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Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study

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Abstract

Background

Combination therapies of drugs with distinct mechanisms of action are emerging as ways to achieve strict glycemic control, thus preventing the onset and progression of diabetic complications in type 2 diabetes patients. A rapid-acting insulin secretagog, nateglinide, and a potent dipeptidyl peptidase-4 inhibitor, sitagliptin, meet such criteria.

Methods

A total of 121 patients inadequately controlled with sitagliptin monotherapy received 52-week combination therapy (nateglinide + sitagliptin). The primary endpoint was the safety of the therapy, and its efficacy was also evaluated. A meal tolerance test was performed 4 weeks before the start of combination therapy (week −4) and at week 24 and week 52 after the start of combination therapy.

Results

HbA1c levels were lower at week 52 than at week 0 [−0.42% (95% confidence interval −0.53, −0.31)]. Fasting plasma glucose levels tended to decrease from baseline (week 0) to week 52 [−4.8 mg/dl (−9.4, −0.2)]. In the meal tolerance test, postprandial plasma glucose levels and area under the curve of glucose from before to 2 h after the meal load were lower at week 24 and week 52 than at week −4. In addition, the levels of insulin and active glucagon-like peptide-1 were higher at week 52 than at week −4. Furthermore, the incidence of adverse events in combination therapy with sitagliptin was similar to those previously shown in nateglinide monotherapy.

Conclusion

Compared with sitagliptin monotherapy, the combination therapy of nateglinide plus sitagliptin was more effective in type 2 diabetes patients at improving glycemic control while showing similar safety.

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Acknowledgements

The authors thank all of the patients and investigators who took part in this study. The principal investigators in this study were: Dr. Keiichi Oikawa, Oikawa Medical Clinic; Dr. Shigeru Hirano, Hirano Medical Clinic; Dr. Masayuki Noritake, Noritake Clinic; Dr. Naoki Itabashi, Itabashi Diabetes and Dermatology Clinic; Dr. Takahiko Tokuyama, Tokuyama Clinic; Dr. Munehiro Honda, KKR Mishuku Hospital; Dr. Marohito Murakami, Hino Municipal Hospital; Drs. Yasushi Iwaita and Yoshihiro Takamiya, Koukan Clinic; Dr. Toshiki Fukui, NTT West Takamatsu Hospital; Dr. Satoshi Murao, KKR Takamatsu Hospital. Nateglinide was jointly developed by EA Pharma Co., Ltd., and Astellas Pharma Inc. This study was primarily sponsored and funded by EA Pharma Co., Ltd.

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Author notes

  1. Nobuo Kondo

    Present address: University Research Administration Center, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan

Authors and Affiliations

  1. Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan

    Takahisa Hirose

  2. Clinical Development Department, EA Pharma Co., Ltd., 2-1-1 Irifune, Chuo-ku, Tokyo, 104-0042, Japan

    Chihiro Saitoh, Ichiro Oikawa & Nobuo Kondo

Authors
  1. Takahisa Hirose
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  2. Chihiro Saitoh
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  3. Ichiro Oikawa
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  4. Nobuo Kondo
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Corresponding author

Correspondence to Takahisa Hirose.

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Conflict of interest

T. Hirose received consultancy fees from EA Pharma Co., Ltd.; lecture fees from MSD K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd., Novo Nordisk Pharma Ltd, Sanofi K.K., AstraZeneca K.K., and Daiichi Sankyo Co., Ltd.; and research funds from MSD K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd, Kissei Pharmaceutical Co., Ltd., Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., Sanofi K.K., Ono pharmaceutical Co., Ltd., AstraZeneca K.K., and Daiichi Sankyo Co., Ltd. C. Saitoh and I. Oikawa are employees of EA Pharma Co., Ltd. N. Kondo was an employee of EA Pharma Co., Ltd.

Human rights statement

This research involves human participants. The study protocol was approved by the Sakayori Clinic Institutional Review Board on July 23, 2012 (approval number is not applicable).

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent was obtained from all patients for being included in the study.

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Hirose, T., Saitoh, C., Oikawa, I. et al. Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study. Diabetol Int 9, 168–178 (2018). https://doi.org/10.1007/s13340-017-0341-z

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