Skip to main content

Advertisement

SpringerLink
Log in

Ten years of experience with DPP-4 inhibitors for the treatment of type 2 diabetes mellitus

  • Review Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Achieving and maintaining recommended glycemic targets without causing adverse e ffects, including hypoglycemia, is challenging, especially in older patients with type 2 diabetes mellitus (T2DM). The introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors, more than 10 years ago, has provided an alternative to conventional medications for the intensification of glucose-lowering treatment after failure of metformin monotherapy, and therefore, marked an important advance in the management of T2DM. By prolonging the activity of incretin hormones, DPP-4 inhibitors induce insulin release and decrease glucagon secretion in a glucose-dependent manner. This results in a more physiologic glycemic control as compared to that ensured by insulin secretagogues (sulfonylureas and glinides). Overall, DPP-4 inhibitors have a favorable safety profile and can be used without dose adjustments in older adults and in patients with mild renal impairment; they have a neutral effect on body weight and do not cause hypoglycemia by themselves. Safety issues, reported mainly in post-marketing surveillance programs and including cardiovascular outcomes and the risk of acute pancreatitis, are being extensively investigated. The aim of this review is to discuss the impact of DPP-4 inhibitors on the treatment of T2DM, after 10 years of experience, with an emphasis on diabetes care in Italy. We will first describe T2DM treatment in Italy and then provide an overview of the main findings from randomized controlled trials, real-world studies and post-marketing surveillance programs with DPP-4 inhibitors.

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

Similar content being viewed by others

References

  1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators (2017) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390(10100):1211–1259. https://doi.org/10.1016/S0140-6736(17)32154-2

    Article  Google Scholar 

  2. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. https://doi.org/10.1038/nrendo.2017.151

    Article  PubMed  Google Scholar 

  3. ARNO (2017) Osservatorio ARNO Diabete CINECA-SID. Il profilo assistenziale della popolazione con diabete. Rapporto 2017 (Observatory ARNO Diabetes CINECA-SID. The care profile of the population with diabetes. Report 2017). http://arno.cineca.it/journal/wp-content/uploads/2017/10/Diabete_2017_con-copertina.pdf. Accessed 1 August 2018

  4. SID-SIGG (2017) Società Italiana di Diabetologia (SID) e Società Italiana di Gerontologia e Geriatria (SIGG). Position statement—Personalizzazione del trattamento dell’iperglicemia nell’anziano con diabete tipo 2 (Italian Society of Diabetology [SID] and Italian Society of Gerontology and Geriatrics [SIGG]. Position statement—customization of the treatment of hyperglycemia in the elderly with type 2 diabetes). https://www.sigg.it/wp-content/uploads/2017/11/SID-SIGG-Documento-ufficiale.pdf. Accessed 1 Aug 2018

  5. Soe K, Sacerdote A, Karam J, Bahtiyar G (2011) Management of type 2 diabetes mellitus in the elderly. Maturitas 70(2):151–159. https://doi.org/10.1016/j.maturitas.2011.07.006

    Article  CAS  PubMed  Google Scholar 

  6. Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ (2013) Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 382(9902):1413–1423. https://doi.org/10.1016/S0140-6736(13)61500-7

    Article  CAS  PubMed  Google Scholar 

  7. Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldanius PM (2013) Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet 382(9890):409–416. https://doi.org/10.1016/S0140-6736(13)60995-2

    Article  CAS  PubMed  Google Scholar 

  8. Strain WD, Paldanius PM (2017) Dipeptidyl peptidase-4 inhibitor development and post-authorisation programme for vildagliptin—clinical evidence for optimised management of chronic diseases beyond type 2 diabetes. Eur Endocrinol 13(2):62–67. https://doi.org/10.17925/EE.2017.13.02.62

    Article  PubMed  PubMed Central  Google Scholar 

  9. Deacon CF (2018) Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides 100:150–157. https://doi.org/10.1016/j.peptides.2017.10.011

    Article  CAS  PubMed  Google Scholar 

  10. Scheen AJ (2012) DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab 38(2):89–101. https://doi.org/10.1016/j.diabet.2011.11.001

    Article  CAS  PubMed  Google Scholar 

  11. Vildagliptin. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000771/WC500020327.pdf. Accessed 1 Aug 2018

  12. Sitagliptin. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000722/WC500039054.pdf. Accessed 1 Aug 2018

  13. Saxagliptin. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf. Accessed 1 Aug 2018

  14. Linagliptin. Summary of Product Characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002110/WC500115745.pdf. Accessed 1 Aug 2018

  15. Alogliptin. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002182/WC500152271.pdf. Accessed 1 Aug 2018

  16. AMD-SID (2018) Associazione Medici Diabetologi (AMD)—Società Italiana di Diabetologia (SID). Standard italiani per la cura del diabete mellito (Doctors Diabetologists Association [AMD]—Italian Society of Diabetology [SID]. Italian standards for the treatment of diabetes mellitus). http://www.siditalia.it/pdf/Standard%20di%20Cura%20AMD%20-%20SID%202018_protetto.pdf. Accessed 1 Aug 2018

  17. American Diabetes Association (2017) Standards of medical care in diabetes—2017. Diabetes Care 40(Supplement 1):S1–S135. http://care.diabetesjournals.org/content/diacare/suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_final.pdf. Accessed 1 Aug 2017

  18. ISTAT (2017) Il diabete in Italia. Anni 2000–2016 (Diabetes in Italy. Years 2000–2016). https://www.istat.it/it/files//2017/07/REPORT_DIABETE.pdf. Accessed 1 Aug 2018

  19. Pugliese G, Solini A, Bonora E, Fondelli C, Orsi E, Nicolucci A et al (2014) Chronic kidney disease in type 2 diabetes: lessons from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study. Nutr Metab Cardiovasc Dis 24(8):815–822. https://doi.org/10.1016/j.numecd.2014.02.013

    Article  CAS  PubMed  Google Scholar 

  20. Baviera M, Avanzini F, Marzona I, Tettamanti M, Vannini T, Cortesi L et al (2017) Cardiovascular complications and drug prescriptions in subjects with and without diabetes in a Northern region of Italy, in 2002 and 2012. Nutr Metab Cardiovasc Dis 27(1):54–62. https://doi.org/10.1016/j.numecd.2016.10.006

    Article  CAS  PubMed  Google Scholar 

  21. The Medicines Utilization Monitoring Centre (2017) National Report on Medicine Use in Italy 2016. AIFA, Italian Medicine Agency, Rome. http://www.agenziafarmaco.gov.it. Accessed 1 Aug 2018

  22. AIFA (2015) Piano Terapeutico per la prescrizione di Incretine/inibitori DPP-4 nel trattamento del diabete tipo 2 (aggiornamento marzo 2015) (Therapeutic Plan for the prescription of Incretine / DPP-4 inhibitors in the treatment of type 2 diabetes [update March 2015]). http://www.siditalia.it/images/Documenti/NEWS/Nuovo_piano_terapeutico_incretine.pdf. Accessed 1 Aug 2018

  23. Niskanen L, Hahl J, Haukka J, Leppa E, Miettinen T, Mushnikov V et al (2018) Type 2 diabetes and treatment intensification in primary care in Finland. Acta Diabetol 55(11):1171–1179. https://doi.org/10.1007/s00592-018-1199-7

    Article  CAS  PubMed  Google Scholar 

  24. ARNO (2015) Società Italiana di Diabetologia. Osservatorio ARNO Diabete Anziani. Il profilo assistenziale della popolazione anziana con diabete Elaborazioni su dati anno 2015 (a cura di Cineca-SID) (Italian Society of Diabetology. ARNO Observatory for Elderly Diabetes. The care profile of the elderly population with diabetes. Elaborations on data for 2015 [edited by Cineca-SID]). http://arno.cineca.it/portal/wp-content/uploads/2017/04/2017-Osservatorio-ARNO-Diabete-Anziani.pdf. Accessed 1 Aug 2018

  25. Solini A, Penno G, Bonora E, Fondelli C, Orsi E, Trevisan R et al (2013) Age, renal dysfunction, cardiovascular disease, and antihyperglycemic treatment in type 2 diabetes mellitus: findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study. J Am Geriatr Soc 61(8):1253–1261. https://doi.org/10.1111/jgs.12381

    Article  PubMed  Google Scholar 

  26. Ahren B, Mathieu C, Bader G, Schweizer A, Foley JE (2014) Efficacy of vildagliptin versus sulfonylureas as add-on therapy to metformin: comparison of results from randomised controlled and observational studies. Diabetologia 57(7):1304–1307. https://doi.org/10.1007/s00125-014-3222-z

    Article  CAS  PubMed  Google Scholar 

  27. Scheen AJ (2018) The safety of gliptins: updated data in 2018. Expert Opin Drug Saf 17(4):387–405. https://doi.org/10.1080/14740338.2018.1444027

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Y, Hong J, Chi J, Gu W, Ning G, Wang W (2014) Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas—a meta-analysis from randomized clinical trials. Diabetes Metab Res Rev 30(3):241–256. https://doi.org/10.1002/dmrr.2482

    Article  CAS  PubMed  Google Scholar 

  29. Zhou JB, Bai L, Wang Y, Yang JK (2016) The benefits and risks of DPP4-inhibitors vs. sulfonylureas for patients with type 2 diabetes: accumulated evidence from randomised controlled trial. Int J Clin Pract 70(2):132–141. https://doi.org/10.1111/ijcp.12761

    Article  CAS  PubMed  Google Scholar 

  30. Trevisan R (2017) The role of vildagliptin in the therapy of type 2 diabetic patients with renal dysfunction. Diabetes Ther 8(6):1215–1226. https://doi.org/10.1007/s13300-017-0302-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brath H, Paldanius PM, Bader G, Mathieu C (2017) Relationship between duration of type 2 diabetes and effectiveness of DPP-4 inhibitor versus sulfonylurea as add-on therapy: a post hoc analysis. Diabetes Ther 8(4):829–836. https://doi.org/10.1007/s13300-017-0276-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fadini GP, Bottigliengo D, D’Angelo F, Cavalot F, Bossi AC, Zatti G et al (2018) Comparative effectiveness of DPP-4 inhibitors versus sulfonylurea for the treatment of type 2 diabetes in routine clinical practice: a retrospective multicenter real-world study. Diabetes Ther 9(4):1477–1490. https://doi.org/10.1007/s13300-018-0452-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B (2016) Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev 32(3):289–296. https://doi.org/10.1002/dmrr.2717

    Article  CAS  PubMed  Google Scholar 

  34. D’Alessio DA, Denney AM, Hermiller LM, Prigeon RL, Martin JM, Tharp WG et al (2009) Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes. J Clin Endocrinol Metab 94(1):81–88. https://doi.org/10.1210/jc.2008-1135

    Article  CAS  PubMed  Google Scholar 

  35. Utzschneider KM, Tong J, Montgomery B, Udayasankar J, Gerchman F, Marcovina SM et al (2008) The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose. Diabetes Care 31(1):108–113. https://doi.org/10.2337/dc07-1441

    Article  CAS  PubMed  Google Scholar 

  36. Zhao Y, Yang L, Xiang Y, Liu L, Huang G, Long Z et al (2014) Dipeptidyl peptidase 4 inhibitor sitagliptin maintains beta-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab 99(5):E876–E880. https://doi.org/10.1210/jc.2013-3633

    Article  CAS  PubMed  Google Scholar 

  37. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al (2015) Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38(1):140–149. https://doi.org/10.2337/dc14-2441

    Article  PubMed  Google Scholar 

  38. Deacon CF, Mannucci E, Ahren B (2012) Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes Obes Metab 14(8):762–767. https://doi.org/10.1111/j.1463-1326.2012.01603.x

    Article  CAS  PubMed  Google Scholar 

  39. Esposito K, Chiodini P, Maiorino MI, Bellastella G, Capuano A, Giugliano D (2014) Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 4(6):e005442. https://doi.org/10.1136/bmjopen-2014-005442

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A (2012) Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344:e1369. https://doi.org/10.1136/bmj.e1369

    Article  CAS  PubMed  Google Scholar 

  42. Mishriky BM, Cummings DM, Tanenberg RJ (2015) The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 109(2):378–388. https://doi.org/10.1016/j.diabres.2015.05.025

    Article  CAS  PubMed  Google Scholar 

  43. Wu D, Li L, Liu C (2014) Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Obes Metab 16(1):30–37. https://doi.org/10.1111/dom.12174

    Article  CAS  PubMed  Google Scholar 

  44. Ling J, Ge L, Zhang DH, Wang YF, Xie ZL, Tian JH et al (2018) DPP-4 inhibitors for the treatment of type 2 diabetes: a methodology overview of systematic reviews. Acta Diabetol. https://doi.org/10.1007/s00592-018-1164-5 (Epub ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ling J, Cheng P, Ge L, Zhang DH, Shi AC, Tian JH et al (2018) The efficacy and safety of dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a Bayesian network meta-analysis of 58 randomized controlled trials. Acta Diabetol. https://doi.org/10.1007/s00592-018-1222-z (Epub ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  46. Esposito K, Chiodini P, Capuano A, Maiorino MI, Bellastella G, Giugliano D (2014) 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 46(1):43–51. https://doi.org/10.1007/s12020-013-0090-0

    Article  CAS  PubMed  Google Scholar 

  47. Cheng D, Fei Y, Liu Y, Li J, Chen Y, Wang X, Wang N (2014) Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with moderate to severe renal impairment: a systematic review and meta-analysis. PLoS One 9(10):e111543. https://doi.org/10.1371/journal.pone.0111543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Howse PM, Chibrikova LN, Twells LK, Barrett BJ, Gamble JM (2016) Safety and efficacy of incretin-based therapies in patients with type 2 diabetes mellitus and CKD: a systematic review and meta-analysis. Am J Kidney Dis 68(5):733–742. https://doi.org/10.1053/j.ajkd.2016.06.014

    Article  CAS  PubMed  Google Scholar 

  49. Li R, Wang R, Li H, Sun S, Zou M, Cheng G (2016) Short-term and long-term effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with renal impairment: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 32(6):460–469. https://doi.org/10.1002/dmrr.2731

    Article  CAS  PubMed  Google Scholar 

  50. Singh-Franco D, Harrington C, Tellez-Corrales E (2016) An updated systematic review and meta-analysis on the efficacy and tolerability of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes with moderate to severe chronic kidney disease. SAGE Open Med 4:1–16. https://doi.org/10.1177/2050312116659090

    Article  Google Scholar 

  51. Thomas MC, Paldanius PM, Ayyagari R, Ong SH, Groop PH (2016) Systematic literature review of DPP-4 inhibitors in patients with type 2 diabetes mellitus and renal impairment. Diabetes Ther 7(3):439–454. https://doi.org/10.1007/s13300-016-0189-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Halimi S, Raccah D, Schweizer A, Dejager S (2010) Role of vildagliptin in managing type 2 diabetes mellitus in the elderly. Curr Med Res Opin 26(7):1647–1656. https://doi.org/10.1185/03007995.2010.485881

    Article  CAS  PubMed  Google Scholar 

  53. Inzucchi SE, Nauck MA, Hehnke U, Woerle HJ, von Eynatten M, Henry RR (2015) Improved glucose control with reduced hypoglycaemic risk when linagliptin is added to basal insulin in elderly patients with type 2 diabetes. Diabetes Obes Metab 17(9):868–877. https://doi.org/10.1111/dom.12490

    Article  CAS  PubMed  Google Scholar 

  54. Schweizer A, Dejager S (2013) Experience with vildagliptin in patients>/=75 years with type 2 diabetes and moderate or severe renal impairment. Diabetes Ther 4(2):257–267. https://doi.org/10.1007/s13300-013-0027-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schweizer A, Dejager S, Foley JE, Shao Q, Kothny W (2011) Clinical experience with vildagliptin in the management of type 2 diabetes in a patient population>/=75 years: a pooled analysis from a database of clinical trials. Diabetes Obes Metab 13(1):55–64. https://doi.org/10.1111/j.1463-1326.2010.01325.x

    Article  CAS  PubMed  Google Scholar 

  56. Sicras-Mainar A, Navarro-Artieda R (2014) Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly. Drug Des Devel Ther 8:811–818. https://doi.org/10.2147/DDDT.S65327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Karyekar CS, Ravichandran S, Allen E, Fleming D, Frederich R (2013) Tolerability and efficacy of glycemic control with saxagliptin in older patients (aged>/= 65 years) with inadequately controlled type 2 diabetes mellitus. Clin Interv Aging 8:419–430. https://doi.org/10.2147/CIA.S41246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q (2009) Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J Am Geriatr Soc 57(11):2011–2019. https://doi.org/10.1111/j.1532-5415.2009.02484.x

    Article  PubMed  Google Scholar 

  59. Rosenstock J, Wilson C, Fleck P (2013) Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes Metab 15(10):906–914. https://doi.org/10.1111/dom.12102

    Article  CAS  PubMed  Google Scholar 

  60. Umezawa S, Kubota A, Maeda H, Kanamori A, Matoba K, Jin Y et al (2015) Two-year assessment of the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes: Post hoc analysis of the ASSET-K study. BMC Endocr Disord 15:34. https://doi.org/10.1186/s12902-015-0033-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fu J, Zhu J, Hao Y, Guo C, Zhou Z (2016) Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials. Sci Rep 6:29104. https://doi.org/10.1038/srep29104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang J, Huang C, Wu S, Xu Y, Cai T, Chai S et al (2017) The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. PLoS One 12(12):e0187537. https://doi.org/10.1371/journal.pone.0187537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mathieu C, Barnett AH, Brath H, Conget I, de Castro JJ, Goke R et al (2013) Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: a real-life worldwide observational study (EDGE). Int J Clin Pract 67(10):947–956. https://doi.org/10.1111/ijcp.12252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fadini GP, Zatti G, Baldi I, Bottigliengo D, Consoli A, Giaccari A et al (2018) Use and effectiveness of dapagliflozin in routine clinical practice: an Italian multicentre retrospective study. Diabetes Obes Metab 20(7):1781–1786. https://doi.org/10.1111/dom.13280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Montilla S, Marchesini G, Sammarco A, Trotta MP, Siviero PD, Tomino C et al (2014) Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutr Metab Cardiovasc Dis 24(12):1346–1353. https://doi.org/10.1016/j.numecd.2014.07.014

    Article  CAS  PubMed  Google Scholar 

  66. Gokhale M, Buse JB, Jonsson Funk M, Lund J, Pate V, Simpson RJ, Sturmer T (2017) No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives. Diabetes Obes Metab 19(7):970–978. https://doi.org/10.1111/dom.12906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mathieu C, Kozlovski P, Paldanius PM, Foley JE, Modgill V, Evans M, Serban C (2017) Clinical safety and tolerability of vildagliptin—insights from randomised trials, observational studies and post-marketing surveillance. Eur Endocrinol 13(2):68–72. https://doi.org/10.17925/EE.2017.13.02.68

    Article  PubMed  PubMed Central  Google Scholar 

  68. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373(3):232–242. https://doi.org/10.1056/NEJMoa1501352

    Article  CAS  PubMed  Google Scholar 

  69. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM et al (2015) Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA(R)). Diab Vasc Dis Res 12(3):164–174. https://doi.org/10.1177/1479164115570301

    Article  CAS  PubMed  Google Scholar 

  70. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369(14):1317–1326. https://doi.org/10.1056/NEJMoa1307684

    Article  CAS  PubMed  Google Scholar 

  71. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369(14):1327–1335. https://doi.org/10.1056/NEJMoa1305889

    Article  CAS  PubMed  Google Scholar 

  72. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N et al (2018) Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. https://doi.org/10.1001/jama.2018.18269

  73. McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V et al (2015) Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17,000 patients. Diabetes Obes Metab 17(11):1085–1092. https://doi.org/10.1111/dom.12548

    Article  CAS  PubMed  Google Scholar 

  74. McMurray JJV, Ponikowski P, Bolli GB, Lukashevich V, Kozlovski P, Kothny W et al (2018) Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail 6(1):8–17. https://doi.org/10.1016/j.jchf.2017.08.004

    Article  PubMed  Google Scholar 

  75. Bonora E, Cigolini M (2016) DPP-4 inhibitors and cardiovascular disease in type 2 diabetes mellitus. Expectations, observations and perspectives. Nutr Metab Cardiovasc Dis 26(4):273–284. https://doi.org/10.1016/j.numecd.2016.03.002

    Article  CAS  PubMed  Google Scholar 

  76. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C (2014) Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med 370(9):794–797. https://doi.org/10.1056/NEJMp1314078

    Article  CAS  PubMed  Google Scholar 

  77. Pinto LC, Rados DV, Barkan SS, Leitao CB, Gross JL (2018) Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: a meta-analysis with trial sequential analysis. Sci Rep 8(1):782. https://doi.org/10.1038/s41598-017-19055-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tkac I, Raz I (2017) Combined analysis of three large interventional trials with gliptins indicates increased incidence of acute pancreatitis in patients with type 2 diabetes. Diabetes Care 40(2):284–286. https://doi.org/10.2337/dc15-1707

    Article  CAS  PubMed  Google Scholar 

  79. Abbas AS, Dehbi HM, Ray KK (2016) Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. Diabetes Obes Metab 18(3):295–299. https://doi.org/10.1111/dom.12595

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Lorenza Lanini, an independent medical writer, and Melanie Gatt (PhD), who provided editorial assistance, on behalf of Springer Healthcare Communications. This support was funded by Novartis.

Author information

Authors and Affiliations

  1. Department of Clinical and Surgical Science, University of Magna Graecia of Catanzaro, Catanzaro, Italy

    Giorgio Sesti

  2. Department of Medicine, University of Padova, Padova, Italy

    Angelo Avogaro & Benedetta Maria Bonora

  3. Department of Medical Sciences, University of Turin, Turin, Italy

    Sara Belcastro

  4. Department of Medical Sciences and Rehabilitation, IRCCS Istituto Auxologico Italiano, Milan, Italy

    Marina Croci & Cecilia Invitti

  5. Department of Clinical and Experimental Medicine A.O.U. Pisana, Pisa, Italy

    Giuseppe Daniele

  6. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Hospital Trust of Verona, Verona, Italy

    Marco Dauriz & Enzo Bonora

  7. Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy

    Francesco Dotta & Caterina Formichi

  8. Unit of Endocrinology, Diabetes and Metabolism, Department of Systems Medicine, S. Giovanni Calibita Fatebenefratelli Hospital, University of Rome Tor Vergata, Rome, Italy

    Simona Frontoni & Fabiana Picconi

  9. Diabetes Unit, Fondazione IRCCS’Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy

    Emanuela Orsi & Veronica Resi

  10. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Veronica Resi

  11. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

    Francesco Purrello

Authors
  1. Giorgio Sesti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angelo Avogaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Belcastro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benedetta Maria Bonora
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Croci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuseppe Daniele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marco Dauriz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesco Dotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caterina Formichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Simona Frontoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cecilia Invitti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Emanuela Orsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Fabiana Picconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Veronica Resi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Enzo Bonora
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Francesco Purrello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giorgio Sesti.

Ethics declarations

Conflict of interest

Giorgio Sesti has received speaker/consulting honoraria from Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Sanofi, Amgem, GlaxoSmithKline, Mylan, Abbott, and Servier. Angelo Avogaro has received research grants, lecture or advisory board fees from Merck Sharp & Dome, AstraZeneca, Novartis, Bayer, Boeringher-Ingelheim, Sanofi, Mediolanum, Janssen, NovoNordisk, Eli Lilly, Servier, Vifor Pharma, Jannsen, and Takeda. Sara Belcastro is a consultant for Novo nordisk, Mundipharma, Novartis, and Merck & co. Simona Frontoni has received honoraria for participating in advisory boards or speaking engagement from all companies producing medicine for diabetes care over the last 10 years. Her institution received research grant from Novo Nordisk, MSD, Ibsa. Cecilia Invitti has received a speaker honorarium from Guidotti. Benedetta Maria Bonora, Marina Croci, Giuseppe Daniele, Marco Dauriz, Francesco Dotta, Caterina Formichi, Emanuela Orsi, Fabiana Picconi and Veronica Resi declare that they have no conflict of interest. Enzo Bonora has received honoraria for participating in advisory boards or speaking engagement from all companies producing medicine for diabetes care over the last 10 years. His institution received research grant from Novo Nordisk, Takeda, AstraZeneca. Francesco Purrello has received honoraria for participating in advisory boards or speaking engagement from Eli Lilly, Novo Nordisk, Sanofi, MSD, AstraZeneca, Boheringer, GSK, Novartis, Menarini. His institution received research grant from Eli Lilly, Novo Nordisk, AstraZeneca.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Additional information

Managed by Massimo Federici.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sesti, G., Avogaro, A., Belcastro, S. et al. Ten years of experience with DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. Acta Diabetol 56, 605–617 (2019). https://doi.org/10.1007/s00592-018-1271-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-018-1271-3

Keywords

Search

Navigation