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Efficacy and safety of sitagliptin add-on therapy in Japanese patients with type 2 diabetes on insulin monotherapy

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Abstract

Introduction

This multicenter, randomized study assessed the efficacy and safety of the dipeptidyl peptidase 4 inhibitor sitagliptin added to insulin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM).

Materials and methods

This study had an initial 16-week, double-blind treatment period in which 266 patients on diet/exercise and insulin monotherapy for ≥12 weeks were randomized (1:1) to sitagliptin 50 mg q.d. (N = 129; mean baseline HbA1c = 8.9 %) or placebo (N = 137; mean baseline HbA1c = 8.9 %). It was followed by a 36-week, open-label treatment period in which all patients received sitagliptin 50 mg q.d., which could have been increased to 100 mg q.d. for patients meeting predefined glycemic criteria.

Results

After 16 weeks, treatment with sitagliptin resulted in significant placebo-adjusted mean decreases from baseline in HbA1c, fasting plasma glucose, and 2-h postmeal glucose of −0.9 % (p < 0.001), −11.4 mg/dl (p = 0.007), and −39.9 mg/dl (p < 0.001), respectively. During the double-blind period, adverse experiences (AEs) were reported with similar frequency in both treatment groups and the incidence of gastrointestinal AEs was low. The incidence of hypoglycemia AEs in the sitagliptin group (20.2 %) was higher than in the placebo group (12.4 %), but the between-group difference was not statistically significant (p = 0.097). Small increases from baseline in body weight were observed with sitagliptin [sitagliptin: 0.6 kg (p < 0.001), placebo: 0.1 kg (p = 0.498)]. In the open-label period, sustained improvements in glycemic parameters were observed with sitagliptin treatment, and sitagliptin was generally well tolerated.

Conclusions

In Japanese patients with T2DM inadequately controlled on insulin monotherapy, the addition of sitagliptin provided significant improvements in glycemic parameters and was generally well tolerated.

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References

  1. Kanatsuka A, Kawai K, Hirao K. Research on antihyperglycemic therapies in patients with type 2 diabetes mellitus in Japan (I): drug therapies and actual drug use. J Japan Diabetes Soc. 2006;49:409–15.

    CAS  Google Scholar 

  2. Kanatsuka A, Kawai K, Hirao K. Research on antihyperglycemic drug therapies in patients with type 2 diabetes mellitus in Japan (II): the effectiveness on glycemic control (JDDM7). J Japan Diabetes Soc. 2006;49:919–27.

    Google Scholar 

  3. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–57.

    Article  PubMed  CAS  Google Scholar 

  4. Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91:4612–9.

    Article  PubMed  CAS  Google Scholar 

  5. Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, et al. Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006;46:876–86.

    Article  PubMed  CAS  Google Scholar 

  6. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther. 2007;81:761–7.

    Article  PubMed  CAS  Google Scholar 

  7. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008;24:489–96.

    Article  PubMed  CAS  Google Scholar 

  8. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–7.

    Article  PubMed  CAS  Google Scholar 

  9. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–43.

    Article  PubMed  CAS  Google Scholar 

  10. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–45.

    Article  PubMed  CAS  Google Scholar 

  11. Iwamoto Y, Tajima N, Kadowaki T, Nonaka K, Taniguchi T, Nishii M, Arjona Ferreira JC, Amatruda JM. Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial. Diabetes Obes Metab. 2010;12:613–22.

    Article  PubMed  CAS  Google Scholar 

  12. Iwamoto Y, Taniguchi T, Nonaka K, Okamoto T, Okuyama K, Arjona Ferreira JC, Amatruda J. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57:383–94.

    Article  PubMed  CAS  Google Scholar 

  13. Kashiwagi A, Kadowaki T, Tajima N, Nonaka K, Taniguchi T, Nishii M, Arjona Ferreira JC, Amatruda JM. Sitagliptin added to treatment with ongoing pioglitazone for up to 52 weeks improves glycemic control in Japanese patients with type 2 diabetes. J Diabetes Invest. 2011;2:381–90.

    Google Scholar 

  14. Nonaka K, Kakikawa T, Sato A, Okuyama K, Fujimoto G, Kato N, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008;79:291–8.

    Article  PubMed  CAS  Google Scholar 

  15. Odawara M, Kadowaki T, Tajima N, Nishii M, Taniguchi T, Arjona Ferreira JC. Long-term safety, tolerability, and efficacy of the dipeptidyl peptidase-4 inhibitor sitagliptin in Japanese patients with type 2 diabetes. Diabetol Int. 2011;2:94–105.

    Google Scholar 

  16. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564–71.

    Article  PubMed  CAS  Google Scholar 

  17. Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, Langdon RB, Stein PP, Alba M. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24:537–50.

    Article  PubMed  CAS  Google Scholar 

  18. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–68.

    Article  PubMed  CAS  Google Scholar 

  19. Tajima N, Kadowaki T, Odawara M, Nishii M, Taniguchi T, Arjona Ferreira JC. Addition of sitagliptin to ongoing glimepiride therapy in Japanese patients with type 2 diabetes over 52 weeks leads to improved glycemic control. Diabetol Int. 2011;2:32–44.

    Article  Google Scholar 

  20. Vilsboll T, Rosenstock J, Yki-Jarvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167–77.

    Article  PubMed  CAS  Google Scholar 

  21. Chen KW, Boyko EJ, Bergstrom RW, Leonetti DL, Newell-Morris L, Wahl PW, Fujimoto WY. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially nondiabetic Japanese-American men. Diabetes Care. 1995;18:747–53.

    Article  PubMed  CAS  Google Scholar 

  22. Kim DJ, Lee MS, Kim KW, Lee MK. Insulin secretory dysfunction and insulin resistance in the pathogenesis of Korean type 2 diabetes mellitus. Metabolism. 2001;50:590–3.

    Article  PubMed  CAS  Google Scholar 

  23. Matsumoto K, Miyake S, Yano M, Ueki Y, Yamaguchi Y, Akazawa S, Tominaga Y. Glucose tolerance, insulin secretion, and insulin sensitivity in nonobese and obese Japanese subjects. Diabetes Care. 1997;20:1562–8.

    Article  PubMed  CAS  Google Scholar 

  24. Suzuki H, Fukushima M, Usami M, Ikeda M, Taniguchi A, Nakai Y, et al. Factors responsible for development from normal glucose tolerance to isolated postchallenge hyperglycemia. Diabetes Care. 2003;26:1211–5.

    Article  PubMed  CAS  Google Scholar 

  25. Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, Tominaga M, Oikawa S, Noda M, Kawamura T, Sanke T, Namba M, Hashiramoto M, Sasahara T, Nishio Y, Kuwa K, Ueki K, Takei I, Umemoto M, Murakami M, Yamakado M, Yatomi Y, Ohashi H; Committee on the Standardization of Diabetes Mellitus-Related Laboratory Testing of Japan Diabetes Society. International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. J Diabetes Invest. 2012;3:39–40.

    Google Scholar 

  26. Liang K, Zeger S. Longitudinal data analysis of continuous and discrete responses for pre-post designs. Sankhya Ind J Stat. 2000;62:134–48.

    Google Scholar 

  27. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.

    Article  PubMed  CAS  Google Scholar 

  28. Pi-Sunyer FX. The effects of pharmacologic agents for type 2 diabetes mellitus on body weight. Postgrad Med. 2008;120:5–17.

    Article  PubMed  Google Scholar 

  29. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 2002;287:360–72.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Alan Meehan and Kathleen Newcomb (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) for their assistance in writing and preparing this paper for submission and publication.

Conflict of interest

Authors Kadowaki, Tajima, and Odawara were advisory board members for this study. Authors Minamide, Kawashima, and Yanagida are employees of ONO Pharmaceutical Co., Ltd., Japan, and authors Okamoto and Arjona Ferreira are employees of MSD K.K. or Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. This study was sponsored by MSD K.K., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, the manufacturer of sitagliptin, and by Ono Pharmaceutical Co., Ltd., Japan.

Author information

Authors and Affiliations

  1. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Takashi Kadowaki

  2. Jikei University School of Medicine, Tokyo, Japan

    Naoko Tajima

  3. The Third Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan

    Masato Odawara

  4. ONO Pharmaceutical Co., Ltd., 8-2 Kyutaromachi 1-chome Chuo-ku, Osaka, 541-8564, Japan

    Toshiomi Minamide, Masaru Kawashima & Daisuke Yanagida

  5. MSD K.K., Tokyo, Japan

    Taro Okamoto

  6. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA

    Juan Camilo Arjona Ferreira

Authors
  1. Takashi Kadowaki
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  2. Naoko Tajima
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  3. Masato Odawara
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  4. Toshiomi Minamide
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  5. Masaru Kawashima
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  6. Daisuke Yanagida
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  7. Taro Okamoto
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  8. Juan Camilo Arjona Ferreira
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Corresponding author

Correspondence to Toshiomi Minamide.

Additional information

This study is registered in ClinicalTrials.gov: NCT00854035, “A Phase III, Randomized, Placebo-Controlled, Double-Blind Clinical Trial and Subsequent Open-Label, Extension Clinical Trial to Study the Efficacy and Safety of Addition of MK-0431/ONO-5435 in Japanese Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Diet/Exercise Therapy and Insulin Monotherapy”, http://clinicaltrials.gov/ct2/show/NCT00854035.

Appendix: MK-0431/ONO-5435-15 P106 Primary Investigator list:

Appendix: MK-0431/ONO-5435-15 P106 Primary Investigator list:

Yoshio Kurihara (Kurihara Diabetic Care Clinic), Takuma Narita(Akita University Hospital), Kenji Yaginuma (Social Insurance Nihonmatsu Hospital), Tadasu Kasahara (Johsai Hospital), Yoshihiko Suzuki (HDC Atlas Clinic), Yukiko Onishi (The Institute For Adult Diseases, Asahi Life Foundation), Tadashi Okabe (Okabe Clinic), Keiko Tsunoda (Ekimaetsunoda Clinic), Masaaki Miyamoto (Nippon Medical School Hospital), Mako Tougo (Senpo Tokyo Takanawa Hospital), Tomio Inoue (Ageo Central General Hospital), Manabu Narimiya (Nishisaitamachuo National Hospital), Koichi Shinohara (Yashio Central General Hospital), Sane Ishikawa (Saitama Medical Center Jichi Medical University), Nobuichi Kuribayashi (Misaki Naika Clinic), Shuichi Watanabe (Kobari General Clinic), Yoh Miyashita (Toho University Sakura Medical Center), Makoto Ujihara (National Hospital Organization Yokohama Medical Center), Ikuro Matsuba (Matsuba Clinic), Takashi Iizuka (Asahi Internal Medicine Department Clinic), Junro Fuse (Kosugi Central Clinic), Mizuki Kaneshiro (Tsuruma Kaneshiro Diabetes Clinic), Fuyuki Minagawa (Minagawa Medical Clinic), Yoshiya Katsura (Tokyo Medical University Ibaraki Medical Center), Tadashi Iitsuka (Ibaraki Seinan Medical Center Hospital), Atsushi Ueda (Namegata District General Hospital), Hideo Takahashi (Minamiakatsuka Clinic), Shuichi Fukuda (Wakakusa Clinic), Katsunori Suzuki (Saiseikai Niigata Daini Hospital), Yoshiko Funase (Aizawa Hospital), Michio Nakagawa (Matsumoto Nakagawa Hospital), Mitsuo Imura (Yaizu City Hospital), Akira Yamauchi (Medical Care Law Person Corporation Rikeikai Suruga Clinic), Shigeki Endo (Endo Clinic), Hideki Okamoto (Meitetsu Hospital), Genichi Watanabe (Watanabe Clinic), Takanobu Toriyama (Nagoya Kyoritsu Clinic), Nobuo Takahashi (Takahashi Family Clinic), Makoto Hayashi (Matsunami General Hospital), Kazuyoshi Nishino (Jujo Rehabilitation Hospital), Shizuo Kajiyama (Kajiyama Clinic), Takaaki Yoshimasa (Yoshimasa Diabetes & Endocrine Clinic), Masako Deguchi (Japanese Red Cross Kyoto Daini Hospital), Kazuyuki Tobe (Toyama University Hospital), Rika Usuda (Toyama Prefectural Central Hospital), Yasuro Kumeda (Minamiosaka Hospital, Keigaku-Kai, Social Medical Corporation), Toshihiko Shiraiwa (Shiraiwa Medical Clinic), Shizuka Kaneko (Takatsuki Red Cross Hospital), Masanori Emoto (Osaka City University Hospital), Akira Ichibangase (Komatu Hospital, Kyojin-Kai Medical Corporation), Akihisa Imagawa (Osaka University), Takashi Ishihara (Kobe City Medical Center General Hospital), Kenta Hara (Kobe University Hospital), Jun-Ichiro Miyagawa (Hyogo College Of Medicine), Masahiro Emoto (Yamaguchi University Hospital), Masahiro Matsumoto (Kitakyushu Municipal Medical Center), Kiyohide Nunoi (St.Mary’s Hospital), Daisuke Goto (Kyushu Central Hospital Of The Mutual Aid Association Of Public School Teachers), Makoto Kunisaki (Kunisaki Makoto Clinic), Kentaro Yamada (Kurume University Hospital).

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Kadowaki, T., Tajima, N., Odawara, M. et al. Efficacy and safety of sitagliptin add-on therapy in Japanese patients with type 2 diabetes on insulin monotherapy. Diabetol Int 4, 160–172 (2013). https://doi.org/10.1007/s13340-013-0109-z

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  • DOI: https://doi.org/10.1007/s13340-013-0109-z

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