Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus

Abstract

BackgroundCombination therapy with canagliflozin and insulin was investigated in a prescribed substudy of the canagliflozin Cardiovascular Assessment Study (CANVAS); however, it was not evaluated in Japanese patients with type 2 diabetes mellitus (T2DM). Since the usage profile of insulin therapy and pathologic features of Japanese patients differ from those of Caucasian patients, we determined the clinical benefit of such a combination therapy in Japanese patients.MethodsPatients who had inadequate glycemic control despite insulin, diet and exercise therapies were randomized into placebo (n = 70) and canagliflozin 100 mg (n = 76) groups that were administered once daily in addition to their prior insulin therapy in this double-blind, placebo-controlled study. The primary endpoint was the change in glycated hemoglobin (HbA1c) levels from the baseline to week 16.ResultsThere was a statistically significant decrease in HbA1c levels from the baseline in the canagliflozin group (−0.97 ± 0.08 %) compared with the placebo group (0.13 ± 0.08 %) at week 16 [last observation carried forward (LOCF)]. The decrease in HbA1c levels in the canagliflozin group was independent of the insulin regimen (premixed, long-acting and long-acting plus rapid- or short-acting). Compared with the placebo group, canagliflozin significantly decreased fasting plasma glucose levels (−34.1 ± 4.8 vs −1.4 ± 5.0 mg/dL) and body weights (−2.13 ± 0.25 vs 0.24 ± 0.26 %), and significantly increased HDL cholesterol (3.3 ± 1.0 vs −0.5 ± 1.0 mg/dL) and HOMA2- %B (10.15 ± 1.37 vs 0.88 ± 1.42 %). The overall incidence of adverse events was similar between the two groups. The incidence and incidence per subject-year exposure of hypoglycemia (hypoglycemic symptoms and/or decreased blood glucose) were slightly higher in the canagliflozin group (40.0 % and 7.97) than in the placebo group (29.6 % and 4.51). However, hypoglycemic events in both groups were mild in severity and dose-reduction of insulin by <10 % from the baseline following hypoglycemic events decreased the incidence per subject-year exposure in the canagliflozin group. The incidence of hypoglycemia between the groups did not differ according to the insulin regimen.ConclusionCanagliflozin in combination with insulin was effective in improving glycemic control and reducing body weight and well tolerated by Japanese patients with T2DM.Trial Registration ClinicalTrials.gov identifier: NCT02220920Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0407-4) contains supplementary material, which is available to authorized users.

Dapagliflozin as add‐on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: A randomized controlled trial

“…This risk is further increased with the use of SGLT2 inhibitors, likely due to increased glucosuria . The reported incidence of genital infections and UTIs was lower in the present study than in comparable studies in other populations; however, similar results have been reported in other studies of SGLT2 inhibitors in Asian populations . Adverse events of renal function were infrequent in both treatment groups (2.2% and 3.8% for dapagliflozin and placebo, respectively), and were primarily reported in relation to variation in blood creatinine values in protocol‐mandated regular laboratory checks without clinically symptomatic AEs.…”

Safety and efficacy of canagliflozin in elderly patients with type 2 diabetes mellitus: a 1-year post-marketing surveillance in Japan

“…Taking these results into account, we guessed that Japanese physicians may be cautious of ADRs potentially caused by SGLT2 inhibitors after the issue of recommendation for SGLT2 inhibitors, resulting in the increase of withdrawal rate due to AEs. All ADRs observed in this survey were already known events that were reported in the previous clinical trials of canagliflozin conducted in Japan [9][10][11][12][13] , and there were no clinically significant concerns in the changes of laboratory variables during our survey period. Recently, the Food and Drug Administration (FDA) and the European Medicines Agency also warned of the risk of ketoacidosis with SGLT2 inhibitors 14 .…”

Efficacy of Canagliflozin as an Add-on to Triple Drug Treatment With Glimepiride, Metformin and Teneligliptin

“…20 The drug has been shown to be effective in reducing body weight and improving glycemic control, when used in combination with insulin. 21 Gavin et al (2015) have reported that the drug can provide improved outcomes, such as reduction in HbA1c, body weight and systolic blood pressure in T2DM patients, independent of racial background. 22 Several studies conducted on Indian T2DM patients have also demonstrated the effectiveness of the drug in enabling glycemic control and reducing body weight.…”