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Effect of antihyperglycemic drug monotherapy to prevent the progression of mild hyperglycemia in early type 2 diabetic patients: the Japan Early Diabetes Intervention Study (JEDIS)

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Abstract

To effectively prevent the worsening of hyperglycemia in type 2 diabetes mellitus, it is of interest to see the clinical efficacy of early introduction of pharmacotherapy in addition to lifestyle intervention which is not always easy to continue throughout life. This is a randomized unblinded comparative clinical study on suppressive effects of lifestyle intervention alone and additional monotherapies for mild hyperglycemia at an early stage of treatment-naïve type 2 diabetic patients, whose fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) are less than 140 mg/dl and 7.4%, respectively. The control group (group N = arm N) received conventional lifestyle intervention assisted by routine facilities, while the pharmacological intervention group (group D composed of 4 arms) was additionally treated by monotherapy with one of four kinds of oral antihyperglycemic agents i.e., sulfonylurea (SU), α-glucosidase inhibitor, biguanide and dipeptidyl peptidase-4 inhibitor. The participants were scheduled to follow up for 3 years to maintain glycemic control below primary endpoint which was defined as the first occurrence of FPG ≥140 mg/dl and HbA1c ≥7.4% simultaneously even by increasing doses of oral drug in group D, if necessary. The outcomes of occurrences of primary endpoint were not different between group N and group D composed of 4 arms during 3 years by Kaplan–Meyer plots (p = 0.405). On the other hand, ΔFPG (Δ: incremental change from baseline) and ΔHbA1c in group D significantly decreased when compared to those of group N during 3 years (p < 0.05 and p < 0.01 respectively). Significant reductions of ΔBMI were seen similarly in both groups throughout the study (p < 0.05), but did not differ between two groups. Among these 5 arms, significant decreases of ΔHbA1c were observed in three monotherapy arms of group D compared to arm N for 3 years (p < 0.05 or p < 0.01), except for arm SU in which ΔBMI and ΔHbA1c tended to increase at the latter half of the study. The final achievement rates of target HbA1c less than 7.4, 7.0 and 6.5% in all the participants tended to be higher in group D than in group N (p < 0.047 for 7.4%, but not significant for others). In conclusion, the early introduction of pharmacological monotherapy in addition to lifestyle intervention seem to suppress mild hyperglycemia with small doses of antihyperglycemic agents for 3 years, except for the use of SU drug. Although a larger scale of trial will be necessary to conclude, the early treatment with suitable monotherapy could be effective to bring and keep “safe level of glycemia”.

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Acknowledgement

This study was supported by the grant from Japan Diabetes Foundation. We want to express sincere thanks to all the members joined in this study, including medical doctors and staffs in practice, listed in Investigators’ list as shown below. Especially, the late Professor Emeritus of Tokyo University Kinori Kosaka who strongly pushed to start and progress this study is greatly appreciated. We also want to express deep thanks to Professors Emeritus Hideto Sakai (Tokai University) and Kazuyuki Shimada (Jichi Medical University) and Professor Hidetoshi Yamashita (Yamagata University) who steadily supported us in the study as medical specialist in the field of nephrology, cardiology and ophthalmology, respectively. Professor Mitsuhiko Noda (Saitama Medical University) and Professor Emeritus of Washington University Wilfred Y Fujimoto are also appreciated for their valuable advice and suggestions when we prepare the protocol of this study JEDIS.

Investigators’ list

Chieko Imamoto(Imamoto Internal Medicine Clinic), Kenichi Suzuki(Suzuki kenichi Internal Medicine Clinic), Toshihide Oizumi(San-yudo Hospital), Yoshihiro Emura(Emura Gastroenterologic AL Clinic), Koichi Kawai(Kawai Clinic), Toru Hiyoshi(Japanese Red Cross Medical Center), Sigehisa Inokuma(Inokuma Clinic), Masafumi Matsuda(Saitama Medical University Medical Center), Hiroshi Katahira(Katahira Internal Medicine Clinic), Shun Ishibashi(Jichi Medical University Hospital), Hiroshi Suga(Suga Clinic), Kazuko Nomura(Nomura Iin), Yoshiko Kumagaya(Ozawa Clinic), Shoji Kawazu(Kokoro-to-Karada-no-GenkiPlaza), Takeshi Momotsu(Sado General Hospital), Eriko Sasaki(Komorokogen Hospital), Harumi Iwasaki(Haru Clinic), Shigeo Yamashita(JR Tokyo General Hospital), Yasuaki Ishimaru(Yasuyo Ishimaru Memorial Kumagaya Diabetes Clinic), Yoshiko Maruno(Maruno Clinic), Koji Oida(Fukui Chuoh Clinic), Yukihiro Bando(Fukui-ken Saiseikai Hospital), Mitsuyasu Itho(Fujita Health University Hospital), Kayoko Ryomoto(Osaka Rosai Hospital), Takako Wada(Toyo-Kohan-Clinic), Yasuhiko Hara(Ehime Prefectural Imabari Hospital), Satoko Chosa(Wakamatsu Memorial Hospital), Nobuyuki Abe(Abe Diabetes Clinic), Eiyu Katsuren(Katsuren Medical Clinic), Yoshiko Nishida(Japanese Red Cross Medical Center Kumamoto), Masashi Taguchi(University of Occupational and Enviromental Health, Japan).

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Authors and Affiliations

  1. The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi, Bakuro-cho, Chuo-ku, Tokyo, 103-0002, Japan

    Shoji Kawazu & Yasuhiko Iwamoto

  2. Jichi Medical University, Tochigi, Japan

    Yasunori Kanazawa & Takeshi Kuzuya

  3. Saitama Medical University, Saitama, Japan

    Shigehiro Katayama

  4. Department of Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan

    Hideki Origasa

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  1. Shoji Kawazu
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  2. Yasunori Kanazawa
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  3. Yasuhiko Iwamoto
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  4. Shigehiro Katayama
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  5. Hideki Origasa
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  6. Takeshi Kuzuya
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The JEDIS (Japan Early Diabetes Intervention Study) Research Group

Corresponding author

Correspondence to Shoji Kawazu.

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Conflict of interest statements

All the authors declare that they have no conflict of interest.

Human rights statement and informed concent

All procedures followed were in accordance with the ethical standards of the responsible committee on institutional human experimentation and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients for being included in the study.

Additional information

Members of the JEDIS (Japan Early Diabetes Intervention Study) Research Group are listed in “Acknowledgement”.

In 2012, HbA1c values which were standardized by JDS (Japan Diabetes Society) were officially revised to use NGSP (National Glycohemoglobin Standardization Program) values, the latter being approximately 0.4% higher than old JDS values. So, HbA1c values which appear in this report are all expressed as NGSP values [1, 2].

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Kawazu, S., Kanazawa, Y., Iwamoto, Y. et al. Effect of antihyperglycemic drug monotherapy to prevent the progression of mild hyperglycemia in early type 2 diabetic patients: the Japan Early Diabetes Intervention Study (JEDIS). Diabetol Int 8, 350–365 (2017). https://doi.org/10.1007/s13340-017-0319-x

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