Efficacy and Safety of Canagliflozin Treatment in Older Subjects With Type 2 Diabetes Mellitus: A Randomized Trial

Abstract

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.

Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes

“…Reductions from baseline in alanine aminotransferase and serum urate were observed in the CANA groups compared with MET. Consistent with previous studies of CANA (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), all CANA groups experienced early reductions in eGFR and commensurate increases in serum creatinine that attenuated over 26 weeks (Supplementary Fig. 3).…”

“…Smaller differences in HbA 1c were seen between treatment arms containing CANA100 and CANA300 in this study compared with previous studies where a dose response had been observed (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). However, HbA 1c lowering with CANA has been observed to be less dose-dependent as baseline HbA 1c increases (40).…”

“…CANA lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE); increased UGE results in insulinindependent glucose-lowering effects, as well as a mild osmotic diuresis and net caloric loss that can lead to weight loss and blood pressure (BP) reductions (24,25). Across phase 3 studies in a broad range of patients with type 2 diabetes, CANA provided reductions in HbA 1c , body weight, and BP and was generally well tolerated as monotherapy and in combination with other AHAs, including MET (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). This study evaluated the efficacy and safety of initial combination therapy with CANA 100 mg (CANA100) or CANA 300 mg (CANA300) plus MET in drug-naïve patients with type 2 diabetes over 26 weeks.…”

“…Canagliflozin (CANA) is an SGLT2 inhibitor developed for the treatment of adults with type 2 diabetes (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). CANA lowers the renal threshold for glucose, thereby increasing urinary glucose excretion (UGE); increased UGE results in insulinindependent glucose-lowering effects, as well as a mild osmotic diuresis and net caloric loss that can lead to weight loss and blood pressure (BP) reductions (24,25).…”

Effect of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, on measurement of serum 1,5‐anhydroglucitol (坎格列净，一种钠‐葡萄糖共转运体2抑制剂，对血清1,5‐脱水葡萄糖醇测定的影响)

“…6 The efficacy of canagliflozin in improving glycemic control, as measured by reductions in HbA1c and fasting and postprandial plasma glucose (FPG and PPG, respectively), and the overall safety and tolerability profile of canagliflozin in patients with T2DM have been reported previously. [7][8][9][10][11][12][13] Herein we report findings from a post hoc analysis of 1,5-AG levels using archived samples from a subset of patients who participated in a randomized, double-blind, placebocontrolled, Phase 3 study of canagliflozin monotherapy in patients with T2DM. 7 Detailed methods from the Phase 3 study of canagliflozin monotherapy have been reported elsewhere.…”