Advertisement

Diabetology International

, Volume 10, Issue 1, pp 51–57 | Cite as

Metformin monotherapy in children and adolescents with type 2 diabetes mellitus in Japan

  • Nobuo MatsuuraEmail author
  • Shin Amemiya
  • Shigetaka Sugihara
  • Tatsuhiko Urakami
  • Nobuyuki Kikuchi
  • Hiroshi Kato
  • Yasuhide Yodo
  • on behalf of the Study Group of the Pediatric Clinical Trial of Metformin in Japan
Original Article
  • 71 Downloads

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.

Keywords

Metformin Metformin monotherapy Childhood and adolescent T2DM Safety Adverse effects 

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

Notes

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.

Compliance and ethical standards

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).

References

  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    Reinehr T. Type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2013;15:270–81.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.Google Scholar
  13. 13.
    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).Google Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 17.
    Narashimhan S, Weinstock R. Youth-onset of type 2 diabetes mellitus: lessons learned from the TODAY Study. Mayo Clin Proc. 2014;89:806–16.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar

Copyright information

© The Japan Diabetes Society 2018

Authors and Affiliations

  • Nobuo Matsuura
    • 1
    • 7
    Email author
  • Shin Amemiya
    • 2
  • Shigetaka Sugihara
    • 3
  • Tatsuhiko Urakami
    • 4
  • Nobuyuki Kikuchi
    • 5
  • Hiroshi Kato
    • 6
  • Yasuhide Yodo
    • 6
  • on behalf of the Study Group of the Pediatric Clinical Trial of Metformin in Japan
  1. 1.Department of Early Childhood EducationSeitoku UniversityMatsudoJapan
  2. 2.Department of PediatricsSaitama Medical UniversitySaitamaJapan
  3. 3.Department of PediatricsTokyo Women’s Medical University Medical Center EastTokyoJapan
  4. 4.Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
  5. 5.Department of PediatricsYokohama City Minato Red Cross HospitalYokohamaJapan
  6. 6.Sumitomo Dainippon Pharma Co., Ltd.TokyoJapan
  7. 7.Pediatric ClinicBibai City HospitalBibaiJapan

Personalised recommendations