Abstract
Objective
To evaluate the safety and effectiveness of metformin monotherapy for 52 weeks, including 24 weeks of treatment and a 28-week extension period for evaluation of long-term safety, in 37 Japanese pediatric patients with type 2 diabetes mellitus.
Research design and methods
This study design was an open-label, non-randomized, multicenter trial. The primary effectiveness endpoint was the changes from baseline to the final visit at 24 weeks in HbA1c. The secondary endpoints were the rate for achieving the treatment goal, and the changes in glycated albumin, fasting blood glucose, fasting insulin, HOMA-IR, and fasting serum lipids. Metformin was administrated at the dose of 500 mg/day up to a maximum of 2000 mg/day taken in two or three divided doses.
Results
The mean change of HbA1c at the final visit at 24 weeks for 20 metformin-naïve patients (Group A) was − 0.66 ± 0.95% and that of 17 already-on metformin patients (Group B) was − 0.98 ± 1.62%. These figures proved the effectiveness of metformin as defined before the study. Secondary effectiveness endpoints were also improved. The improvement of blood glucose, fasting insulin and serum lipid levels proved the effectiveness of metformin without increasing body weight. Adverse effects such as nausea and diarrhea were observed in 35 of the 37 subjects and drug-related adverse events were observed in 19 patients. However, these events were not serious and did not increase with long-term treatment.
Conclusions
Metformin is safe and effective for Japanese pediatric patients with T2DM.
Similar content being viewed by others
Abbreviations
- T2DM:
-
Type 2 diabetes mellitus
- T1DM:
-
Type 1 diabetes mellitus
- HbA1c:
-
Hemoglobin A1c
- FPG:
-
Fasting plasma glucose
- GA:
-
Glycated albumin
- HOMA-IR:
-
Homeostasis model assessment for insulin resistance
- FAS:
-
Full analysis set
- CI:
-
Confidence interval
- BMI-SDS:
-
Body mass index standard deviation score
- ISPAD:
-
International Society for Pediatric and Adolescent Diabetes
- GCP:
-
Good clinical practice
- SU:
-
Sulfonylurea
- α-GI:
-
α-Glucosidase inhibitor
- NGSP:
-
National Glycohemoglobin Standardization Program
- AEs:
-
Adverse events
- ADRs:
-
Adverse drug reactions
- M/F:
-
Male/female
References
Urakami T, Harada K, Kubota S, Owada M, Nitadori Y, Kitagawa T. Annual incidence and clinical characteristics of type 2 diabetes in children as detected by urine glucose screening in the Tokyo metropolitan area. Diabetes Care. 2005;28:1876–81.
Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2013;15:270–81.
Today Study Group, Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–56.
Yokoyama H, Okudaira M, Otani T, Sato A, Miura J, Takaike H, Yamada H, Muto K, Uchigata Y, Ohashi, Iwamoto Y. Higher incidence of diabetic nephropathy in type 2 than type 1 diabetes in early-onset diabetes in Japan. Kidney Int. 2000;58:302–11.
Bjorstad P, Cherney DZ, Maahs DM, Nadeau KJ. Diabetic kidney disease in adolescents with type 2 diabetes: new insights and potential therapies. Curr Diabetes Rep. 2016;16:11.
Levers-Landis CE, Walders-Abramson N, Amodei N, Drews KL, Kaplan J, Levitt LE, Lavietes S, Salestsky R, Seldman D, Yasuda P. Longitudinal correlates of health risk behaviors in children and adolescents with type 2 diabetes. J Pediatr. 2015;166:1258–64.
Copeland MC, Silverstein J, Moore KR, Prazar GE, Raymer T, Shiffman RN, Springer SC, Thaker VV, Anderson M, Spann SJ, Flinn SK. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131:364–82.
Rosenbloom AL, Silverstein JH, Amemiya S, et al. Type 2 diabetes mellitus in childhood and adolescents. ISPAD Clinical Practice Consensus Guidelines 2009 Compendium. Pediatr Diabetes. 2009;10(suppl. 12):17–32.
Zeitler P, Fu J, Tandon N, et al. Type 2 diabetes mellitus in childhood and adolescents. ISPAD Clinical Practice Consensus Guidelines 2014 Compendium. Pediatr Diabetes. 2014;15(suppl. 20):26–46.
Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effects of metformin in pediatric patients with type 2 diabetes. Diabetes Care. 2002;25:89–94.
Gottschalk M, Danne T, Vlajnic A, Cara JF. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes. Diabetes Care. 2007;30:790–4.
van der Aa MP, van de Garte E, van Mil E, Knibbe C, van der Vorst M. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial. Nutr Diabetes. 2016;6:1–10.
Matsuura N, Takeuchi M, Amemiya S, Sugihara S, Yokota Y, Tanaka T, Nakamura H, Sasaki N, Ooki Y, Urakami T, Miyamoto S, Kikuchi N, Kobayashi K, Horikawa R, Kikuchi T. Clinical trial of metformin in children and adolescents with type 2 diabetes mellitus in Japan. J Jpn Diabetes Soc. 2008;51:427–34 (Japanese).
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type 2 diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;102:491–7.
Hazel-Femandez L, Xu Y, Moretz C, Meah Y, Baltz J, Jian J, Kimball E, Bouchard J. Historical cohort analysis of treatment patterns for patients with type 2 diabetes initiating metformin monotherapy. Curr Med Res Opin. 2015;31:1703–16.
Odawara M, Kawamori R, Tajima N, Iwamoto Y, Kageyama S, Yodo Y, Ueki F, Hotta N. Long-term treatment study of global standard dose of metformin in Japanese patients with type 2 diabetes mellitus. Diabetol Int. 2017;8:286–95.
Narashimhan S, Weinstock R. Youth-onset of type 2 diabetes mellitus: lessons learned from the TODAY Study. Mayo Clin Proc. 2014;89:806–16.
Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler P, White Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatr Diabetes. 2016;17:212–21.
Acknowledgements
The first clinical trial was supported by a Grant for clinical research from the Ministry of Health, Labor and Welfare of Japan. We also thank Eriko Aoyama, Miwa Nonaka, and Chie Takami of the Research Center for Clinical Pharmacology, Academic Clinical Trial Unit of Kitasato University, for analyzing the data from each investigator in the first clinical trial. We thank the study participants, the investigators and contributors from each study site of the first and second clinical trials.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Conflicts of interest
This clinical trial was funded by Sumitomo Dainippon Pharma Co., Ltd. NM and SA are co-first authors and the chairpersons of the first and second trials, respectively, and contributed to the discussion and wrote the manuscript. SS and SA were members of the coordinating committee for the first trial and SA, SS and TU for the second trial. NM and NK are members of the safety evaluation committee for the second trial. All of these members have received honoraria from Sumitomo Dainippon Pharma. No other potential conflicts of interest relevant to this article were reported. HK and YY are employees of Sumitomo Dainippon Pharma and managed the second trial and carried out statistical analysis, respectively.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.
Informed consent
Informed consent or a substitute for it was obtained from all patients included in the study.
Ethical approval
This study was approved by the ethics committee of the Sumitomo Dainippon Pharma (approval no. D3004001, approval date: 19 April 2011) and by the ethics committee of Saitama Medical University (approval no. 918, approval date: 24 May 2011).
Additional information
Nobuo Matsuura and Shin Amemiya are co-first authors and chairpersons of the first and second trials, respectively.
About this article
Cite this article
Matsuura, N., Amemiya, S., Sugihara, S. et al. Metformin monotherapy in children and adolescents with type 2 diabetes mellitus in Japan. Diabetol Int 10, 51–57 (2019). https://doi.org/10.1007/s13340-018-0361-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13340-018-0361-3