Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Incretin-based therapies for type 2 diabetes mellitus

Nature Reviews Endocrinology volume 5, pages 262–269 (2009)Cite this article

Abstract

Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.

Key Points

  • Incretins exert antidiabetic actions in a glucose-dependent manner

  • Glucagon-like peptide 1 receptor (GLP-1R) agonists, but not dipeptidyl peptidase-4 (DPP-4) inhibitors, inhibit gastric emptying and might cause weight loss

  • DPP-4 inhibitors can be administered orally and are well tolerated

  • GLP-1R agonists must be administered by subcutaneous injection and commonly cause nausea

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: GLP-1 receptor agonists exert diverse actions on distinct target tissues, which lead to reduction of blood glucose level and body weight in humans.
Figure 2: Mechanism of action of DPP-4 inhibitors.

Similar content being viewed by others

References

  1. Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-17–36: a physiological incretin in man. Lancet 2, 1300–1304 (1987).

    Article  CAS  Google Scholar 

  2. Deacon, C. F. Therapeutic strategies based on glucagon-like peptide 1. Diabetes 53, 2181–2189 (2004).

    Article  CAS  Google Scholar 

  3. Drucker, D. J. The biology of incretin hormones. Cell. Metab. 3, 153–165 (2006).

    Article  CAS  Google Scholar 

  4. Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).

    Article  CAS  Google Scholar 

  5. Deacon, C. F., Johnsen, A. H. & Holst, J. J. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo . J. Clin. Endocrinol. Metab. 80, 952–957 (1995).

    CAS  PubMed  Google Scholar 

  6. Kieffer, T. J., McIntosh, C. H. & Pederson, R. A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136, 3585–3596 (1995).

    Article  CAS  Google Scholar 

  7. Cervera, A. et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 294, E846–E852 (2008).

    Article  CAS  Google Scholar 

  8. Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 17–36 amide but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).

    Article  CAS  Google Scholar 

  9. Højberg, P. V. et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52, 199–207 (2008).

    Article  Google Scholar 

  10. Zander, M., Madsbad, S., Madsen, J. L. & Holst, J. J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824–830 (2002).

    Article  CAS  Google Scholar 

  11. Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).

    Article  CAS  Google Scholar 

  12. DeFronzo, R. A. et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28, 1092–1100 (2005).

    Article  CAS  Google Scholar 

  13. Kendall, D. M. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28, 1083–1091 (2005).

    Article  CAS  Google Scholar 

  14. Zinman, B. et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med. 146, 477–485 (2007).

    Article  Google Scholar 

  15. Heine, R. J. et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann. Intern. Med. 143, 559–569 (2005).

    Article  CAS  Google Scholar 

  16. Nauck, M. A. et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 50, 259–267 (2007).

    Article  CAS  Google Scholar 

  17. Bunck, M. C. et al. β-cell function and glycemic control following one year exenatide therapy, and after 12 week wash out, in patients with type 2 diabetes. Presented at the 68th Annual Meeting of the American Diabetes Association, 2008 June 6–10, San Francisco, US (2008).

    Google Scholar 

  18. Vilsbøll, T. et al. Liraglutide, a long-acting human GLP-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes mellitus. Diabetes Care 6, 160–610 (2007).

    Google Scholar 

  19. Seino, Y., Rasmussen, M. F., Zdravkovic, M. & Kaku, K. Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: a double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes. Diabetes Res. Clin. Pract. 81, 161–168 (2008).

    Article  CAS  Google Scholar 

  20. Zinman, B. et al. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met + TZD). Presented at the 44th Annual Meeting of the European Association for the Study of Diabetes, 2008 September 7–11, Rome, Italy (2008).

    Google Scholar 

  21. Garber, A. et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373, 473–481 (2009).

    Article  CAS  Google Scholar 

  22. Marre, M. et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabetic Medicine 14 Jan doi:10.1111/j.1464–54912009.02666.x (2009).

  23. Nauck, M. et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care 32, 84–90 (2008).

    Article  Google Scholar 

  24. Russell-Jones, D. et al. Significantly better glycemic control and weight reduction with liraglutide, a once-daily human GLP-1 analog, compared with insulin glargine: all as add-on to metformin and a sulfonylurea in type 2 diabetes. Presented at the 68th Annual meeting of the American Diabetes Association, 6–10 June 2008, San Francisco, USA (2008).

    Google Scholar 

  25. Blonde, L. et al. Liragluide: superiror glycemia control vs exenatide when added to metformin and/or SU in type 2 diabetes. Presented at the Annual meeting of the Canadian Diabetes Association, 16 October 2008, Montreal, Quebec, Canada (2008).

    Google Scholar 

  26. Ratner, R. E. et al. A dose-finding study of the new GLP-1 agonist AVE0010 in type 2 diabetes insufficiently controlled with metformin. Presented at the 68th Annual meeting of the American Diabetes Association, 2008 June 6–10, San Francisco, USA (2008).

    Google Scholar 

  27. Kim, D, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 30, 1487–1493 (2007).

    Article  CAS  Google Scholar 

  28. Drucker, D. J. et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372, 1240–1250 (2008).

    Article  CAS  Google Scholar 

  29. Baggio, L. L. et al. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 53, 2492–2500 (2004).

    Article  CAS  Google Scholar 

  30. Bloom, M. et al. Albugon fusion protein; a long-acting analog of GLP-1 that provides lasting anti-diabetic effect in animals. Presented at the 63rd Annual Meeting of the American Diabetes Association, 2003 June, New Orleans, LO, USA (2003).

    Google Scholar 

  31. Matthews, J. E. et al. Pharmacodynamics, pharmacokinetics, safety and tolerability of albiglutide, a long-acting GLP-1 mimetic, in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, 4810–4817 (2008).

    Article  CAS  Google Scholar 

  32. Balena, R. et al. Eight weeks of treatment with the long acting, human GLP-1 analogue R1583 improves glycemic control and lowers body weight in subjects with type 2 diabetes mellitus (T2DM) treated with metformin: a double-blind placebo-controlled phase 2 Study. Presented at the 68th Annual Meeting of the American Diabetes Association, 2008 June 6–10, San Francisco, US (2008).

    Google Scholar 

  33. Ratner, R. et al. safety and tolerability of high doses of the long acting, human GLP-1 analogue R1583 in diabetic subjects treated with metformin: a double-blind, placebo-controlled phase 2 study. Presented at the 68th Annual Meeting of the American Diabetes Association, 2008 June 6–10, San Francisco, USA (2008).

    Google Scholar 

  34. Baggio, L. L. et al. The long-acting albumin-exendin-4 GLP-1R agonist CJC-1134 engages central and peripheral mechanisms regulating glucose homeostasis. Gastroenterology 134, 1137–1147 (2008).

    Article  CAS  Google Scholar 

  35. Ahmad, S. R. & Swann, J. Exenatide and rare adverse events. N. Engl. J. Med. 358, 1970–1972 (2008).

    CAS  PubMed  Google Scholar 

  36. Raufman, J.-P. et al. Truncated glucagon-like peptide-1 interacts with exendin receptors on disperced acini from guinea pig pancreas. Identification of a mammalian homologue of the reptilian peptide exendin-4. J. Biol. Chem. 267, 21432–21437 (1992).

    CAS  PubMed  Google Scholar 

  37. Hansotia, T. et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53, 1326–1335 (2004).

    Article  CAS  Google Scholar 

  38. Aschner, P. et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 29, 2632–2637 (2006).

    Article  CAS  Google Scholar 

  39. Charbonnel, B. et al. 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 29, 2638–2643 (2006).

    Article  CAS  Google Scholar 

  40. Rosenstock, J. et al. 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. 28, 1556–1568 (2006).

    Article  CAS  Google Scholar 

  41. Goldstein, B. J. et al. 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 30, 1979–1987 (2007).

    Article  CAS  Google Scholar 

  42. Scott, R. et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes. Metab. 10, 959–969 (2008).

    Article  CAS  Google Scholar 

  43. Raz, I. et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr. Med. Res. Opin. 24, 537–550 (2008).

    Article  CAS  Google Scholar 

  44. Pi-Sunyer, F. X. et al. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes Res. Clin. Pract. 76, 132–138 (2007).

    Article  CAS  Google Scholar 

  45. Rosenstock, J. et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care 30, 217–223 (2007).

    Article  CAS  Google Scholar 

  46. Bolli, G. et al. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes. Metab. 10, 82–90 (2008).

    CAS  PubMed  Google Scholar 

  47. Lankas, G. R. et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 54, 2988–2994 (2005).

    Article  CAS  Google Scholar 

  48. Chan, J. C. et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes. Metab. 10, 545–555 (2008).

    Article  CAS  Google Scholar 

  49. Defronzo, R. A. et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes mellitus and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care 31, 2315–2317 (2008).

    Article  CAS  Google Scholar 

  50. Nauck, M. A. et al. 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. 63, 46–55 (2009).

    Article  CAS  Google Scholar 

  51. Fonseca, V. et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 50, 1148–1155 (2007).

    Article  CAS  Google Scholar 

  52. Garcia-Soria, G. et al. The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 10, 293–300 (2008).

    Article  CAS  Google Scholar 

  53. Ghofaili, K. A. et al. Effect of exenatide on β cell function after islet transplantation in type 1 diabetes. Transplantation 83, 24–28 (2007).

    Article  Google Scholar 

  54. Froud, T. et al. The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects. Transplantation 86, 36–45 (2008).

    Article  Google Scholar 

  55. Inzucchi, S. E. & McGuire, D. K. New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond. Circulation 117, 574–584 (2008).

    Article  Google Scholar 

  56. Sokos, G. G. et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J. Card. Fail. 12, 694–699 (2006).

    Article  CAS  Google Scholar 

  57. Nikolaidis, L. A. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109, 962–965 (2004).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, University of Toronto, Toronto, Canada

    Julie A. Lovshin & Daniel J. Drucker

Authors
  1. Julie A. Lovshin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. Drucker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel J. Drucker.

Ethics declarations

Competing interests

D. Drucker declared associations with the following companies: Amylin Pharmaceuticals, Arena Pharmaceuticals Inc., Arisaph Pharmaceuticals Inc, Conjuchem Inc., Eli Lilly Inc., Emisphere Technologies Inc., GlaxoSmithKline, Glenmark Pharmaceuticals, Hoffman LaRoche Inc., Isis Pharmaceuticals Inc., Mannkind Inc., Merck Research Laboratories, Metabolex Inc., Novartis Pharmaceuticals, Novo Nordisk Inc., Phenomix Inc., Takeda, Transition Pharmaceuticals (advisor/consultant); Arena Pharmaceuticals Inc, Merck Research Laboratories, Metabolex Inc. and Novo Nordisk Inc (advisor/consultant and research/grant support). J. Lovshin declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lovshin, J., Drucker, D. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5, 262–269 (2009). https://doi.org/10.1038/nrendo.2009.48

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2009.48

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing