Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes

Takashi Kadowaki, Nobuya Inagaki, Kazuoki Kondo, Kenichi Nishimura, Genki Kaneko, Nobuko Maruyama, Nobuhiro Nakanishi, Yumi Watanabe, Maki Gouda, Hiroaki Iijima, Takashi Kadowaki, Nobuya Inagaki, Kazuoki Kondo, Kenichi Nishimura, Genki Kaneko, Nobuko Maruyama, Nobuhiro Nakanishi, Yumi Watanabe, Maki Gouda, Hiroaki Iijima

Abstract

Aim: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.

Methods: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward).

Results: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.

Conclusions: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.

Trial registration: ClinicalTrials.gov NCT02220907.

Keywords: DPP-4 inhibitor; SGLT2 inhibitor; canagliflozin; teneligliptin; type 2 diabetes mellitus.

Conflict of interest statement

T. K. has received consulting fees and/or speakersʼ bureau fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd, Ono Pharmaceutical Co., Ltd, Sanofi K.K. and Takeda Pharmaceutical Co., Ltd, research support from Daiichi Sankyo Co., Ltd and Takeda Pharmaceutical Co., Ltd, scholarship grants from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd, Mitsubishi Tanabe Pharma Corp., Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd and Takeda Pharmaceutical Co., Ltd, and belongs to courses endowed by MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Novo Nordisk Pharma Ltd, and Takeda Pharmaceutical Co., Ltd. N. I. has received consulting fees and/or speakersʼ bureau fees from Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Sanofi K.K. and Takeda Pharmaceutical Co., Ltd, research support from Eli Lilly Japan K.K., MSD K.K. and Mitsubishi Tanabe Pharma Corp., and 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. K. K., K. N., G. K., N. M., N. N., Y. W., M. G. 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
Changes in A, HbA1c; B, FPG and C, body weight from baseline during the study period. Data represent mean (95% CI). D, Scatter plot of the change in HbA1c vs percent change in body weight from baseline to the end of treatment in individual patients. FPG: 1 mg/dL = 0.0555 mmol/L.
Figure 2
Figure 2
Changes in A, blood glucose; B, C‐peptide and C, glucagon levels in the mixed‐meal tolerance tests at baseline, week 24 and week 52. Data represent mean ± standard deviation. Glucose: 1 mg/dL = 0.0555 mmol/L; C‐peptide: 1 ng/mL = 0.333 nmol/L; Glucagon: 1 pg/mL = 1 ng/L.

References

    1. Wilding JP, Rajeev SP, DeFronzo RA. Positioning SGLT2 inhibitors/incretin‐based therapies in the treatment algorithm. Diabetes Care. 2016;39(suppl 2):S154–S164.
    1. Seino Y, Kuwata H, Yabe D. Incretin‐based drugs for type 2 diabetes: focus on East Asian perspectives. J Diabetes Investig. 2016;7(suppl 1):102–109.
    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. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium‐glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.
    1. Merovci A, Solis‐Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–514.
    1. Sharma MD. Potential for combination of dipeptidyl peptidase‐4 inhibitors and sodium‐glucose co‐transporter‐2 inhibitors for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015;17:616–621.
    1. Scheen AJ. DPP‐4 inhibitor plus SGLT‐2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12:1407–1417.
    1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–1083.
    1. Møller 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. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient‐centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of diabetes. Diabetologia. 2015;58:429–442.
    1. Berkowitz SA, Krumme AA, Avorn J, et al. Initial choice of oral glucose‐lowering medication for diabetes mellitus: a patient‐centered comparative effectiveness study. JAMA Intern Med. 2014;174:1955–1962.
    1. Fujihara K, Igarashi R, Matsunaga S, et al. Comparison of baseline characteristics and clinical course in Japanese patients with type 2 diabetes among whom different types of oral hypoglycemic agents were chosen by diabetes specialists as initial monotherapy (JDDM 42). Medicine (Baltimore). 2017;96:e6122.
    1. Esposito K, Chiodini P, Maiorino MI, et al. Glycaemic durability with dipeptidyl peptidase‐4 inhibitors in type 2 diabetes: a systematic review and meta‐analysis of long‐term randomised controlled trials. BMJ Open. 2014;4:e005442.
    1. Goda M, Kadowaki T. Teneligliptin for the treatment of type 2 diabetes. Drugs Today (Barc). 2013;49:615–629.
    1. Morishita R, Nakagami H. Teneligliptin: expectations for its pleiotropic action. Expert Opin Pharmacother. 2015;16:417–426.
    1. Kadowaki T, Marubayashi F, Yokota S, Katoh M, Iijima H. Safety and efficacy of teneligliptin in Japanese patients with type 2 diabetes mellitus: a pooled analysis of two phase III clinical studies. Expert Opin Pharmacother. 2015;16:971–981.
    1. Kadowaki T, Kondo K. Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. J Diabetes Invest. 2013;4:576–584.
    1. Bryson A, Jennings PE, Deak L, Paveliu FS, Lawson M. The efficacy and safety of teneligliptin added to ongoing metformin monotherapy in patients with type 2 diabetes: a randomized study with open label extension. Expert Opin Pharmacother. 2016;17:1309–1316.
    1. Rosenthal N, Meininger G, Ways K, et al. Canagliflozin: a sodium glucose co‐transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Ann N Y Acad Sci. 2015;1358:28–43.
    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, randomised, double‐blind, placebo‐controlled trial. Diabetes Obes Metab. 2017;19:874–882.
    1. Einarson TR, Garg M, Kaur V, Hemels ME. Composite endpoints in trials of type‐2 diabetes. Diabetes Obes Metab. 2014;16:492–499.
    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 Invest. 2015;6:210–218.
    1. Araki E, Tanizawa Y, Tanaka Y, et al. Long‐term treatment with empagliflozin as add‐on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015;17:665–674.
    1. Kaku K, Maegawa H, Tanizawa Y, et al. Dapagliflozin as monotherapy or combination therapy in Japanese patients with type 2 diabetes: an open‐label study. Diabetes Ther. 2014;5:415–433.
    1. Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin‐mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:82–91.
    1. Jabbour SA, Hardy E, Sugg J, Parikh S, Study 10 Group . Dapagliflozin is effective as add‐on therapy to sitagliptin with or without metformin: a 24‐week, multicenter, randomized, double‐blind, placebo‐controlled study. Diabetes Care. 2014;37:740–750.
    1. Mathieu C, Herrera Marmolejo M, González González JG, et al. Efficacy and safety of triple therapy with dapagliflozin add‐on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:1134–1137.
    1. Stein P, Berg JK, Morrow L, et al. Canagliflozin, a sodium glucose co‐transporter 2 inhibitor, reduces post‐meal glucose excursion in patients with type 2 diabetes by a non‐renal mechanism: results of a randomized trial. Metabolism. 2014;63:1296–1303.
    1. Eto T, Inoue S, Kadowaki T. Effects of once‐daily teneligliptin on 24‐h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4‐week, randomized, double‐blind, placebo‐controlled trial. Diabetes Obes Metab. 2012;14:1040–1046.
    1. Tanaka H, Takano K, Iijima H, et al. Factors affecting canagliflozin‐induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther. 2017;34:436–451.
    1. Oguma T, Kuriyama C, Nakayama K, et al. The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats. J Pharmacol Sci. 2015;127:456–461.
    1. Inagaki N, Goda M, Yokota S, Maruyama N, Iijima H. Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52‐week open‐label study. Expert Opin Pharmacother. 2015;16:1577–1591.
    1. Gilbert RE, Weir MR, Fioretto P, et al. Impact of age and estimated glomerular filtration rate on the glycemic efficacy and safety of canagliflozin: a pooled analysis of clinical studies. Can J Diabetes. 2016;40:247–257.
    1. Kim YG, Hahn S, TJ O, Kwak SH, Park KS, Cho YM. Differences in the glucose‐lowering efficacy of dipeptidyl peptidase‐4 inhibitors between Asians and non‐Asians: a systematic review and meta‐analysis. Diabetologia. 2013;56:696–708.
    1. Park H, Park C, Kim Y, Rascati KL. Efficacy and safety of dipeptidyl peptidase‐4 inhibitors in type 2 diabetes: meta‐analysis. Ann Pharmacother. 2012;46:1453–1469.
    1. Kanamoria A, Matsuba I. Factors associated with reduced efficacy of sitagliptin therapy: analysis of 93 patients with type 2 diabetes treated for 1.5 years or longer. J Clin Med Res. 2013;5:217–221.
    1. Kubota A, Yabe D, Kanamori A, et al. Factors influencing the durability of the glucose‐lowering effect of sitagliptin combined with a sulfonylurea. J Diabetes Invest. 2014;5:445–448.

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