Skip to main content
SpringerLink
Log in

Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy

  • Review
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

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. International Diabetes Federation. Diabetes Atlas. 4th edition. Available at: www.diabetesatlas.org. Accessed November 1, 2010.

  2. Yorkshire & Humber Public Health Observatory. APHO diabetes prevalence model. Available at: www.yhpho.org.uk/resource/view.aspx?RID=81090. Accessed November, 2010.

  3. Lankas GR, Leiting B, Roy RS, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005;54:2988–2994.

    Article  PubMed  CAS  Google Scholar 

  4. Kirby M, Yu DM, O’Connor S, et al. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci. 2010;118:31–41.

    Article  CAS  Google Scholar 

  5. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Experimental Therapeut. 2008;325:175–182.

    Article  CAS  Google Scholar 

  6. Heise T, Graefe-Mody EU, Hüttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab. 2009;11:786–794.

    Article  PubMed  CAS  Google Scholar 

  7. Blech S, Ludwig-Schwellinger E, Gräfe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010;38:667–678.

    Article  PubMed  CAS  Google Scholar 

  8. Retlich S, Duval V, Ring A, et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg–10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet. 2010;49:829–840.

    Article  PubMed  CAS  Google Scholar 

  9. Scheen AJ. Dipeptidylpeptitase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010;49:573–588.

    Article  PubMed  CAS  Google Scholar 

  10. Graefe-Mody U, Friedrich C, Port A, et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster 822-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.

  11. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of MK-0431 (sitagliptin), a selective dipeptidyl-peptidase-IV (DPP-IV) inhibitor. Clin Pharmacol Therapeut. 2006;38:PII–46.

    Google Scholar 

  12. Chan JC, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008;10:545–555.

    Article  PubMed  CAS  Google Scholar 

  13. Christopher R, Covington P, Davenport M, et al. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther. 2008;30:513–527.

    Article  PubMed  CAS  Google Scholar 

  14. Del Prato S, Barnett AH, Huismann H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes. Diabetes Obes Metab. 2011;13:258–267.

    Article  PubMed  Google Scholar 

  15. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomised, double-blind, placebo controlled study. Diabetes Obes Metab. 2011;13:65–74.

    Article  PubMed  CAS  Google Scholar 

  16. Owens DR, Swallow R, Woerle HJ, et al. Linagliptin improves glycaemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain and low risk of hypoglycaemia. Poster 548-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.

  17. Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, placebo controlled study. Diabetes Obes Metab. 2011;doi: 10.1111/j.1463-1326.2011.01391.x.

  18. Lewin AJ, Arvay L, Liu D, et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster 821-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.

  19. Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy improves glycemic control in Japanese patients with T2DM over 12 weeks. Poster 696-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.

  20. Kawamori R, Inagaki N, Araki E, et al. Linagliptin provides superior glycemic control compared to voglibose as monotherapy in Japanese patients with type 2 diabetes. Poster 632-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.

  21. Forst T, Uhlig-Laske B, Ring A, 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. Diabetic Med. 2010;27:1409–1419.

    Article  PubMed  CAS  Google Scholar 

  22. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47.

    Article  PubMed  CAS  Google Scholar 

  23. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194–206.

    Article  PubMed  CAS  Google Scholar 

  24. Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40:209–294.

    Article  PubMed  CAS  Google Scholar 

  25. Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7.

    Article  PubMed  Google Scholar 

  26. Shah P, Schumann DM, Ardestani A, et al. The DPP-4 inhibitor linagliptin restores β-cell function in human isolated islets. Poster 1742-P from the 70th American Diabetes Association Scientific Sessions, 25–29 June 2010, Orlando, Florida, USA.

  27. Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes. 2003;52:741–750.

    Article  PubMed  CAS  Google Scholar 

  28. Duttaroy A, Voelker F, Merriam K, et al. The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in neonatal rats. Eur J Pharmacol. 2011;650:703–707.

    Article  PubMed  CAS  Google Scholar 

  29. National Kidney Foundation. Diabetes and Chronic Kidney Disease; Stages 1–4. Available at: www.kidney.org/atoz/pdf/diabetes.pdf. Accessed November, 2010.

  30. Tayside Diabetes MCN Handbook. Pharmalogical management of glycaemic control in people with type 2 diabetes. Available at: www.diabetes-healthnet.ac.uk/HandBook/TreatementsWithHypoAgents2.aspx. Accessed November 1, 2010.

  31. US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009.

    Google Scholar 

  32. Plantinga LC, Crews DC, Coresh J, et al. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5:673–682.

    Article  PubMed  Google Scholar 

  33. Fox CS, Larson MG, Leip EP, Meigs JB, Wilson PW, Levy D. Glycemic status and development of kidney disease: the Framingham Heart Study. Diabetes Care. 2005;28:2436–2440.

    Article  PubMed  Google Scholar 

  34. Koopman RJ, Mainous AG 3rd, Liszka HA, et al. Evidence of nephropathy and peripheral neuropathy in US adults with undiagnosed diabetes. Ann Fam Med. 2006;4:427–432.

    Article  PubMed  Google Scholar 

  35. Barnett AH. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006;11:1454–1470.

    Article  Google Scholar 

  36. National Institute for Health and Clinical Excellence (NICE). CG87 type 2 diabetes — newer agents (May 2009). Available at: www.nice.org.uk/nicemedia/live/12165/44318/44318.pdf. Accessed November 1, 2010.

Download references

Author information

Authors and Affiliations

  1. Heart of England National Health Service Foundation Trust (Teaching), University of Birmingham and Biomedical Research Unit, Birmingham, UK

    Anthony H. Barnett

Authors
  1. Anthony H. Barnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony H. Barnett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barnett, A.H. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Therapy 28, 447–459 (2011). https://doi.org/10.1007/s12325-011-0028-y

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-011-0028-y

Keywords

Search

Navigation