Skip to main content
SpringerLink
Log in

Factors Related to the Glucose-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors: A Systematic Review and Meta-Analysis Focusing on Ethnicity and Study Regions

  • Systematic Review
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and objective

Several systematic reviews and meta-analyses have been conducted including an analysis to investigate the difference between ethnic groups in the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors. This study assessed the factors related to the glucose-lowering efficacy and explored potential differences among ethnicities; in particular, Japanese subjects were dealt separately from other Asian subjects.

Methods

A systematic literature search was conducted using the MEDLINE, EMBASE, Cochrane Central Register, Japan Medical Abstracts Society, and ClinicalTrials.gov databases. Electronically searchable study results from the US/EU/Japanese regulatory approval reviews were also used. The weighted mean difference (WMD) for glycosylated hemoglobin (HbA1c) change from baseline in DPP-4 inhibitors compared with placebo was calculated. Heterogeneity was assessed by using the Q statistic and I 2 statistic. Univariate and multivariate meta-regression analyses were performed.

Results

The literature search identified 79 studies with 91 arms and 25,095 patients. The WMD in the change from baseline of HbA1c between the DPP-4 inhibitor group and placebo group was −0.695% (95% confidence interval −0.734 to −0.656) with considerable heterogeneity (I 2 = 69.7%). In univariate meta-regression, factors including study duration, percentage of males, age, duration of diabetes mellitus, baseline HbA1c values, body mass index, body weight, and percentage of Asian subjects showed associations with the glucose-lowering efficacy. Additionally, studies in Asian subjects, studies in Japanese subjects, and studies conducted in Japan showed relations when three classifications regarding ethnicity and study regions were applied. In multivariate meta-regression, studies in Japanese subjects/studies conducted in Japan as well as the baseline HbA1c values were identified as influencing factors.

Conclusion

These identified factors—Japanese subjects/studies conducted in Japan and the baseline HbA1c values—should be taken into account when planning and conducting future clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. World Health Organization. Global report on diabetes. 2016. http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf?ua=1&ua=1. Accessed 14 Jun 2016.

  2. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137–49. doi:10.1016/j.diabres.2013.11.002.

    Article  CAS  PubMed  Google Scholar 

  3. International Diabetes Federation. Diabetes atlas, seventh edition. 2015. http://www.diabetesatlas.org/component/attachments/?task=download&id=116. Accessed 14 Jun 2016.

  4. Survey of the state of diabetes in Japan in 1997 [in Japanese]. 1997. http://www.mhlw.go.jp/toukei/kouhyo/indexkk_4_1.html. Accessed 14 Jun 2016.

  5. National Health and Nutrition Survey Japan, 2012 [in Japanese]. 2012. http://www.mhlw.go.jp/bunya/kenkou/eiyou/h24-houkoku.html. Accessed 14 Jun 2016.

  6. Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response. Diabetes Care. 2013;36(6):1789–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88(4):787–835. doi:10.1016/j.mcna.2004.04.013.

    Article  CAS  PubMed  Google Scholar 

  8. Kim DJ, Lee MS, Kim KW, Lee MK. Insulin secretory dysfunction and insulin resistance in the pathogenesis of Korean type 2 diabetes mellitus. Metabolism. 2001;50(5):590–3. doi:10.1053/meta.2001.22558.

    Article  CAS  PubMed  Google Scholar 

  9. Qian L, Xu L, Wang X, Fu X, Gu Y, Lin F, et al. Early insulin secretion failure leads to diabetes in Chinese subjects with impaired glucose regulation. Diabetes Metab Res Rev. 2009;25(2):144–9. doi:10.1002/dmrr.922.

    Article  CAS  PubMed  Google Scholar 

  10. Matsumoto K, Miyake S, Yano M, Ueki Y, Yamaguchi Y, Akazawa S, et al. Glucose tolerance, insulin secretion, and insulin sensitivity in nonobese and obese Japanese subjects. Diabetes Care. 1997;20(10):1562–8.

    Article  CAS  PubMed  Google Scholar 

  11. Fukushima M, Usami M, Ikeda M, Nakai Y, Taniguchi A, Matsuura T, et al. Insulin secretion and insulin sensitivity at different stages of glucose tolerance: a cross-sectional study of Japanese type 2 diabetes. Metabolism. 2004;53(7):831–5.

    Article  CAS  PubMed  Google Scholar 

  12. Flatt PR, Bailey CJ, Green BD. Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes. Front Biosci. 2008;13:3648–60.

    Article  CAS  PubMed  Google Scholar 

  13. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.

    Article  CAS  PubMed  Google Scholar 

  14. Seino Y, Kuwata H, Yabe D. Incretin-based drugs for type 2 diabetes: focus on East Asian perspectives. J Diabetes Investig. 2016;7(Suppl 1):102–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013;56(4):696–708. doi:10.1007/s00125-012-2827-3.

    Article  CAS  PubMed  Google Scholar 

  16. Park H, Park C, Kim Y, Rascati KL. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: meta-analysis. Ann Pharmacother. 2012;46(11):1453–69. doi:10.1345/aph.1R041.

    Article  PubMed  Google Scholar 

  17. Monami M, Cremasco F, Lamanna C, Marchionni N, Mannucci E. Predictors of response to dipeptidyl peptidase-4 inhibitors: evidence from randomized clinical trials. Diabetes Metab Res Rev. 2011;27(4):362–72. doi:10.1002/dmrr.1184.

    Article  CAS  PubMed  Google Scholar 

  18. Esposito K, Cozzolino D, Bellastella G, Maiorino MI, Chiodini P, Ceriello A, et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2011;13(7):594–603. doi:10.1111/j.1463-1326.2011.01380.x.

    Article  CAS  PubMed  Google Scholar 

  19. Esposito K, Chiodini P, Capuano A, Maiorino MI, Bellastella G, Giugliano D. Baseline glycemic parameters predict the hemoglobin A1c response to DPP-4 inhibitors: meta-regression analysis of 78 randomized controlled trials with 20,053 patients. Endocrine. 2014;46(1):43–51. doi:10.1007/s12020-013-0090-0.

    Article  CAS  PubMed  Google Scholar 

  20. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi:10.1136/bmj.b2700.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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 Investig. 2012;3(1):39–40.

    Article  PubMed  PubMed Central  Google Scholar 

  22. R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2015. http://www.R-project.org/. Accessed 14 Jun 2016.

  23. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study 010 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31(12):2315–7. doi:10.2337/dc08-1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63(1):46–55. doi:10.1111/j.1742-1241.2008.01933.x.

    Article  CAS  PubMed  Google Scholar 

  25. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009;25(10):2361–71. doi:10.1185/03007990903156111.

    Article  CAS  PubMed  Google Scholar 

  26. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. Alogliptin Study 007 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11(2):167–76. doi:10.1111/j.1463-1326.2008.01016.x.

    Article  CAS  PubMed  Google Scholar 

  27. Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study. Curr Med Res Opin. 2011;27(9):1781–92. doi:10.1185/03007995.2011.599371.

    Article  CAS  PubMed  Google Scholar 

  28. Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study. Diabetes Obes Metab. 2011;13(11):1028–35. doi:10.1111/j.1463-1326.2011.01460.x.

    Article  CAS  PubMed  Google Scholar 

  29. Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Alogliptin plus voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension. Curr Med Res Opin. 2011;27(Suppl 3):21–9. doi:10.1185/03007995.2011.614936.

    Article  CAS  PubMed  Google Scholar 

  30. Seino Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to sulfonylurea in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. J Diabetes Investig. 2012;3(6):517–25. doi:10.1111/j.2040-1124.2012.00226.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Seino Y, Miyata Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012;14(10):927–36. doi:10.1111/j.1463-1326.2012.01620.x.

    Article  CAS  PubMed  Google Scholar 

  32. Pan C, Han P, Ji Q, Li C, Lu J, Yang J, et al. Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: a multicentre randomized double-blind placebo-controlled phase 3 study in mainland China, Taiwan, and Hong Kong. J Diabetes. 2016;. doi:10.1111/1753-0407.12425 [Epub ahead of print].

    Google Scholar 

  33. Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med. 2010;27(12):1409–19. doi:10.1111/j.1464-5491.2010.03131.x.

    Article  CAS  PubMed  Google Scholar 

  34. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13(3):258–67. doi:10.1111/j.1463-1326.2010.01350.x.

    Article  PubMed  Google Scholar 

  35. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(1):65–74. doi:10.1111/j.1463-1326.2010.01326.x.

    Article  CAS  PubMed  Google Scholar 

  36. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28(11):1352–61. doi:10.1111/j.1464-5491.2011.03387.x.

    Article  CAS  PubMed  Google Scholar 

  37. Lewin AJ, Arvay L, Liu D, Patel S, von Eynatten M, Woerle HJ. Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther. 2012;34(9):1909–19 e15. doi: 10.1016/j.clinthera.2012.07.008.

  38. Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab. 2012;14(4):348–57. doi:10.1111/j.1463-1326.2011.01545.x.

    Article  CAS  PubMed  Google Scholar 

  39. Ross SA, Rafeiro E, Meinicke T, Toorawa R, Weber-Born S, Woerle HJ. Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, placebo-controlled trial. Curr Med Res Opin. 2012;28(9):1465–74. doi:10.1185/03007995.2012.714360.

  40. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14(6):565–74. doi:10.1111/j.1463-1326.2012.01590.x.

    Article  CAS  PubMed  Google Scholar 

  41. Barnett AH, Patel S, Harper R, Toorawa R, Thiemann S, von Eynatten M, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes Obes Metab. 2012;14(12):1145–54. doi:10.1111/dom.12011.

    Article  CAS  PubMed  Google Scholar 

  42. Bajaj M, Gilman R, Patel S, Kempthorne-Rawson J. Lewis-D’Agostino D, Woerle HJ. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, double-blind study. Diabet Med. 2014;31(12):1505–14. doi:10.1111/dme.12495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen Y, Ning G, Wang C, Gong Y, Patel S, Zhang C, et al. Efficacy and safety of linagliptin monotherapy in Asian patients with inadequately controlled type 2 diabetes mellitus: a multinational, 24-week, randomized, clinical trial. J Diabetes Investig. 2015;6(6):692–8. doi:10.1111/jdi.12346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang W, Yang J, Yang G, Gong Y, Patel S, Zhang C, et al. Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: a multinational 24-week, randomized clinical trial. J Diabetes. 2016;8(2):229–37. doi:10.1111/1753-0407.12284.

    Article  CAS  PubMed  Google Scholar 

  45. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008;10(5):376–86. doi:10.1111/j.1463-1326.2008.00876.x.

    Article  CAS  PubMed  Google Scholar 

  46. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401–11. doi:10.1185/03007990903178735.

    Article  CAS  PubMed  Google Scholar 

  47. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32(9):1649–55. doi:10.2337/dc08-1984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hollander P, Li J, Allen E, Chen R, CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94(12):4810–9. doi:10.1210/jc.2009-0550.

    Article  CAS  PubMed  Google Scholar 

  49. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63(9):1395–406. doi:10.1111/j.1742-1241.2009.02143.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract. 2011;94(2):217–24. doi:10.1016/j.diabres.2011.07.035.

    Article  CAS  PubMed  Google Scholar 

  51. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28(3):268–75. doi:10.1002/dmrr.1306.

    Article  CAS  PubMed  Google Scholar 

  52. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4(1):36. doi:10.1186/1758-5996-4-36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. White JL, Buchanan P, Li J, Frederich R. A randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy. BMC Endocr Disord. 2014;14:17. doi:10.1186/1472-6823-14-17.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Moses RG, Kalra S, Brook D, Sockler J, Monyak J, Visvanathan J, et al. A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab. 2014;16(5):443–50. doi:10.1111/dom.12234.

    Article  CAS  PubMed  Google Scholar 

  55. Seino Y. Efficacy and safety of saxagliptin in Japanese patients with type 2 diabetes—two multi-centre, randomized, double-blind, placebo-controlled studies [in Japanese]. Jpn Pharmacol Ther. 2014;42(7):503–18.

    CAS  Google Scholar 

  56. Matthaei S, Catrinoiu D, Celiński A, Ekholm E, Cook W, Hirshberg B, et al. Randomized, double-blind trial of triple therapy with saxagliptin add-on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38(11):2018–24. doi:10.2337/dc15-0811.

    Article  CAS  PubMed  Google Scholar 

  57. AstraZeneca. Evaluate saxagliptin in adult indian patients with type 2 diabetes inadequate glycemic control [ClinicalTrials.gov identifier NCT00918879]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00918879?term=NCT00918879&rank=1. Accessed 7 Jul 2016.

  58. Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab. 2005;7(6):692–8. doi:10.1111/j.1463-1326.2005.00539.x.

    Article  CAS  PubMed  Google Scholar 

  59. Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drug-naive patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Metab Res. 2007;39(3):218–23. doi:10.1055/s-2007-970422.

    Article  CAS  PubMed  Google Scholar 

  60. Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76(1):132–8. doi:10.1016/j.diabres.2006.12.009.

    Article  CAS  PubMed  Google Scholar 

  61. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30(4):890–5. doi:10.2337/dc06-1732.

    Article  CAS  PubMed  Google Scholar 

  62. Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9(2):166–74. doi:10.1111/j.1463-1326.2006.00684.x.

    Article  CAS  PubMed  Google Scholar 

  63. Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjornsdottir S, Camisasca RP, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008;10(11):1047–56. doi:10.1111/j.1463-1326.2008.00859.x.

    Article  CAS  PubMed  Google Scholar 

  64. Kikuchi M, Abe N, Kato M, Terao S, Mimori N, Tachibana H. Vildagliptin dose-dependently improves glycemic control in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2009;83(2):233–40. doi:10.1016/j.diabres.2008.10.006.

    Article  CAS  PubMed  Google Scholar 

  65. Kikuchi M, Haneda M, Koya D, Tobe K, Onishi Y, Couturier A, et al. Efficacy and tolerability of vildagliptin as an add-on to glimepiride in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2010;89(3):216–23. doi:10.1016/j.diabres.2010.04.017.

    Article  CAS  PubMed  Google Scholar 

  66. Kikuchi M, Iwamoto Y, Inagaki N, Yoshioka T, Mimori N, Ebina H. Clinical evaluation of vildagliptin in patients with type 2 diabetes [in Japanese]. J New Rem Clin. 2010;59(2):121–36.

    Google Scholar 

  67. Pan C, Xing X, Han P, Zheng S, Ma J, Liu J, et al. Efficacy and tolerability of vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14(8):737–44. doi:10.1111/j.1463-1326.2012.01593.x.

    Article  CAS  PubMed  Google Scholar 

  68. Odawara M, Hamada I, Suzuki M. Efficacy and safety of vildagliptin as add-on to metformin in Japanese patients with type 2 diabetes mellitus. Diabetes Ther. 2014;5(1):169–81. doi:10.1007/s13300-014-0059-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564–71. doi:10.1007/s00125-006-0416-z.

    Article  CAS  PubMed  Google Scholar 

  70. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632–7. doi:10.2337/dc06-0703.

    Article  CAS  PubMed  Google Scholar 

  71. Charbonnel B, Karasik A, Liu J, Wu M. Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29(12):2638–43. doi:10.2337/dc06-0706.

    Article  CAS  PubMed  Google Scholar 

  72. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):1556–68. doi:10.1016/j.clinthera.2006.10.007.

    Article  CAS  PubMed  Google Scholar 

  73. Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP, et al. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res Opin. 2007;23(6):1329–39. doi:10.1185/030079907X188152.

    Article  CAS  PubMed  Google Scholar 

  74. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30(8):1979–87. doi:10.2337/dc07-0627.

    Article  CAS  PubMed  Google Scholar 

  75. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9(5):733–45. doi:10.1111/j.1463-1326.2007.00744.x.

    Article  CAS  PubMed  Google Scholar 

  76. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007;61(1):171–80. doi:10.1111/j.1742-1241.2006.01246.x.

    Article  CAS  PubMed  Google Scholar 

  77. Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24(2):537–50. doi:10.1185/030079908X260925.

    Article  CAS  PubMed  Google Scholar 

  78. Scott R, Loeys T, Davies MJ, Engel SS. Sitagliptin Study 801 Group. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008;10(10):959–69. doi:10.1111/j.1463-1326.2007.00839.x.

    Article  CAS  PubMed  Google Scholar 

  79. Nonaka K, Kakikawa T, Sato A, Okuyama K, Fujimoto G, Kato N, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2008;79(2):291–8. doi:10.1016/j.diabres.2007.08.021.

    Article  CAS  PubMed  Google Scholar 

  80. Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, et al. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009;83(1):106–16. doi:10.1016/j.diabres.2008.10.009.

    Article  CAS  PubMed  Google Scholar 

  81. Iwamoto Y, Taniguchi T, Nonaka K, Okamoto T, Okuyama K, Arjona Ferreira JC, et al. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57(5):383–94.

    Article  CAS  PubMed  Google Scholar 

  82. Kashiwagi A, Kadowaki T, Tajima N, Nonaka K, Taniguchi T, Nishii M, et al. Sitagliptin added to treatment with ongoing pioglitazone for up to 52 weeks improves glycemic control in Japanese patients with type 2 diabetes. J Diabetes Investig. 2011;2(5):381–90. doi:10.1111/j.2040-1124.2011.00120.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Barzilai N, Guo H, Mahoney EM, Caporossi S, Golm GT, Langdon RB, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin. 2011;27(5):1049–58. doi:10.1185/03007995.2011.568059.

    Article  CAS  PubMed  Google Scholar 

  84. Tajima N, Kadowaki T, Odawara M, Nishii M, Taniguchi T, Arjona Ferreira JC. Addition of sitagliptin to ongoing glimepiride therapy in Japanese patients with type 2 diabetes over 52 weeks leads to improved glycemic control. Diabetol Int. 2011;2(1):32–44. doi:10.1007/s13340-011-0022-2.

    Article  Google Scholar 

  85. Yang W, Guan Y, Shentu Y, Li Z, Johnson-Levonas AO, Engel SS, et al. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes. 2012;4(3):227–37. doi:10.1111/j.1753-0407.2012.00213.x.

    Article  CAS  PubMed  Google Scholar 

  86. Nicolle LE, Capuano G, Ways K, Usiskin K. Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study. Curr Med Res Opin. 2012;28(7):1167–71. doi:10.1185/03007995.2012.689956.

    Article  CAS  PubMed  Google Scholar 

  87. Fonseca V, Staels B, Morgan JD 2nd, Shentu Y, Golm GT, Johnson-Levonas AO, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications. 2013;27(2):177–83. doi:10.1016/j.jdiacomp.2012.09.007.

    Article  PubMed  Google Scholar 

  88. Dobs AS, Goldstein BJ, Aschner P, Horton ES, Umpierrez GE, Duran L, et al. Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes. J Diabetes. 2013;5(1):68–79. doi:10.1111/j.1753-0407.2012.00223.x.

    Article  CAS  PubMed  Google Scholar 

  89. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1(3):208–19. doi:10.1016/s2213-8587(13)70084-6.

    Article  CAS  PubMed  Google Scholar 

  90. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582–92. doi:10.1007/s00125-013-3039-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tajima N, Kadowaki T, Okamoto T, Sato A, Okuyama K, Minamide T, et al. Sitagliptin added to voglibose monotherapy improves glycemic control in patients with type 2 diabetes. J Diabetes Investig. 2013;4(6):595–604. doi:10.1111/jdi.12116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kadowaki T, Tajima N, Odawara M, Nishii M, Taniguchi T, Ferreira JC. Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks. J Diabetes Investig. 2013;4(2):174–81. doi:10.1111/jdi.12001.

    Article  CAS  PubMed  Google Scholar 

  93. Amin NB, Aggarwal N, Pall D, Paragh G, Denney WS, Le V, et al. Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes Metab. 2015;17(8):751–9. doi:10.1111/dom.12474.

    Article  CAS  PubMed  Google Scholar 

  94. Ji L, Han P, Wang X, Liu J, Zheng S, Jou YM, et al. Randomized clinical trial of the safety and efficacy of sitagliptin and metformin co-administered to Chinese patients with type 2 diabetes mellitus. J Diabetes Investig. 2016;7(5):727–36. doi:10.1111/jdi.12511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Moses RG, Round E, Shentu Y, Golm GT, O’Neill EA, Gantz I, et al. A randomized clinical trial evaluating the safety and efficacy of sitagliptin added to the combination of sulfonylurea and metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. J Diabetes. 2016;8(5):701–11. doi:10.1111/1753-0407.12351.

    Article  CAS  PubMed  Google Scholar 

  96. Merck Sharp & Dohme Corp. Clinical trial to evaluate the safety and efficacy of the addition of sitagliptin in participants with type 2 diabetes mellitus receiving acarbose monotherapy (MK-0431-130) [ClinicalTrials.gov identifier NCT01177384]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01177384?term=NCT01177384&rank=1. Accessed 7 Jul 2016.

  97. Boehringer Ingelheim/Eli Lilly and Company. Safety and efficacy of empagliflozin (BI 10773) and sitagliptin versus placebo over 76 weeks in patients with type 2 diabetes [ClinicalTrials.gov identifier NCT01289990]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01289990?term=NCT01289990&rank=1. Accessed 7 Jul 2016.

  98. Pfizer. Study of safety and efficacy of PF-04991532 in subjects with type 2 diabetes [ClinicalTrials.gov identifier NCT01338870]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01338870?term=NCT01338870&rank=1. Accessed 7 Jul 2016.

  99. Pfizer. Study of safety and efficacy of PF-04991532 in subjects with type 2 diabetes mellitus [ClinicalTrials.gov identifier NCT01336738]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01336738?term=NCT01336738&rank=1. Accessed 7 Jul 2016.

  100. Merck Sharp & Dohme Corp. A study in China evaluating the safety and efficacy of adding sitagliptin to stable therapy with sulfonylurea with or without metformin in participants with type 2 diabetes mellitus (T2DM) (MK-0431-253) [ClinicalTrials.gov identifier NCT01590771]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01590771?term=NCT01590771&rank=1. Accessed 7 Jul 2016.

  101. Merck Sharp & Dohme Corp. Omarigliptin (MK-3102) clinical trial – placebo- and sitagliptin-controlled monotherapy study in japanese patients with type 2 diabetes mellitus (MK-3102-020) [ClinicalTrials.gov identifier NCT01703221]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01703221?term=NCT01703221&rank=1. Accessed 7 Jul 2016.

  102. Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care. 2006;29(9):2137–9. doi:10.2337/dc06-1120.

    Article  CAS  PubMed  Google Scholar 

  103. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13(1):7–18. doi:10.1111/j.1463-1326.2010.01306.x.

    Article  CAS  PubMed  Google Scholar 

  104. Singh AK. Incretin response in Asian type 2 diabetes: are Indians different? Indian J Endocrinol Metab. 2015;19(1):30–8. doi:10.4103/2230-8210.146861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Kayo Fujita, Masayuki Kaneko & Mamoru Narukawa

Authors
  1. Kayo Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayuki Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mamoru Narukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kayo Fujita.

Ethics declarations

Funding

The preparation of this manuscript was not supported by any external funding.

Conflict of interest

The authors have no conflicts of interest that are directly relevant to this research. Kayo Fujita is an employee of Pfizer Japan Inc.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fujita, K., Kaneko, M. & Narukawa, M. Factors Related to the Glucose-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors: A Systematic Review and Meta-Analysis Focusing on Ethnicity and Study Regions. Clin Drug Investig 37, 219–232 (2017). https://doi.org/10.1007/s40261-016-0478-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-016-0478-8

Keywords

Search

Navigation