Abstract
Aims
Managing insulin therapy is a challenge for both patients and healthcare providers.
The primary aim of this trial was to compare the efficacy and safety of insulin degludec (IDeg) in a fixed versus flexible dosing schedule. The secondary aim and subject of this manuscript was to compare a simple versus a stepwise titration algorithm.
Materials and methods
This was a 26-week, controlled, multicenter, open-label, randomized, treat-to-target phase 3b trial of Japanese patients with type 2 diabetes inadequately treated with insulin glargine and with/without antidiabetic drugs orally. The trial had a 2 × 2 factorial design whereby 458 patients were randomized 1:1:1:1 to one of two titration algorithms and one of two dosing schedules. IDeg dose was adjusted weekly using a clinician-led, treat-to-target approach in order to ensure optimal insulin titration and glycemic control following self-measured blood glucose (SMBG) readings.
Results
Mean insulin dose at the end of the trial was similar in both simple and stepwise titration algorithms. Glycemic control improved in both titration algorithms, with noninferiority in glycated hemoglobin (HbA1c) reduction confirmed when comparing simple and stepwise titration algorithms and no significant differences in fasting plasma glucose or SMBG at 26 weeks. No safety concerns were observed in terms of adverse events, and rates of hypoglycemia were not significantly different between the two algorithms.
Conclusions
This trial demonstrated comparable efficacy with noninferior HbA1c and comparable safety of once-daily IDeg using either a simple or stepwise titration algorithm in Japanese patients with type 2 diabetes inadequately controlled with insulin glargine.
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References
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl 1):S62–9.
Japan Diabetes Society. Treatment Guide for Diabetes 2012. Tokyo: Bunkodo Co. Ltd; 2012.
Peyrot M, Barnett AH, Meneghini LF, et al. Factors associated with injection omission/non-adherence in the global attitudes of patients and physicians in insulin therapy study. Diabetes Obes Metab. 2012;14:1081–7.
Peyrot M, Barnett AH, Meneghini LF, et al. Insulin adherence behaviours and barriers in the multinational global attitudes of patients and physicians in insulin therapy study. Diabet Med. 2012;29:682–90.
Davies M, Storms F, Shutler S, The ATLANTUS Study Group, et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28:1282–8.
Kennedy L, Herman WH, Strange P, GOAL A1C Team, et al. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: the Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial. Diabetes Care. 2006;29:1–8.
Blonde L, Merilainen M, Karwe V, et al. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets—the TITRATE study. Diabetes Obes Metab. 2009;11:623–31.
Meneghini L, Koenen C, Wenig W, et al. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes–results of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab. 2007;9:902–13.
Ligthelm RJ. Self-titration of biphasic insulin aspart 30/70 improves glycaemic control and allows easy intensification in a Dutch clinical practice. Prim Care Diabetes. 2009;3:97–102.
Oyer DS, Shepherd MD, Coulter FC, INITIATEplus Study Group, et al. A(1c) control in a primary care setting: self-titrating an insulin analog premix (INITIATEplus trial). Am J Med. 2009;122:1043–9.
IDF Clinical Guidelines Taskforce. Global guideline for T2DM. Brussels: International Diabetes Federation; 2012.
Ikushima I, Kaku K, Hirao K, et al. Pharmacokinetic and pharmacodynamic properties of insulin degludec in Japanese subjects with type 1 diabetes mellitus reflect similarities with Caucasian subjects. J Diabetes Investig. 2016;7:270–5.
Heise T, Hermanski L, Nosek L, et al. Insulin degludec: four times lower pharmacodynamics variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14:859–64.
Heise T, Nosek L, Bottcher SG, et al. Ultra-long acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14:944–50.
Onishi Y, Iwamoto Y, Yoo SJ, et al. Insulin degludec compared with insulin glargine in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, Pan-Asian, treat-to-target trial. J Diabetes Investig. 2013;4:605–12.
Rodbard HW, Cariou B, Zinman B, et al. Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial. Diabet Med. 2013;30:1298–304.
Ratner RE, Gough SCL, Mathieu C, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a preplanned meta-analysis of phase 3 trials. Diabetes Obes Metab. 2013;15:175–84.
Philis-Tsimikas A, Brod M, Niemeyer M, et al. Insulin degludec once-daily in type 2 diabetes: simple or step-wise titration (BEGIN: Once simple Use). Adv Ther. 2013;30:607–22.
Garg SK, Admane K, Freemantle N, et al. Patient-led versus physician-led titration of insulin glargine in uncontrolled patients with type 2 diabetes: a randomized multinational ATLAS Study. Endocr Pract. 2015;21:143–57.
Kadowaki T, Jinnouchi H, Kaku K, et al. Efficacy and safety of once-daily insulin degludec dosed flexibly at convenient times versus fixed dosing at the same time each day in a Japanese cohort with type 2 diabetes: a randomized, 26-week, treat-to-target trial. J Diabetes Investig. 2016. doi:10.1111/jdi.12502.
World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. Last amended by the 59th WMA Assembly Seoul, October 2008.
International Conference of Harmonisation. ICH Harmonised Tripartite Guideline. Good Clinical Practice 01 May 1996.
Acknowledgments
The authors thank the investigators, trial staff, and patients for their participation. The authors would also like to thank Sam Mason and Daria Renshaw, Watermeadow Medical, UK, for medical writing and submission support (funded by Novo Nordisk).
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TK is a member of the National Advisory Board for Novo Nordisk Japan; reports funded research courses from MSD, Nippon Boehringer Ingelheim, Novartis, Takeda and Novo Nordisk; lecture fees from Astellas, AstraZeneca, Eli Lilly, Kissei, Kowa, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Novo Nordisk, Ono, Sumitomo Dainippon, and Takeda; manuscript fees from Eli Lilly; scholarship grants and endowments from Daiichi Sankyo, Mitsubishi Tanabe, Sumitomo Dainippon, and Takeda; and funds for clinical research from Daiichi Sankyo, Sanwa Kagaku, and Takeda. HJ has received lecture fees and clinical research grants from AstraZeneca, Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Takeda, Novartis Pharmaceuticals, Novo Nordisk and Sanofi. KK has received lecture fees from Astellas, Kissei, Sumitomo Dainippon Pharma, Sanwa Kagaku Kenkyusho Co., Sanofi, Novo Nordisk Pharma, Takeda, Ono Pharmaceutical Co., MSD, Novartis, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Taisho Toyama Pharmaceutical Co. and Kowa Pharmaceuticals. MLH and JH-W are employees of Novo Nordisk. SN has received honoraria for lectures from Novo Nordisk Pharma Ltd. All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript and were involved in data interpretation, drafting/critically revising the article, and shared in the final responsibility for the content of the manuscript and the decision to submit it for publication, and take full responsibility for the contents.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki 1964 and later versions.
Informed consent
Informed consent or substitute for it was obtained from all patients for being included in the study.
Funding
The study was funded by Novo Nordisk A/S. The sponsor was responsible for the trial design, supply of trial products, monitoring, data collection, statistical analyses, and preparation of the clinical study report.
Additional information
Registered at clinicaltrials.gov: NCT01880736 (NN1250-4060).
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Kadowaki, T., Jinnouchi, H., Kaku, K. et al. Insulin degludec in a simple or stepwise titration algorithm in a Japanese population of patients with type 2 diabetes: a randomized, 26-week, treat-to-target trial. Diabetol Int 8, 87–94 (2017). https://doi.org/10.1007/s13340-016-0284-9
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DOI: https://doi.org/10.1007/s13340-016-0284-9