Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus

Nobuya Inagaki, Shin-Ichi Harashima, Kohei Kaku, Kazuoki Kondo, Nobuko Maruyama, Makiko Otsuka, Yutaka Kawaguchi, Hiroaki Iijima, Nobuya Inagaki, Shin-Ichi Harashima, Kohei Kaku, Kazuoki Kondo, Nobuko Maruyama, Makiko Otsuka, Yutaka Kawaguchi, Hiroaki Iijima

Abstract

Aim: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin.

Materials and methods: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values.

Results: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period.

Conclusions: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.

Keywords: SGLT2 inhibitor; canagliflozin; hypoglycaemia; insulin; type 2 diabetes mellitus.

Conflict of interest statement

N. I. has received consulting fees and/or speakers’ bureau fees from Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Sanofi K.K. and Takeda Pharmaceutical Co., Ltd.; has received research support from Eli Lilly Japan K.K., MSD K.K. and Mitsubishi Tanabe Pharma Corp.; and has received scholarship grants from Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Japan Diabetes Foundation, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd. and Taisho Toyama Pharmaceutical Co., Ltd. S. H. has received consulting fees and/or speakers’ bureau fees from Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corp., MSD K.K., Novo Nordisk Pharma Ltd. and Sanofi K.K. K. Ka. has received speakers' bureau fees from Astellas Pharma Inc., AstraZeneca K.K., Kissei Pharmaceutical Co., Ltd., Kowa pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd.; and has received scholarship grants from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd. and Takeda Pharmaceutical Co., Ltd. K. Ko., N. M., M. O., Y. K. and H. I. are employees of Mitsubishi Tanabe Pharma Corp.

© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Glycated haemoglobin (HbA1c) measured from baseline to the end of treatment (LOCF). Each point and bar represents mean ± SD. Abbreviations: CAN/CAN, canagliflozin/canagliflozin group; LOCF, last observation carried forward, P/CAN, placebo/canagliflozin group

References

    1. International Diabetes Federation . Diabetes Atlas. 7th ed. . 2015. Accessed May 1, 2017.
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10‐year follow‐up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
    1. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long‐term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23(suppl 2):B21–B29.
    1. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges? Diabetes Care. 2014;37:1499–1508.
    1. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33:1389–1394.
    1. Kalra S, Mukherjee JJ, Venkataraman S, et al. Hypoglycemia: the neglected complication. Indian J Endocrinol Metab. 2013;17:819–834.
    1. Fujita Y, Inagaki N. Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: clinical data and mechanism of action. J Diabetes Investig. 2014;5:265–275.
    1. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium‐glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care. 2015;38:2344–2353.
    1. Tang H, Cui W, Li D, et al. Sodium‐glucose co‐transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: a meta‐analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19:142–147.
    1. John M, Gopinath D, Jagesh R. Sodium‐glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: clinical perspectives. Indian J Endocrinol Metab. 2016;20:22–31.
    1. Yokote K, Terauchi Y, Nakamura I, Sugamori H. Real‐world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA‐ELDER): final results of a post‐marketing surveillance study. Expert Opin Pharmacother. 2016;17:1995–2003.
    1. Yabe D, Nishikino R, Kaneko M, Iwasaki M, Seino Y. Short‐term impacts of sodium/glucose co‐transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events. Expert Opin Drug Saf. 2015;14:795–800.
    1. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 2013;1281:64–91.
    1. Moller JB, Pedersen M, Tanaka H, et al. Body composition is the main determinant for the difference in type 2 diabetes pathophysiology between Japanese and Caucasians. Diabetes Care. 2014;37:796–804.
    1. Ikezaki H, Ai M, Schaefer EJ, et al. Ethnic differences in glucose homeostasis markers between the Kyushu‐Okinawa Population Study and the Framingham Offspring Study. Sci Rep. 2016;6:36725.
    1. Inagaki N, Kondo K, Yoshinari T, Maruyama N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double‐blind, placebo‐controlled, 12‐week study. Diabetes Obes Metab. 2013;15:1136–1145.
    1. Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24‐week, randomized, double‐blind, placebo‐controlled, Phase III study. Expert Opin Pharmacother. 2014;15:1501–1515.
    1. Inagaki N, Kondo K, Yoshinari T, Kuki H. Efficacy and safety of canagliflozin alone or as add‐on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: a 52‐week open‐label study. J Diabetes Investig. 2015;6:210–218.
    1. Kadowaki T, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add‐on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24‐week, randomized, double‐blind, placebo‐controlled trial. Diabetes Obes Metab. 2017;19:874–882.
    1. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium‐glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38:403–411.
    1. Inagaki N, Harashima S, Maruyama N, Kawaguchi Y, Goda M, Iijima H. Efficacy and safety of canagliflozin in combination with insulin: a double‐blind, randomized, placebo‐controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2016;15:89.
    1. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384–1395.
    1. Kahn SE, Cooper ME, Del PS. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–1083.
    1. Hayashino Y, Izumi K, Okamura S, Nishimura R, Origasa H, Tajima N. Duration of diabetes and types of diabetes therapy in Japanese patients with type 2 diabetes: The Japan Diabetes Complication and its Prevention prospective study 3 (JDCP study 3). J Diabetes Investig. 2017;8:243–249.
    1. Kanatsuka A, Sato Y, Kawai K, Hirao K, Kobayashi M, Kashiwagi A. Evaluation of insulin regimens as an effective option for glycemic control in patients with type 2 diabetes: a propensity score‐matched cohort study across Japan (JDDM31). J Diabetes Investig. 2014;5:539–547.
    1. Lorber D. Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2014;7:169–183.
    1. Tajima N, Noda M, Origasa H, et al. Evidence‐based practice guideline for the treatment for diabetes in Japan 2013. Diabetol Int. 2015;6:151–187.
    1. Carver C. Insulin treatment and the problem of weight gain in type 2 diabetes. Diabetes Educ. 2006;32:910–917.
    1. Balkau B, Home PD, Vincent M, Marre M, Freemantle N. Factors associated with weight gain in people with type 2 diabetes starting on insulin. Diabetes Care. 2014;37:2108–2113.
    1. Yki‐Jarvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care. 2001;24:758–767.
    1. Home PD, Dain MP, Freemantle N, et al. Four‐year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents. Diabetes Res Clin Pract. 2015;108:350–359.
    1. Holman RR, Farmer AJ, Davies MJ, et al. Three‐year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361:1736–1747.
    1. Chow LS, Chen H, Miller ME, Marcovina SM, Seaquist ER. Biomarkers associated with severe hypoglycaemia and death in ACCORD. Diabet Med. 2016;33:1076–1083.
    1. Cryer PE. Mechanisms of hypoglycemia‐associated autonomic failure in diabetes. N Engl J Med. 2013;369:362–372.
    1. Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153:1039–1048.
    1. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849–2852.

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