JDM  Vol.4 No.3 , August 2014
Clinical Characteristics of Japanese Type 2 Diabetic Patients Responsive to Sitagliptin

Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabetic patients, inadequately controlled (HbA1c ≥ 6.5%) with oral hypoglycemic agents (OHA) other than DPP-4 inhibitors or with diet and exercise only, were enrolled. We added 50mg of sitagliptin to the therapeutic regimens of 410 patients including 68 OHA naive patients, while the other 591 patients were switched from a single OHA to 50 mg of sitagliptin. After 6 months, glycemic control was significantly improved due to both reduced insulin resistance, as demonstrated by a significant HOMA-R reduction, and recovery of pancreatic β cell function, as assessed by HOMA-β and the proinsulin/insulin (PI/I) ratio. In the bivariable analysis, a good response, defined as an HbA1c reduction during the 6 months of at least 0.9%, was associated with high HbA1c and PI/I at baseline and combination treatments with sulfonylurea, biguanide and α-glucosidase inhibitors, but not with obesity. On the other hand, in the multivariable regression analysis, only high baseline HbA1c and combination treatment with anα-glucosidase inhibitor were significantly associated with a good response to sitagliptin. In patients with type 2 diabetes, the addition of sitagliptin or switching from another OHA to this agent achieved an HbA1c reduction without overloading β cells. In particular, we suggest that a good response to sitagliptin can be expected when this agent is combined with an α-glucosidase inhibitor (UMIN No. #000014157).

Cite this paper: Inukai, K. , Hirata, T. , Sumita, T. , Watanabe, M. , Ikegami, Y. , Ito, D. , Kurihara, S. , Yasukawa, N. , Morimoto, J. , Takata, N. , Kanazawa, K. , Neda, T. , Sumitani, Y. , Inoue, K. , Noguchi, Y. , Hosaka, T. , Ishida, H. and Katayama, S. (2014) Clinical Characteristics of Japanese Type 2 Diabetic Patients Responsive to Sitagliptin. Journal of Diabetes Mellitus, 4, 172-178. doi: 10.4236/jdm.2014.43025.

[1]   Tarrani, A.A. and Bailey, C.J. (2011) Management of Type 2 Diabetes: New and Future Developments in Treatment. Lancet, 378, 182-197.

[2]   Arai, K., Matoba, K., Hirao, K., Matsuba, I., Takai, M., Takeda, H., Kanamori, A., Yamauchi, M., Mori, H. and Terauchi, Y. (2010) Present Status of Sulfonylurea Treatment for Type 2 Diabetes in Japan: Second Report of a Cross-Sectional Survey of 15,652 Patients. Endocrine Journal, 57, 499-507.

[3]   Onuma, H., Inukai, K., Watanabe, M., Sumitani, Y., Hosaka, T. and Ishida, H. (2014) Effects of Long-Term Monotherapy with Glimepiride vs Glibenclamide on Glycemic Control and Macrovascular Events in Japanese Type 2 Diabetic Patients. Journal of Diabetes Mellitus, 4, 33-37.

[4]   Schweizer, A., Dejager, S., Foley, J.E. and Kothny, W. (2011) Assessing the General Safety and Tolerability of Vildagliptin: Value of Pooled Analyses from a Large Safety Database versus Evaluation of Individual Studies. Vascular Health and Risk Management, 7, 49-57.

[5]   Pratley, R.E. (2009) Alogliptin: A New, Highly Selective Dipeptidyl Peptidase-4 Inhibitor for the Treatment of Type 2 Diabetes. Expert Opinion on Pharmacotherapy, 10, 503-512.

[6]   Araki, E., Kawamori, R., Inagaki, N., Watada, H., Hayashi, N., Horie, Y., Sarashina, A., Thiemann, S., Eynatten, M., Dugi, K. and Woerle, H.J. (2011) Long-Term Safety of Linagliptin Monotherapy in Japanese Patients with Type 2 Diabetes. Diabetes, Obesity and Metabolism, 13, 542-550.

[7]   Eto, T., Inoue, S. and Kadowaki, T. (2012) Effects of Once-Daily Teneligliptin on 24-h Blood Glucose Control and Safety in Japanese Patients with Type 2 Diabetes Mellitus: A 4-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes, Obesity and Metabolism, 14, 1040-1046.

[8]   Ervinna, N., Mita, T., Yasunari, E., Azuma, K., Tanaka, R., Fujimura, S., Sukmawati, D., Nomiyama, T., Kanazawa, A., Kawamori, R., Fujitani, Y. and Watada, H. (2013) Anagliptin, a DPP-4 Inhibitor, Suppresses Proliferation of Vascular Smooth Muscles and Monocyte Inflammatory Reaction and Attenuates Atherosclerosis in Male Apo E-Deficient Mice. Endocrinology, 154, 1260-1270.

[9]   Gerrald, K.R., Van Scoyoc, E., Wines, R.C., Runge, T. and Jonas, D.E. (2012) Saxagliptin and Sitagliptin in Adult Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Diabetes, Obesity and Metabolism, 14, 481-492.

[10]   Williams-Herman, D., Engel, S.S., Round, E., Johnson, J., Golm, G.T., Guo, H., Musser, B.J., Davies, M.J., Kaufman, K.D. and Goldstein, B.J. (2010) Safety and Tolerability of Sitagliptin in Clinical Studies: A Pooled Analysis of Data from 10,246 Patients with Type 2 Diabetes. BMC Endocrine Disorders, 10, 7.

[11]   Iwamoto, Y., Taniguchi, T., Nonaka, K., Okamoto, T., Okuyama, K., Arjona Ferreira, J.C. and Amatruda, J. (2010) Dose-Ranging Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus. Endocrine Journal, 57, 383-394.

[12]   Park, H., Park, C., Kim, Y. and Rascati, K.L. (2012) Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes: Meta-Analysis. Annals of Pharmacotherapy, 46, 1453-1469.

[13]   Lee, S., Yabe, D., Nohtomi, K., Takada, M., Morita, R., Seino, Y. and Hirano, T. (2010) Intact Glucagon-Like Peptide-1 Levels Are Not Decreased in Japanese Patients with Type 2 Diabetes. Endocrine Journal, 57, 119-126.

[14]   Lamers, D., Famulla, S., Wronkowitz, N., Hartwig, S., Lehr, S., Ouwens, D.M., Eckardt, K., Kaufman, J.M., Ryden, M., Müller, S., Hanisch, F.G., Ruige, J., Arner, P., Sell, H. and Eckel, J. (2011) Dipeptidyl Peptidase 4 Is a Novel Adipokine Potentially Linking Obesity to the Metabolic Syndrome. Diabetes, 60, 1917-1925.

[15]   Kang, Z.F., Deng, Y., Zhou, Y., Fan, R.R., Chan, J.C., Laybutt, D.R., Luzuriaga, J. and Xu, G. (2013) Pharmacological Reduction of NEFA Restores the Efficacy of Incretin-Based Therapies through GLP-1 Receptor Signalling in the Beta Cell in Mouse Models of Diabetes. Diabetologia, 56, 423-433.

[16]   Ranganath, L.R., Beety, J.M. and Morgan, L.M. (1996) Attenuated GLP-1 Secretion in Obesity: Cause or Consequence? Gut, 38, 916-919.

[17]   Yusta, B., Baggio, L.L., Estall, J.L., Koehler, J.A., Holland, D.P., Li, H., Pipeleers, D., Ling, Z. and Drucker, D.J. (2006) GLP-1 Receptor Activation Improves Beta Cell Function and survival Following Induction of Endoplasmic Reticulum Stress. Cell Metabolism, 4, 391-406.

[18]   Raz, I., Hanefeld, M., Xu, L., Caria, C., Williams-Herman, D. and Khatami, H. (2006) Sitagliptin Study 023 Group, Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy in Patients with type 2 Diabetes Mellitus. Diabetologia, 49, 2564-2571.

[19]   F-Wind and Chikushi-JRN Group (2012) Contributing Factors Related to Efficacy of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin in Japanese Patients with Type 2 Diabetes. Diabetes Research and Clinical Practice, 95, e27-e28.

[20]   Maeda, H., Kubota, A., Tanaka, Y., Terauchi, Y. and Matsuba, I. (2012) The Safety, Efficacy and Predictors for HbA1c Reduction of Sitagliptin in the Treatment of Japanese Type 2 Didbetes. Diabetes Research and Clinical Practice, 95, e20-e22.

[21]   Bando, Y., Kanehara, H., Aoki, K., Hisada, A., Toya, D. and Nobuyoshi, T. (2012) Obesity May Attenuate the HbA1c-Lowering Effect of Sitagliptin in Japanese Type 2 Diabetic Patients. Journal of Diabetes Investigation, 3, 170-174.

[22]   Solis-Herrera, C., Triplitt, C., Garduno-Garcia, J.J., Adams, J., Defronzo, R.A. and Cersosimo, E. (2013) Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or with Metformin in Type 2 Diabetes: A Double-Tracer Study. Diabetes Care, 36, 2756-2762.

[23]   Green, B.D., Irwin, N., Duffy, N.A., Gault, V.A., O’Harte, F.P. and Flatt, P.R. (2006) Inhibition of Dipeptidyl Peptidase-IV Activity by Metformin Enhances the Antidiabetic Effects of Glucagon-Like Peptide-1. European Journal of Pharmacology, 547, 192-199.

[24]   Aoki, K., Masuda, K., Miyazaki, T., Togashi, Y. and Terauchi, Y. (2010) Effects of Miglitol, Sitagliptin or Their Combination on Plasma Glucose, Insulin and Incretin Levels in Non-Diabetic Men. Endocrine Journal, 57, 667-672.