Investigation of the Effect of Canagliflozin on the Disposition Index, a Marker of Pancreatic Beta Cell Function, in Patients with Type 2 Diabetes

Mitsuyoshi Takahara,1 Toshihiko Shiraiwa,2 Taka-aki Matsuoka,3 Kaoru Yamamoto,2 Yoshifumi Maeno,2 Yuka Shiraiwa,2 Yoko Yoshida,2 Naoto Katakami,4 Hiroaki Iijima,5 Hideyuki Katsumata,6 Kenji Arakawa,5 Toshio Hashimoto,5 Iichiro Shimomura3 1Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 2Shiraiwa Medical Clinic, Osaka, Japan; 3Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 4Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, Osaka, Japan; 5Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 6Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, JapanCorrespondence: Taka-aki MatsuokaDepartment of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, JapanTel +81-6-6879-3732Fax +81-6-6879-3739Email matsuoka@endmet.med.osaka-u.ac.jpAim: Our aim was to investigate the effects of add-on canagliflozin with glimepiride dose adjustment or glimepiride dose adjustment on pancreatic beta cell function in patients with type 2 diabetes mellitus and inadequate glycemic control despite stable triple therapy (metformin, teneligliptin, and glimepiride) plus diet/exercise therapy.Methods: Forty patients on stable triple therapy were randomized to glimepiride dose adjustment without (glimepiride group) or with add-on canagliflozin 100 mg (canagliflozin group) for 24 weeks. The glimepiride dose was adjusted every 4 weeks based on continuous glucose monitoring over the previous 2 weeks according to a prespecified algorithm. After the 24-week treatment period, the patients returned to the pre-intervention regimen for 1 week (wash-out period). Patients underwent 75 g OGTTs at the start of the run-in period and at the end of the wash-out period. The primary endpoint was the change in disposition index (DI).Results: Thirty-nine patients completed the study (canagliflozin, n = 19; glimepiride, n = 20). The change in DI was +5.1% and − 11.0% in the canagliflozin and glimepiride groups, respectively, with a between-group difference ratio of 18.0% (P = 0.330). HbA1c, fasting plasma glucose, body weight, and daily-life continuous glucose monitoring-derived parameters improved in the canagliflozin group. Hypoglycemia occurred in 60% (44 episodes) and 70% (79 episodes) of patients in the canagliflozin and glimepiride groups, respectively. The change in DI was significantly correlated with the changes in glycemic control and variability in overall cohort.Conclusion: Adding canagliflozin to the triple therapy improved beta cell function by 18%, but it did not reach statistical significance. This study also demonstrated a correlation between the change in DI and glycemic control. As canagliflozin improved both glucose level and variability with relatively lower risk of hypoglycemia compared with glimepiride dose adjustment, adding canagliflozin to the triple therapy may be clinically beneficial.Trial Registration: UMIN000030208/jRCTs051180036.Keywords: beta cell function, canagliflozin, glimepiride, glycemic control, type 2 diabetes mellitus