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


METHODS
Patients 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.


RESULTS
There 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.


CONCLUSIONS
Canagliflozin 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: NCT02220920.
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nobuya
N
Inagaki
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shin-Ichi
S
Harashima
Clinical Research Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Nobuko
N
Maruyama
Data Science Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Yutaka
Y
Kawaguchi
Medical Science Center, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Maki
M
Goda
Medical Science Center, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. Iijima.Hiroaki@mm.mt-pharma.co.jp.
Hiroaki
http://orcid.org/0000-0003-4621-2394
H
Iijima
D000328:Adult; D000368:Aged; D044466:Asian People; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D000068896:Canagliflozin / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015431:Weight Loss / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000068896:Canagliflozin
Canagliflozin; Combination therapy; Insulin; Japanese patients; SGLT2 inhibitor; Type 2 diabetes mellitus