Diabetology International

, Volume 9, Issue 3, pp 158–167 | Cite as

Factors involved in decreasing the therapeutic effect of sitagliptin: a subanalysis of the JAMP study

  • Hideo NunomeEmail author
  • Hiroshi Sakura
  • Naotake Hashimoto
  • Kazuo Sasamoto
  • Hiroshi Ohashi
  • Sumiko Hasumi
  • Noriko Ujihara
  • Tadasu Kasahara
  • Osamu Tomonaga
  • Masashi Honda
  • Yasuhiko Iwamoto
  • for the JAMP Study Investigators
Original Article



As a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes (JAMP study), we examined factors that decreased blood glucose control effect of sitagliptin after 3 months and patients requiring an addition or increase of diabetes treatment.


We selected patients in whom glycated hemoglobin (HbA1c) levels decreased by month 3 after initiation of sitagliptin treatment and conducted two analyses: (1) in patients who did not change drugs until month 12, we compared changes in HbA1c levels between concomitant drugs and examined factors that decreased blood glucose control effect of sitagliptin; (2) compared changes in HbA1c levels and backgrounds between patients who did and did not require an addition to or increased dose of the antidiabetic agent.


Four hundred and ninety-eight patients were chosen. In 369 patients without drug change until month 12, changes in HbA1c levels during months 3–12 were not significantly different among concomitant drugs; factors causing rebound HbA1c were smoking and weight gain. Patient characteristics were compared between those who did and did not require an additional drug or a dose increase (n = 114) (n = 384). Drug changes were associated with longer disease duration, younger age, higher rate of smoking, and higher degree of insulin resistance but not with concomitantly administered drugs.


Smoking and weight gain were factors that decreased the effect of sitagliptin on reducing blood glucose levels. Differences in concomitant drugs did not affect sitagliptin’s effects on glycemic control. A dose increase or the addition of the antidiabetic drug was not associated with concomitant drugs.


DPP4-inhibitor Type 2 diabetes mellitus Sitagliptin HbA1c rebound factor Decreasing the therapeutic effect 



We express our sincere gratitude to Mr. Shogo Shishikura (MSD K.K.,) (Teikyo University Graduate School of Public Health, MPH) for scientific advice, including references, and for revising the manuscript. We also thank Nouvelle Place Inc. for conducting data analyses.

JAMP Study Investigators: Akiko Sato (Maruyama Internal Medicine Clinic); Akira Miyashita (Miyashita Surgery Clinic); Asako Kokubo (Kokubo Clinic); Atsuro Tsuchiya (Tsuchiya Clinic); Dai Hirohara (Hanazono Clinic); Daiji Kogure (Kogure Clinic); Daijo Kasahara (Kasahara Clinic); Hideki Tanaka (Internal Medicine, Seiwa Clinic); Hideki Tanaka (Internal Medicine, Nishiarai Hospital); Hideo Tezuka (Tezuka Clinic); Hiroyuki Kuroki (Internal Medicine, Johsai Hospital); Jun Ogino (Department of Diabetes, Endocrine and Metabolic Diseases, Tokyo Women’s Medical University Yachiyo Medical Center); Kanu Kin (Internal Medicine, Nishiarai Lifestyle-related diseases Clinic); Kanu Kin (Internal Medicine, Nishiarai Hospital); Kazuko Muto (Tokyo Women’s Medical University); Kazuo Suzuki (Kenkokan Suzuki Clinic of Internal Medicine); Keiko Iseki (Iseki Clinic); Keita Watanabe (Watanabe Clinic); Kenshi Higami (Higami Hospital); Kenzo Matsumura (Matsumura Gastroenterological Clinic); Kiyotaka Nakajima (Ebisu Clinic); Koki Shin (Shin Clinic); Kuniya Koizumi (Kuniya Clinic); Maki Saneshige (Mugishima Medical Clinic); Makio Sekine (Sekine Clinic); Makoto Yaida (Urban Heights Clinic); Mari Kiuchi (Physician, Kanauchi Medical Clinic); Mari Mugishima (Mugishima Medical Clinic); Mari Osawa (Department of Diabetes Mellitus, Institute of Geriatrics, Tokyo Women’s Medical University); Masae Banno (Banno Medical Clinic); Masahiro Yamamoto (Internal Medicine 1, Shimane University Faculty of Medicine); Masatake Hiratsuka (Higashishinagawa Clinic); Masumi Hosoya (Yasui Clinic); Michika Atsuta (Internal Medicine, Nishiarai Lifestyle-related diseases Clinic); Mitsutoshi Kato (Kato Clinic of Internal Medicine); Miwa Morita (Internal Medicine 1, Shimane University Faculty of Medicine); Munehiro Miyamae (Johsai Hospital); Mutsumi Iijima (Abe Hospital); Naomi Okuyama (Shinjuku Mitsui Building Clinic); Nobuo Hisano (Mejiro Medical Clinic); Norihiro Tsuchiya (Omotesando Naika Ganka); Rie Wada (Kanauchi Medical Clinic); Rie Wada (Nerimasakuradai Clinic); Ryuji Momose (Momo Medical Clinic); Sachiko Otake (Tokyo Women’s Medical University); Satoko Maruyama (Shinjuku Mitsui Building Clinic); Satoru Takada (Internal Medicine, Social welfare corporation Shineikai Takinogawa Hospital); Shigeki Dan (Ube Internal Medicine and Pediatrics Hospital); Shigeki Nishizawa (Nishizawa Medical Clinic); Shigeo Yamashita (Department of Diabetes and Endocrinology, JR Tokyo General Hospital); Shingo Saneshige (Internal Medicine, Kamiochiai Shin Clinic); Shinichi Teno (Teno Clinic); Shinji Tsuruta (Diabetic Medicine, Itabashi Chuo Medical Center); Shinobu Kumakura (Kumakura Medical Clinic); Sumiko Kijima (Abe Hospital); Takashi Kondo (Kondo Clinic); Takeo Onishi (Internal Medicine, Onishi Clinic); Taku Kudo (Internal Medicine, Social welfare corporation Shineikai Takinogawa Hospital); Tatsushi Sugiura (Internal Medicine, Seiwa Clinic); Toshihiko Ishiguro (Kaname Clinic); Yasue Suzuki (Suzuki Medical Clinic); Yasuhiro Tomita (Nakanobu Clinic); Yasuko Takano (Department of Diabetes, Shiseikai Daini Hospital); Yoshihisa Akimoto (Akimoto Yoshi Medical Clinic); Yoshiko Odanaka (Ito Internal Medicine Pediatrics Clinic); Yoshimasa Tasaka (Tokyo Women’s Medical University); Yoshitaka Aiso (Internal Medicine, Diabetes, Aiso Clinic); Yukiko Inoue (Inoue Medical Clinic); Yukinobu Kobayashi (Kobayashi Clinic).


This study was funded by Japan Diabetes Foundation.

Compliance with ethical standards

Conflict of interest

Hiroshi Sakura received honoraria from Mitsubishi Tanabe Pharma Corporation and research grant from Ono Pharmaceutical Co., Ltd. Other authors declare that they have no conflict of interest.

Ethics approval and consent to participate

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. The ethics committee at the Tokyo Women’s Medical University approved the study (Approval Number: 2064) on 11 January 2011. Informed consent or substitute was obtained from all patients included in the study.

Supplementary material

13340_2017_340_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 kb)


  1. 1.
    Iwamoto Y, Tajima N, Kadowaki T, et al. 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.CrossRefPubMedGoogle Scholar
  2. 2.
    Nonaka K, Kakikawa T, Sato A, Okuyama K, Fujimoto G, Kato N, Suzuki H, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008;79(2):291–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Ku EJ, Jung KY, Kim YJ, Kim KM, Moon JH, Choi SH, Cho YM, Park KS, Jang HC, Lim S, Ahrén B. Four-year durability of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes in clinical practice; COSMIC study. PLoS ONE. 2015. Scholar
  5. 5.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G, ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Tajiri Y, Kato N, Kudo T, Hasuo R, Yoshinobu S, Kono S, Nakayama H, Yamada K. Long-term efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes. J Jpn Diabetes Soc. 2014;57(7):513–9.Google Scholar
  7. 7.
    Kanamori A, Matsuba I. Factors associated with reduced efficacy of sitagliptin therapy: analysis of 93 patients with type 2 diabetes treated for 1.5 years or longer. J Clin Med Res. 2013;5(3):217–21.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Tajiri Y, Tsuruta M, Ohki T, Kato T, Sasaki Y, Tanaka K, Kono S, Tojikubo M, Yamada K. Long-term efficacy of sitagliptin for the treatment of type 2 diabetic patients in Japan. Endocr J. 2012;59:197–204.CrossRefPubMedGoogle Scholar
  9. 9.
    Kubota A, Yabe D, Kanamori A, Kuroe A, Takahashi N, Saito T, Matsuba I, Nabe K, Kurose T, Seino Y. Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea. J Diabetes Investig. 2014;5:445–8.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sakura H, Hashimoto N, Sasamoto K, Ohashi H, Hasumi S, Ujihara N, Kasahara T, Tomonaga O, Nunome H, Honda M, Iwamoto Y, JAMP Study Investigators. Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study. BMC Endocr Disord. 2016;16(1):70.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kubota A, Maeda H, Kanamori A, et al. Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients. J Diabetes Investig. 2012;3(6):503–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Maeda H, Kubota A, Tanaka Y, et al. The safety, efficacy and predictors for HbA1c reduction of sitagliptin in the treatment of Japanese type 2 diabetes. Diabetes Res Clin Pract. 2012;95(1):e20–2.CrossRefPubMedGoogle Scholar
  13. 13.
    Seino Y, Nanjo K, Tajima N, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Jpn Diabetes Soc. 2012;55:485–504. Scholar
  14. 14.
    Murthy SN, Dinoso VP Jr, Clearfield HR, Chey WY. Simultaneous measurement of basal pancreatic, gastric acid secretion, plasma gastrin, and secretin during smoking. Gastroenterology. 1977;73:758–61.PubMedGoogle Scholar
  15. 15.
    Taminato T, Seino Y, Goto Y, Inoue Y, Matsukura S, Imura H. Cigarettes smoking inhibits arginine-induced insulin release in man. Horm Metab Res. 1978;10:78–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Aso Y, Ozeki N, Terasawa T, Naruse R, Hara K, Suetsugu M, Takebayashi K, Shibazaki M, Haruki K, Morita K, Inukai T. Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea. Transl Res. 2012;159(1):25–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Eckardt K, Kaufman JM, Ryden M, Muller S, Hanisch FG, Ruige J, Arner P, Sell H, Eckel J. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes. 2011;60:1917–25.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gül OO, Kıyıcı S, Ersoy C, Cander S, Yorulmaz H, Gül CB, Unal OK, Sarandol E, Kırhan E, Sigirli D, Ertürk E, Tuncel E, Imamoğlu S. Effect of sitagliptin monotherapy on serum total ghrelin levels in patients with type 2 diabetes. Diabetes Res Clin Pract. 2011;94(2):212–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang CL, Hsu CH, Huang KC, et al. Preprandial single oral dose of sitagliptin does not affect circulating ghrelin and gastrin levels in normal subjects. Pharmacology. 2010;85:131–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.CrossRefPubMedGoogle Scholar
  21. 21.
    Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia. 2002;45:85–96.CrossRefPubMedGoogle Scholar
  22. 22.
    UK Prospective Diabetes Study Group. UK prospective diabetes 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249–58.CrossRefGoogle Scholar
  23. 23.
    Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, Feng Y, Zhu L, Li C, Howard AD, Moller DE, Thornberry NA, Zhang BB. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic β-cell mass and function in a rodent model of type 2 diabetes. Diabetes. 2006;55:1695–704.CrossRefPubMedGoogle Scholar
  24. 24.
    Moritoh Y, Takeuchi K, Asakawa T, Kataoka O, Odaka H. Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. Eur J Pharmacol. 2008;588:325–32.CrossRefPubMedGoogle Scholar

Copyright information

© The Japan Diabetes Society 2017

Authors and Affiliations

  • Hideo Nunome
    • 1
    Email author
  • Hiroshi Sakura
    • 2
  • Naotake Hashimoto
    • 3
  • Kazuo Sasamoto
    • 4
  • Hiroshi Ohashi
    • 5
  • Sumiko Hasumi
    • 6
  • Noriko Ujihara
    • 7
  • Tadasu Kasahara
    • 8
  • Osamu Tomonaga
    • 9
  • Masashi Honda
    • 10
  • Yasuhiko Iwamoto
    • 11
  • for the JAMP Study Investigators
  1. 1.Diabetes CenterEdogawa HospitalTokyoJapan
  2. 2.Department of MedicineTokyo Women’s Medical University, Medical Center EastTokyoJapan
  3. 3.Department of Diabetes, Endocrine and Metabolic DiseasesTokyo Women’s Medical University Yachiyo Medical CenterChibaJapan
  4. 4.Internal MedicineSuzuki ClinicTokyoJapan
  5. 5.Internal MedicineOyama East ClinicTochigiJapan
  6. 6.Internal MedicineNishiyamado-Keiwa HospitalIbarakiJapan
  7. 7.Department of Medicine, Diabetes Center, Institute of GeriatricsTokyo Women’s Medical UniversityTokyoJapan
  8. 8.Josai HospitalTokyoJapan
  9. 9.Diabetes and Lifestyle CenterTomonaga ClinicTokyoJapan
  10. 10.Nishikawa ClinicTokyoJapan
  11. 11.Tokyo Women’s Medical University/The Institute for Adult Diseases, Asahi Life FoundationTokyoJapan

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