for participating centers. Subjects gave informed, written consent prior to participation.