Inagaki Nobuya, Harashima Shin-Ichi, Maruyama Nobuko, Kawaguchi Yutaka, Goda Maki, Iijima Hiroaki
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Clinical Research Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Cardiovasc Diabetol. 2016 Jun 18;15:89. doi: 10.1186/s12933-016-0407-4.
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.
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.
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.
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.
在卡格列净心血管评估研究（CANVAS）的一项预设子研究中，对卡格列净与胰岛素的联合治疗进行了研究；然而，尚未在日本2型糖尿病（T2DM）患者中进行评估。由于日本患者的胰岛素治疗使用情况和病理特征与白种人患者不同，我们确定了这种联合治疗对日本患者的临床益处。
在这项双盲、安慰剂对照研究中，尽管接受了胰岛素、饮食和运动治疗但血糖控制不佳的患者被随机分为安慰剂组（n = 70）和卡格列净100 mg组（n = 76），除了先前的胰岛素治疗外，每天给药一次。主要终点是糖化血红蛋白（HbA1c）水平从基线到第16周的变化。
在第16周时，卡格列净组的HbA1c水平较基线有统计学意义的下降（-0.97±0.08%），而安慰剂组为（0.13±0.08%）[末次观察结转（LOCF）]。卡格列净组HbA1c水平的下降与胰岛素治疗方案（预混、长效以及长效加速效或短效）无关。与安慰剂组相比，卡格列净显著降低了空腹血糖水平（-34.1±4.8 vs -1.4±5.0 mg/dL）和体重（-2.13±0.25 vs 0.24±0.26%），并显著提高了高密度脂蛋白胆固醇（3.3±1.0 vs -0.5±1.0 mg/dL）和HOMA2-%B（10.15±1.37 vs 0.88±1.42%）。两组不良事件的总发生率相似。卡格列净组低血糖（低血糖症状和/或血糖降低）的发生率和每受试者年暴露发生率略高于安慰剂组（40.0%和7.97）（29.6%和4.51）。然而，两组的低血糖事件严重程度均较轻，低血糖事件后胰岛素剂量从基线降低<10%可降低卡格列净组的每受试者年暴露发生率。两组间低血糖的发生率根据胰岛素治疗方案并无差异。
卡格列净与胰岛素联合使用可有效改善血糖控制并减轻体重，且日本T2DM患者耐受性良好。试验注册ClinicalTrials.gov标识符：NCT02220920。
