Diabetology International

, Volume 4, Issue 4, pp 251–256 | Cite as

Determinants of the HbA1c-lowering effect of sitagliptin when added to ongoing insulin therapy in Japanese patients with type 2 diabetes

  • Yukihiro Bando
  • Kazuhide Ishikura
  • Hideo Kanehara
  • Keiko Aoki
  • Azusa Hisada
  • Daisyu Toya
  • Nobuyoshi Tanaka
Original Article



This study assessed the independent predictors of the HbA1c-lowering effect of sitagliptin when added to ongoing insulin therapy in Japanese patients with type 2 diabetes.


Data were retrieved from the medical records of 179 patients with type 2 diabetes on stable-dose insulin alone or stable-dose insulin and oral hypoglycemic agents who received sitagliptin (25 or 50 mg) added on once daily for inadequate glycemic control for at least 12 weeks. Spearman’s rank correlation coefficient analysis was performed to assess the correlations of two independent continuous variables. Multiple stepwise regression analysis was used to search for independent predictors of reduction in HbA1c levels after 12 weeks of sitagliptin add-on treatment (ΔHbA1c).


Among all subjects, ΔHbA1c was significantly correlated with baseline HbA1c alone (r = 0.410, P < 0.0001). However, multiple stepwise regression analysis using baseline variables revealed that the three independent factors contributing to ΔHbA1c were baseline HbA1c (r2 = 0.16, P < 0.0001), total daily insulin dose (r2 = 0.05, P = 0.002), and diabetes duration (r2 = 0.03, P = 0.006).


The results suggest that an increased total daily insulin dose and prolonged diabetes duration contribute in part to the attenuation of the HbA1c-lowering effect of sitagliptin added to ongoing insulin therapy in Japanese patients with type 2 diabetes. A prospective analysis of a larger population with a longer study duration is warranted to confirm these findings.


HbA1c Sitagliptin Insulin Type 2 diabetes 


Conflict of interest

None of the authors have any conflicts of interest to declare.


  1. 1.
    Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29:1269–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M, Vähätalo M, Virtamo H, Nikkilä K, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia. 2006;49:442–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jarvinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care. 2005;28:254–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28:1282–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Kennedy L, Herman WH, Strange P, Harris A. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: the Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial. Diabetes Care. 2006;29:1–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357:1716–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Drucker DJ, Nauck MA. GLP-1R agonists (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) for the treatment of type 2 diabetes. Lancet. 2006;368:1696–705.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Vilsboll T, Rosenstock J, Järvinen HY, 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 Obese Metab. 2010;12:167–77.CrossRefGoogle Scholar
  13. 13.
    Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin. Diabetes Care. 2010;33:1509–15.PubMedCrossRefGoogle Scholar
  14. 14.
    Takahara M, Shiraiwa T, Kaneto H, Katakami N, Matsuoka T, Shimomura I. Efficacy of sitagliptin on blood glucose fluctuation in Japanese type 2 diabetic patients with basal-supported oral therapy. Endocr J. 2012;59:1131–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Hong ES, Khang AR, Yoon JW, Kang SM, Choi SH, Park KS, et al. Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy in uncontrolled Korean type 2 diabetes: CSI study. Diabetes Obes Metab. 2012;14:795–802.PubMedCrossRefGoogle Scholar
  16. 16.
    Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78:675–88.PubMedCrossRefGoogle Scholar
  17. 17.
    Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, et al. 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.CrossRefGoogle Scholar
  18. 18.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Coresh J, Astor BC, Greene T, Ecnoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population. Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1–12.PubMedCrossRefGoogle Scholar
  20. 20.
    World Medical Association. Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. J Am Med Assoc. 1997;277:925–6.CrossRefGoogle Scholar
  21. 21.
    Vilsboll T, Rosenstock J, Ja¨rvinen HY, 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.PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycemia. Diabetes Obes Metab. 2009;11:1145–52.PubMedCrossRefGoogle Scholar
  23. 23.
    Basu R, Breda E, Oberg AL, Powell CC, Man CD, Basu A, et al. Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance. Diabetes. 2003;52:1738–48.PubMedCrossRefGoogle Scholar
  24. 24.
    UK Prospective Diabetes Study Group. UK prospective diabetes study 16: overview of 6 years of therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249–58.CrossRefGoogle Scholar
  25. 25.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43.PubMedCrossRefGoogle Scholar
  26. 26.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment (HOMA): insulin resistance and beta cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Draznin B, Goodman M, Leitner JW, Sussman KE. Feedback inhibition of insulin on insulin secretion in isolated pancreatic islets. Endocrinology. 1986;118:1054–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Nagakura T, Yasuda N, Yamazaki K, Ikuta H, Tanaka I. Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition. Metabolism. 2003;52:81–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim SA, Shim WH, Lee EH, Lee YM, Beom SH, Kim ES, et al. Predictive clinical parameters for the therapeutic efficacy of sitagliptin in Korean type 2 diabetes mellitus. Diabetes Metab J. 2011;35:159–65.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Lim S, An JH, Shin H, Khang AR, Lee Y, Ahn HY, et al. Factors predicting therapeutic efficacy of combination treatment with sitagliptin and metformin in type 2 diabetic patients: the COSMETIC study. Clin Endocrinol. 2012;77:215–23.CrossRefGoogle Scholar
  31. 31.
    Kutoh E. Sitagliptin is effective and safe as add-on to insulin in patients with absolute insulin deficiency: a case series. J Med Case Rep. 2011;5:117.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Senmaru T, Fukui M, Kobayashi K, Iwase H, Inada S, Okada H, et al. Dipeptidyl peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations. J Diabetes Invest. 2012; doi:10.1111/j.2040-1124.2012.00220.x.

Copyright information

© The Japan Diabetes Society 2013

Authors and Affiliations

  • Yukihiro Bando
    • 1
  • Kazuhide Ishikura
    • 1
  • Hideo Kanehara
    • 1
  • Keiko Aoki
    • 1
  • Azusa Hisada
    • 1
  • Daisyu Toya
    • 1
  • Nobuyoshi Tanaka
    • 1
  1. 1.Department of Internal MedicineFukui-ken Saiseikai HospitalFukuiJapan

Personalised recommendations