Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus

Abstract

Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.

Key points

  • Dipeptidyl peptidase 4 inhibitors (DPP4i) were rationally designed based on the prior knowledge of the physiology of glucagon-like peptide 1 and an understanding of the role of DPP4 in its metabolism.

  • DPP4i are all small molecules that inhibit the catalytic activity of the enzyme without affecting any of the other known functions of the DPP4 protein.

  • The DPP4i class comprises a heterogeneous group of unrelated compounds with differing pharmacokinetic profiles.

  • Potential risks and benefits of DPP4i can be divided into class effects, occurring directly as a consequence of the inhibition of DPP4 activity, and compound-specific effects, related to the individual chemical entities.

  • DPP4i have a favourable therapeutic profile and are proven not to increase cardiovascular risk; they are safe and effective in the majority of patients with type 2 diabetes mellitus.

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Fig. 1: Anti-diabetic actions of GLP1.
Fig. 2: Mechanism of action of DPP4i.

References

  1. 1.

    Deacon, C. F. et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44, 1126–1131 (1995).

    CAS  PubMed  Google Scholar 

  2. 2.

    Davies, M. J. et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 61, 2461–2498 (2018).

    PubMed  Google Scholar 

  3. 3.

    Handelsman, Y. et al. American Association of Clinical Endocrinologists and American College of Endocrinology: clinical practice guidelines for developing a diabetes mellitus comprehensive care plan — 2015. Endocr. Pract. 21 (Suppl 1), 1–87 (2015).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Garber, A. et al. Consensus statement by the American Association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm — 2016 executive summary. Endocr. Pract. 22, 84–113 (2016).

    PubMed  Google Scholar 

  5. 5.

    Holst, J. J. & Deacon, C. F. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47, 663–1670 (1998).

    Google Scholar 

  6. 6.

    Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2, 1300–1304 (1987).

    CAS  PubMed  Google Scholar 

  7. 7.

    Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    CAS  PubMed  Google Scholar 

  8. 8.

    Nauck, M. A. et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744 (1993).

    CAS  PubMed  Google Scholar 

  9. 9.

    Amiel, S. A. Glucagon-like peptide: a therapeutic glimmer. Lancet 343, 4–5 (1994).

    CAS  PubMed  Google Scholar 

  10. 10.

    Mentlein, R., Gallwitz, B. & Schmidt, W. E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829–835 (1993).

    CAS  PubMed  Google Scholar 

  11. 11.

    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).

    CAS  PubMed  Google Scholar 

  12. 12.

    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 

  13. 13.

    Deacon, C. F., Hughes, T. E. & Holst, J. J. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes 47, 764–769 (1998).

    CAS  PubMed  Google Scholar 

  14. 14.

    Pederson, R. A. et al. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. Diabetes 47, 1253–1258 (1998).

    CAS  PubMed  Google Scholar 

  15. 15.

    Ahrén, B. et al. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 25, 869–875 (2002).

    PubMed  Google Scholar 

  16. 16.

    Ahrén, B., Gomis, R., Standl, E., Mills, D. & Schweizer, A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27, 2874–2880 (2004).

    PubMed  Google Scholar 

  17. 17.

    Esposito, K. et al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 13, 594–603 (2011).

    CAS  PubMed  Google Scholar 

  18. 18.

    Scheen, A. J. The safety of gliptins: updated data in 2018. Expert Opin. Drug Saf. 17, 387–405 (2018).

    CAS  PubMed  Google Scholar 

  19. 19.

    Deacon, C. F. Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides 100, 150–157 (2018).

    CAS  PubMed  Google Scholar 

  20. 20.

    Mulvihill, E. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 35, 992–1019 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Mari, A. et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 90, 4888–4894 (2005).

    CAS  PubMed  Google Scholar 

  22. 22.

    Herman, G. A. et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 91, 4612–4619 (2006).

    CAS  PubMed  Google Scholar 

  23. 23.

    Aulinger, B. A. et al. Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. Diabetes 63, 1079–1092 (2014).

    CAS  PubMed  Google Scholar 

  24. 24.

    Nauck, M. A. et al. Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9–39] as a GLP-1 receptor antagonist. Diabetes 65, 2440–2447 (2016).

    CAS  PubMed  Google Scholar 

  25. 25.

    Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    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 (2009).

    PubMed  Google Scholar 

  27. 27.

    Aaboe, K. et al. Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors. Diabetes Obes. Metab. 17, 74–81 (2015).

    CAS  PubMed  Google Scholar 

  28. 28.

    Gasbjerg, L. S. et al. GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study. Diabetologia 61, 413–423 (2018).

    CAS  PubMed  Google Scholar 

  29. 29.

    Christensen, M., Vedtofte, L., Holst, J. J., Vilsbøll, T. & Knop, F. K. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 60, 3103–3109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Christensen, M. B., Calanna, S., Holst, J. J., Vilsbøll, T. & Knop, F. K. Glucose-dependent insulinotropic polypeptide: blood glucose stabilizing effects in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 29, E418–E426 (2014).

    Google Scholar 

  31. 31.

    Ahrén, B. et al. Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 9, 1236–1243 (2009).

    Google Scholar 

  32. 32.

    Farngren, J., Persson, M., Schweizer, A., Foley, J. E. & Ahrén, B. Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes. Diabetes Obes. Metab. 16, 812–828 (2014).

    CAS  PubMed  Google Scholar 

  33. 33.

    Mentlein, R. Dipeptidyl-peptidase IV (CD26) — role in the inactivation of regulatory peptides. Regul. Pept. 85, 9–24 (1999).

    CAS  PubMed  Google Scholar 

  34. 34.

    Hopsu-Havu, V. K. & Glenner, G. G. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemie 7, 197–201 (1966).

    CAS  PubMed  Google Scholar 

  35. 35.

    Mentlein, R. Proline residues in the maturation and degradation of peptide hormones and neuropeptides. FEBS Lett. 234, 251–256 (1988).

    CAS  PubMed  Google Scholar 

  36. 36.

    Schön, E. et al. Dipeptidyl peptidase IV in the immune system. Effects of specific enzyme inhibitors on activity of dipeptidyl peptidase IV and proliferation of human lymphocytes. Biol. Chem. Hoppe. Seyler. 372, 305–311 (1991).

    PubMed  Google Scholar 

  37. 37.

    Villhauer, E. B. et al. 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 46, 2774–2789 (2003).

    CAS  PubMed  Google Scholar 

  38. 38.

    Augeri, D. J. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 48, 5025–5037 (2005).

    CAS  PubMed  Google Scholar 

  39. 39.

    Rasmussen, H. B., Branner, S., Wiberg, F. C. & Wagtmann, N. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 10, 19–25 (2003).

    CAS  PubMed  Google Scholar 

  40. 40.

    Kim, D. et al. 2 R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 48, 141–151 (2005).

    CAS  PubMed  Google Scholar 

  41. 41.

    Feng, J. et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 50, 2297–2300 (2007).

    CAS  PubMed  Google Scholar 

  42. 42.

    Eckhardt, M. et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 50, 6450–6453 (2007).

    CAS  PubMed  Google Scholar 

  43. 43.

    Deacon, C. F. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes. Metab. 13, 7–18 (2011).

    CAS  PubMed  Google Scholar 

  44. 44.

    Herman, G. A. et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin. Pharmacol. Ther. 78, 675–688 (2005).

    CAS  PubMed  Google Scholar 

  45. 45.

    European Medicines Agency. Sitagliptin: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/januvia-epar-product-information_en.pdf (accessed August 2020).

  46. 46.

    Bergman., A. J. et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 30, 1862–1864 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    He, Y. L. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin. Pharmacokinet. 51, 147–162 (2012).

    CAS  PubMed  Google Scholar 

  48. 48.

    European Medicines Agency. Vildagliptin: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/galvus-epar-product-information_en.pdf (accessed August 2020).

  49. 49.

    Boulton, D. W. Clinical pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor. Clin. Pharmacokinet. 56, 11–24 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Boulton, D. W. et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin. Pharmacokinet. 50, 253–265 (2011).

    CAS  PubMed  Google Scholar 

  51. 51.

    European Medicines Agency. Saxagliptin: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/onglyza-epar-product-information_en.pdf (accessed August 2020).

  52. 52.

    White, J. R. Alogliptin for the treatment of type 2 diabetes. Drugs Today 47, 99–107 (2011).

    CAS  PubMed  Google Scholar 

  53. 53.

    European Medicines Agency. Alogliptin: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/vipidia-epar-product-information_en.pdf (accessed August 2020).

  54. 54.

    Graefe-Mody, U., Retlich, S. & Friedrich, C. Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clin. Pharmacokinet. 51, 411–427 (2012).

    CAS  PubMed  Google Scholar 

  55. 55.

    Graefe-Mody, U. et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes. Metab. 13, 939–946 (2011).

    CAS  PubMed  Google Scholar 

  56. 56.

    European Medicines Agency. Linagliptin: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/trajenta-epar-product-information_en.pdf (accessed August 2020).

  57. 57.

    Graefe-Mody, U. et al. Pharmacokinetics of linagliptin in subjects with hepatic impairment. Br. J. Clin. Pharmacol. 74, 75–85 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ahrén, B. et al. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes Obes. Metab. 13, 775–783 (2011).

    PubMed  Google Scholar 

  59. 59.

    Nabeno, M. et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem. Biophys. Res. Commun. 434, 191–196 (2013).

    CAS  PubMed  Google Scholar 

  60. 60.

    Tatosian, D. A. et al. Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. Diabetes Ther. 4, 431–442 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Baranov, O., Kahle, M., Deacon, C. F., Holst, J. J. & Nauck, M. A. Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition: a randomized, prospective comparison of sitagliptin and vildagliptin treatment. Diabetes Obes. Metab. 18, 1100–1109 (2016).

    CAS  PubMed  Google Scholar 

  62. 62.

    Alsalim, W. et al. Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes. Diabetes Obes. Metab. 22, 590–598 (2020).

    CAS  PubMed  Google Scholar 

  63. 63.

    Scheen, A. J., Charpentier, G., Ostgren, C. J., Hellqvist, A. & Gause-Nilsson, I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 26, 540–549 (2010).

    CAS  PubMed  Google Scholar 

  64. 64.

    Rizzo, M. R., Barbieri, M., Marfella, R. & Paolisso, G. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 35, 2076–2082 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kothny, W., Lukashevich, V., Foley, J. E., Rendell, M. S. & Schweizer, A. Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial. Diabetologia 58, 2020–2026 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Deacon, C. F. & Lebovitz, H. E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes. Metab. 18, 333–347 (2016).

    CAS  PubMed  Google Scholar 

  67. 67.

    Inagaki, N., Onouchi, H., Maezawa, H., Kuroda, S. & Kaku, K. Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study. Lancet Diabetes Endocrinol. 3, 191–197 (2015).

    CAS  PubMed  Google Scholar 

  68. 68.

    Addy, C. et al. Pharmacokinetic and pharmacodynamic effects of multiple-dose administration of omarigliptin, a once-weekly dipeptidyl peptidase-4 inhibitor, in obese participants with and without type 2 diabetes mellitus. Clin. Ther. 38, 516–530 (2016).

    CAS  PubMed  Google Scholar 

  69. 69.

    Goldenberg, R. et al. Randomized clinical trial comparing the efficacy and safety of treatment with the once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin or the once-daily DPP-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes. Metab. 19, 394–400 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Kim, Y. G. et al. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia 56, 696–708 (2013).

    CAS  PubMed  Google Scholar 

  71. 71.

    Cai, X., Han, X., Luo, Y. & Ji, L. Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on β-cell function in Asian and Caucasian type 2 diabetes mellitus patients: a meta-analysis. J. Diabetes 7, 347–359 (2015).

    CAS  PubMed  Google Scholar 

  72. 72.

    Gao, W., Wang, Q. & Yu, S. Efficacy, safety and impact on β-cell function of dipeptidyl peptidase-4 inhibitors plus metformin combination therapy in patients with type 2 diabetes and the difference between Asians and Caucasians: a meta-analysis. J. Endocrinol. Invest. 39, 1061–1074 (2016).

    CAS  PubMed  Google Scholar 

  73. 73.

    Kozlovski, P. et al. Effect of race and ethnicity on vildagliptin efficacy: a pooled analysis of phase II and III studies. Diabetes Obes. Metab. 19, 429–435 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Morimoto, C. & Schlossman, S. F. The structure and function of CD26 in the T-cell immune response. Immunol. Rev. 161, 55–70 (1998).

    CAS  PubMed  Google Scholar 

  75. 75.

    Ohnuma, K., Dang, N. H. & Morimoto, C. Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends. Immunol. 29, 295–301 (2008).

    CAS  PubMed  Google Scholar 

  76. 76.

    Hühn, J., Ehrlich, S., Fleischer, B. & von Bonin, A. Molecular analysis of CD26 mediated signal transduction in T cells. Immunol. Lett. 72, 127–32 (2000).

    PubMed  Google Scholar 

  77. 77.

    Anz, D. et al. The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses. Diabetes Obes. Metab. 16, 569–572 (2014).

    CAS  PubMed  Google Scholar 

  78. 78.

    Goodwin, S. R. et al. Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study. J. Clin. Endocrinol. Metab. 98, 743–745 (2013).

    CAS  PubMed  Google Scholar 

  79. 79.

    Dubé, M. P. et al. A randomized, double-blinded, placebo-controlled trial of sitagliptin for reducing inflammation and immune activation in treated and suppressed human immunodeficiency virus infection. Clin. Infect. Dis. 69, 1165–1172 (2019).

    PubMed  Google Scholar 

  80. 80.

    Pratley, R. E., McCall, T., Fleck, P. R., Wilson, C. A. & Mekki, Q. Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J. Am. Geriatr. Soc. 57, 2011–2019 (2009).

    PubMed  Google Scholar 

  81. 81.

    Lehrke, M. et al. Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies. Clin. Ther. 36, 1130–1146 (2014).

    CAS  PubMed  Google Scholar 

  82. 82.

    Hirshberg, B., Parker, A., Edelberg, H., Donovan, M. & Iqbal, N. Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 30, 556–569 (2014).

    CAS  PubMed  Google Scholar 

  83. 83.

    Engel, S. S., Round, E., Golm, G. T., Kaufman, K. D. & Goldstein, B. J. Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther. 4, 119–145 (2013).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Schweizer, A., Dejager, S., Foley, J. E. & Kothny, W. Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies. Vasc. Health Risk Manag. 7, 49–57 (2011).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Scirica, B. M. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369, 1317–1326 (2013).

    CAS  PubMed  Google Scholar 

  86. 86.

    White, W. B. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369, 1327–1335 (2013).

    CAS  PubMed  Google Scholar 

  87. 87.

    Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232–242 (2015).

    CAS  PubMed  Google Scholar 

  88. 88.

    Rosenstock, J. et al. 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. JAMA 321, 69–79 (2019).

    CAS  PubMed  Google Scholar 

  89. 89.

    Rosenstock, J. et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 322, 1155–1166 (2019).

    CAS  PubMed Central  Google Scholar 

  90. 90.

    Aaboe, K. et al. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 12, 323–333 (2010).

    CAS  PubMed  Google Scholar 

  91. 91.

    Butler, P. C., Elashoff, M., Elashoff, R. & Gale, E. A. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 36, 2118–2125 (2013).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Nauck, M. A. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care. 36, 2126–2232 (2013).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Egan, A. G. et al. Pancreatic safety of incretin-based drugs — FDA and EMA assessment. N. Engl. J. Med. 370, 794–797 (2014).

    CAS  PubMed  Google Scholar 

  94. 94.

    Meier, J. J. & Nauck, M. A. Risk of pancreatitis in patients treated with incretin-based therapies. Diabetologia 57, 1320–1324 (2014).

    CAS  PubMed  Google Scholar 

  95. 95.

    Abd El Aziz, M., Cahyadi, O., Meier, J. J., Schmidt, W. E. & Nauck, M. A. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes Obes. Metab. 22, 699–704 (2020).

    CAS  PubMed  Google Scholar 

  96. 96.

    Azoulay, L. et al. Association between incretin-based drugs and the risk of acute pancreatitis. JAMA Intern. Med. 176, 1464–1473 (2016).

    PubMed  Google Scholar 

  97. 97.

    Lai, Y. J., Hu, H. Y., Chen, H. H. & Chou, P. Dipeptidyl peptidase-4 inhibitors and the risk of acute pancreatitis in patients with type 2 diabetes in Taiwan: a population-based cohort study. Medicine 94, e1906 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Dicembrini, I., Montereggi, C., Nreu, B., Mannucci, E. & Monami, M. Pancreatitis and pancreatic cancer in patients treated with dipeptidyl peptidase-4 inhibitors: an extensive and updated meta-analysis of randomized controlled trials. Diabetes Res. Clin. Pract. 159, 107981 (2020).

    CAS  PubMed  Google Scholar 

  99. 99.

    DeVries, J. H. & Rosenstock, J. DPP-4 inhibitor-related pancreatitis: rare but real! Diabetes Care 40, 161–163 (2017).

    PubMed  Google Scholar 

  100. 100.

    Wang, C. Y., Fu, S. H., Yang, R. S. & Hsiao, F. Y. Use of dipeptidyl peptidase-4 inhibitors and the risk of arthralgia: population-based cohort and nested case–control studies. Pharmacoepidemiol. Drug Saf. 28, 500–506 (2019).

    CAS  PubMed  Google Scholar 

  101. 101.

    García-Díez, I. et al. Bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. Eight cases with clinical and immunological characterization. Int. J. Dermatol. 57, 810–816 (2018).

    PubMed  Google Scholar 

  102. 102.

    Douros, A. et al. Dipeptidyl peptidase 4 inhibitors and the risk of bullous pemphigoid among patients with type 2 diabetes. Diabetes Care 42, 1496–1503 (2019).

    CAS  PubMed  Google Scholar 

  103. 103.

    Koyani, C. N. et al. Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. Biochem. Pharmacol. 145, 64–80 (2017).

    CAS  PubMed  Google Scholar 

  104. 104.

    Koyani, C. N. et al. Saxagliptin but not sitagliptin inhibits CaMKII and PKC via DPP9 inhibition in cardiomyocytes. Front. Physiol. 9, 1622 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Davies, M. J. et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 61, 2461–2498 (2018).

    PubMed  Google Scholar 

  106. 106.

    Seferović, P. M. et al. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur. J. Heart Fail. 22, 196–213 (2020).

    PubMed  Google Scholar 

  107. 107.

    Burkey, B. F. et al. Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes. Metab. 10, 1057–1061 (2008).

    CAS  PubMed  Google Scholar 

  108. 108.

    Williams, R. et al. Cardiovascular safety of vildagliptin in patients with type 2 diabetes: a European multi-database, non-interventional post-authorization safety study. Diabetes Obes. Metab. 19, 1473–1478 (2017).

    CAS  PubMed  Google Scholar 

  109. 109.

    McMurray, J. J. V. et al. 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, 8–17 (2018).

    PubMed  Google Scholar 

  110. 110.

    Ligueros-Saylan, M., Foley, J. E., Schweizer, A., Couturier, A. & Kothny, W. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of phase II and III clinical trials. Diabetes Obes. Metab. 12, 495–509 (2010).

    CAS  PubMed  Google Scholar 

  111. 111.

    Barbehenn, E., Almashat, S., Carome, M. & Wolfe, S. Hepatotoxicity of alogliptin. Clin. Pharmacokinet. 53, 1055–1056 (2014).

    PubMed  Google Scholar 

  112. 112.

    Scheen, A. J. Alogliptin: concern about hepatotoxicity? Clin. Pharmacokinet. 53, 1057–1059 (2014).

    PubMed  Google Scholar 

  113. 113.

    Mannucci, E. et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without type 2 diabetes. Diabetes Nutr. Metab. 17, 336–342 (2004).

    CAS  PubMed  Google Scholar 

  114. 114.

    Migoya, E. M. et al. Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1. Clin. Pharmacol. Ther. 88, 801–808 (2010).

    CAS  PubMed  Google Scholar 

  115. 115.

    Bahne, E. et al. Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. JCI Insight 3, 93936 (2018).

    PubMed  Google Scholar 

  116. 116.

    Monami, M., Iacomelli, I., Marchionni, N. & Mannucci, E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr. Metab. Cardiovasc. Dis. 20, 224–235 (2010).

    CAS  PubMed  Google Scholar 

  117. 117.

    Wang, T., McNeill, A. M., Chen, Y., O’Neill, E. A. & Engel, S. S. Characteristics of elderly patients initiating sitagliptin or non-DPP-4-inhibitor oral antihyperglycemic agents: analysis of a cross-sectional US claims database. Diabetes Ther. 9, 309–315 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Barzilai, N. 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. 27, 1049–1058 (2011).

    CAS  PubMed  Google Scholar 

  119. 119.

    Barnett, A. H. et al. 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, 1413–1423 (2013).

    CAS  PubMed  Google Scholar 

  120. 120.

    Strain, W. D., Lukashevich, V., Kothny, W., Hoellinger, M. J. & Paldánius, P. M. 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, 409–416 (2013).

    CAS  PubMed  Google Scholar 

  121. 121.

    Leiter, L. A. et al. Efficacy and safety of saxagliptin in older participants in the SAVOR-TIMI 53 trial. Diabetes Care 38, 1145–1153 (2015).

    CAS  PubMed  Google Scholar 

  122. 122.

    Bethel, M. A. et al. Assessing the safety of sitagliptin in older participants in the trial evaluating cardiovascular outcomes with sitagliptin (TECOS). Diabetes Care. 40, 494–501 (2017).

    PubMed  Google Scholar 

  123. 123.

    Walker, S. R. et al. Dipeptidyl peptidase-4 inhibitors in chronic kidney disease: a systematic review of randomized clinical trials. Nephron. 136, 85–94 (2017).

    CAS  PubMed  Google Scholar 

  124. 124.

    Spanopoulos, D., Barrett, B., Busse, M., Roman, T. & Poole, C. Prescription of DPP-4 inhibitors to type 2 diabetes mellitus patients with renal impairment: a UK primary care experience. Clin. Ther. 40, 152–154 (2018).

    CAS  PubMed  Google Scholar 

  125. 125.

    Bergman, A. J. et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin. Ther. 28, 55–72 (2006).

    CAS  PubMed  Google Scholar 

  126. 126.

    He, Y. L. et al. Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. J. Clin. Pharmacol. 47, 633–641 (2007).

    CAS  PubMed  Google Scholar 

  127. 127.

    Christopher, R. et al. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin. Ther. 30, 513–527 (2008).

    CAS  PubMed  Google Scholar 

  128. 128.

    Bajaj, H. S. et al. Glycemic improvement with a fixed-dose combination of DPP-4 inhibitor + metformin in patients with type 2 diabetes (GIFT study). Diabetes Obes. Metab. 20, 195–199 (2018).

    CAS  PubMed  Google Scholar 

  129. 129.

    Molina-Vega, M., Muñoz-Garach, A., Fernández-García, J. C. & Tinahones, F. J. The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies. Expert Opin. Drug Saf. 17, 815–824 (2018).

    PubMed  Google Scholar 

  130. 130.

    Holland, D. Q. & Neumiller, J. J. Alogliptin in combination with metformin and pioglitazone for the treatment of type 2 diabetes mellitus. Diabetes Metab. Syndr. Obes. 7, 277–288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    North, E. J. & Newman, J. D. Review of cardiovascular outcomes trials of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Curr. Opin. Cardiol. 34, 687–692 (2019).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Buse, J. B. et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 63, 221–228 (2020).

    PubMed  Google Scholar 

  133. 133.

    Zoungas, S. et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 5, 431–437 (2017).

    PubMed  Google Scholar 

  134. 134.

    Lipinski, C. A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 1, 337–341 (2004).

    CAS  PubMed  Google Scholar 

  135. 135.

    Carr, R. D. & Solomon, A. Inhibitors of dipeptidyl peptidase 4 as therapeutic agents for individuals with type 2 diabetes: a 25-year journey. Diabet Med. 33, 718–722 (2020).

    Google Scholar 

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Correspondence to Carolyn F. Deacon.

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No writing assistance or financial support was used in the preparation of this article. C.F.D. has received consultancy and/or lecture fees from companies with an interest in developing and marketing incretin-based therapies for treatment of type 2 diabetes mellitus (Boehringer Ingelheim, Lilly, Merck/MSD and Novo Nordisk). C.F.D.’s spouse is employed by, and holds stock in, Merck/MSD.

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Nature Reviews Endocrinology thanks G. Mingrone, who co-reviewed with L. Gissey, P. Flatt and K. Kaku, for their contribution to the peer review of this work.

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Deacon, C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol (2020). https://doi.org/10.1038/s41574-020-0399-8

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