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  • Review Article
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Cardiovascular effects of gliptins

Nature Reviews Cardiology volume 10, pages 73–84 (2013)Cite this article

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Abstract

Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II–III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile.

Key Points

  • Dipeptidyl peptidase 4 (DPP-4) inhibitors (gliptins) are incretin-based drugs with a role in the management of type 2 diabetes mellitus; they improve glucose control without inducing hypoglycaemia or weight gain

  • Gliptins not only increase the level of glucagon-like peptide 1, but also the concentration of other peptides that might exert vasoactive, and possibly cardioprotective, effects

  • Gliptins exert pleiotropic actions in patients with type 2 diabetes, resulting in favourable effects on postprandial glycaemia and lipaemia, blood pressure, silent inflammation, oxidative stress, and endothelial dysfunction

  • Post-hoc analyses of phase II–III, controlled trials showed no cardiovascular harm with gliptins compared with placebo or other antihyperglycaemic agents, and possibly indicated a cardiovascular protective effect

  • Large, prospective trials involving >40,000 high-risk patients with type 2 diabetes are ongoing to test the noninferiority or superiority of gliptins (mostly compared with placebo), with prespecified, cardiovascular end points

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Figure 1: Mechanisms underlying the beneficial effects of DPP-4 inhibitors on the cardiovascular system.
Figure 2: Effects of DPP-4 inhibitors on cardiovascular risk factors in patients with type 2 diabetes mellitus.

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References

  1. Seshasai, S. R. et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).

    CAS  Google Scholar 

  2. Hemmingsen, B. et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 343, d6898 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Scheen, A. J. Current management strategies for coexisting diabetes mellitus and obesity. Drugs 63, 1165–1184 (2003).

    CAS  PubMed  Google Scholar 

  4. Niswender, K. Diabetes and obesity: therapeutic targeting and risk reduction—a complex interplay. Diabetes Obes. Metab. 12, 267–287 (2010).

    PubMed  Google Scholar 

  5. Ovalle, F. Cardiovascular implications of antihyperglycemic therapies for type 2 diabetes. Clin. Ther. 33, 393–407 (2011).

    CAS  PubMed  Google Scholar 

  6. Scheen, A. J. A review of gliptins in 2011. Expert Opin. Pharmacother. 13, 81–99 (2012).

    CAS  PubMed  Google Scholar 

  7. Scott, L. J. Alogliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs 70, 2051–2072 (2010).

    CAS  PubMed  Google Scholar 

  8. Scott, L. J. Linagliptin: in type 2 diabetes mellitus. Drugs 71, 611–624 (2011).

    CAS  PubMed  Google Scholar 

  9. Yang, L. P. Saxagliptin: a review of its use as combination therapy in the management of type 2 diabetes mellitus in the EU. Drugs 72, 229–248 (2012).

    CAS  PubMed  Google Scholar 

  10. Dhillon, S. Sitagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs 70, 489–512 (2010).

    CAS  PubMed  Google Scholar 

  11. Keating, G. M. Vildagliptin: a review of its use in type 2 diabetes mellitus. Drugs 70, 2089–2112 (2010).

    CAS  PubMed  Google Scholar 

  12. Scheen, A. J. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 38, 89–101 (2012).

    CAS  PubMed  Google Scholar 

  13. Phung, O. J., Scholle, J. M., Talwar, M. & Coleman, C. I. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 303, 1410–1418 (2010).

    CAS  PubMed  Google Scholar 

  14. Gooßen, K. & Gräber, S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes. Metab. 14, 1061–1072 (2012).

    PubMed  Google Scholar 

  15. Liu, S. C., Tu, Y. K., Chien, M. N. & Chien, K. L. Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diabetes Obes. Metab. 14, 810–820 (2012).

    CAS  PubMed  Google Scholar 

  16. Amiel, S. A., Dixon, T., Mann, R. & Jameson, K. Hypoglycaemia in type 2 diabetes. Diabet. Med. 25, 245–254 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Karagiannis, T., Paschos, P., Paletas, K., Matthews, D. R. & Tsapas, A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344, e1369 (2012).

    PubMed  Google Scholar 

  18. Hermansen, K. & Mortensen, L. S. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf. 30, 1127–1142 (2007).

    CAS  PubMed  Google Scholar 

  19. Inzucchi, S. E. et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 55, 1577–1596 (2012).

    CAS  PubMed  Google Scholar 

  20. Ussher, J. R. & Drucker, D. J. Cardiovascular biology of the incretin system. Endocr. Rev. 33, 187–215 (2012).

    CAS  PubMed  Google Scholar 

  21. Grieve, D. J., Cassidy, R. S. & Green, B. D. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? Br. J. Pharmacol. 157, 1340–1351 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ban, K., Hui, S., Drucker, D. J. & Husain, M. Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretin-based therapies. J. Am. Soc. Hypertens. 3, 245–259 (2009).

    PubMed  Google Scholar 

  23. Chrysant, S. G. & Chrysant, G. S. Clinical implications of cardiovascular preventing pleiotropic effects of dipeptidyl peptidase-4 inhibitors. Am. J. Cardiol. 109, 1681–1685 (2012).

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  Google Scholar 

  25. Sivertsen, J., Rosenmeier, J., Holst, J. J. & Vilsbøll, T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat. Rev. Cardiol. 9, 209–222 (2012).

    CAS  PubMed  Google Scholar 

  26. Monami, M. et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp. Diabetes Res. 2011, 215764 (2011).

    PubMed  PubMed Central  Google Scholar 

  27. Mundil, D., Cameron-Vendrig, A. & Husain, M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diab. Vasc. Dis. Res. 9, 95–108 (2012).

    PubMed  Google Scholar 

  28. Jose, T. & Inzucchi, S. E. Cardiovascular effects of the DPP-4 inhibitors. Diab. Vasc. Dis. Res. 9, 109–116 (2012).

    PubMed  Google Scholar 

  29. Richter, B., Bandeira-Echtler, E., Bergerhoff, K. & Lerch, C. L. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD006739 doi:10.1002/ 14651858.CD006739.pub2 (2008).

  30. Murohara, T. Dipeptidyl peptidase-4 inhibitor: another player for cardiovascular protection. J. Am. Coll. Cardiol. 59, 277–279 (2012).

    CAS  PubMed  Google Scholar 

  31. Palmieri, F. E. & Ward, P. E. Dipeptidyl(amino)peptidase IV and post proline cleaving enzyme in cultured endothelial and smooth muscle cells. Adv. Exp. Med. Biol. 247A, 305–311 (1989).

    CAS  PubMed  Google Scholar 

  32. Kirby, M., Yu, D. M., O'Connor, S. & Gorrell, M. D. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin. Sci. (Lond.) 118, 31–41 (2010).

    CAS  Google Scholar 

  33. Brandt, I. et al. Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form. Clin. Chem. 52, 82–87 (2006).

    CAS  PubMed  Google Scholar 

  34. 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 

  35. Mentlein, R., Dahms, P., Grandt, D. & Kruger, R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Pept. 49, 133–144 (1993).

    CAS  PubMed  Google Scholar 

  36. Zaruba, M. M. et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4, 313–323 (2009).

    CAS  PubMed  Google Scholar 

  37. Wang, L. H. et al. Differential processing of substance P and neurokinin A by plasma dipeptidyl(amino)peptidase IV, aminopeptidase M and angiotensin converting enzyme. Peptides 12, 1357–1364 (1991).

    CAS  PubMed  Google Scholar 

  38. Ban, K. et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340–2350 (2008).

    CAS  PubMed  Google Scholar 

  39. Fadini, G. P. et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1α. Diabetes Care 33, 1607–1609 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Huang, C. Y. et al. Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. Br. J. Pharmacol. 167, 1506–1519 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Sauve, M. et al. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 59, 1063–1073 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Glorie, L. L. et al. DPP4 inhibition improves functional outcome after renal ischemia reperfusion injury. Am. J. Physiol. Renal Physiol. 303, F681–F688 (2012).

    CAS  PubMed  Google Scholar 

  43. Ye, Y. et al. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am. J. Physiol. Heart Circ. Physiol. 298, H1454–H1465 (2010).

    CAS  PubMed  Google Scholar 

  44. Ye, Y., Perez-Polo, J. R., Aguilar, D. & Birnbaum, Y. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res. Cardiol. 106, 925–952 (2011).

    CAS  PubMed  Google Scholar 

  45. Rizzo, M., Rizvi, A. A., Spinas, G. A., Rini, G. B. & Berneis, K. Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors. Expert Opin. Investig. Drugs 18, 1495–1503 (2009).

    CAS  PubMed  Google Scholar 

  46. Monami, M., Iacomelli, I., Marchionni, N. & Mannucci, E. Dipeptidyl 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 

  47. Monami, M., Cremasco, F., Lamanna, C., Marchionni, N. & Mannucci, E. Predictors of response to dipeptidyl peptidase-4 inhibitors: evidence from randomized clinical trials. Diabetes Metab. Res. Rev. 27, 362–372 (2011).

    CAS  PubMed  Google Scholar 

  48. 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 

  49. Fakhoury, W. K., Lereun, C. & Wright, D. A meta-analysis of placebo-controlled clinical trials assessing the efficacy and safety of incretin-based medications in patients with type 2 diabetes. Pharmacology 86, 44–57 (2010).

    CAS  PubMed  Google Scholar 

  50. 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 

  51. Kim, W. & Egan, J. M. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol. Rev. 60, 470–512 (2008).

    CAS  PubMed  Google Scholar 

  52. Pratley, R. E. et al. Robust improvements in fasting and prandial measures of β-cell function with vildagliptin in drug-naive patients: analysis of pooled vildagliptin monotherapy database. Diabetes Obes. Metab. 10, 931–938 (2008).

    CAS  PubMed  Google Scholar 

  53. Baetta, R. & Corsini, A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs 71, 1441–1467 (2011).

    CAS  PubMed  Google Scholar 

  54. O'Keefe, J. H. & Bell, D. S. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am. J. Cardiol. 100, 899–904 (2007).

    CAS  PubMed  Google Scholar 

  55. Bonora, E. Antidiabetic medications in overweight/obese patients with type 2 diabetes: drawbacks of current drugs and potential advantages of incretin-based treatment on body weight. Int. J. Clin. Pract. Suppl. 154, 19–28 (2007).

    CAS  Google Scholar 

  56. Mitri, J. & Hamdy, O. Diabetes medications and body weight. Expert Opin. Drug Saf. 8, 573–584 (2009).

    CAS  PubMed  Google Scholar 

  57. Tahrani, A. A., Bailey, C. J., Del Prato, S. & Barnett, A. H. Management of type 2 diabetes: new and future developments in treatment. Lancet 378, 182–197 (2011).

    CAS  PubMed  Google Scholar 

  58. Barnett, A., Allsworth, J., Jameson, K. & Mann, R. A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies. Curr. Med. Res. Opin. 23, 1493–1507 (2007).

    CAS  PubMed  Google Scholar 

  59. Waters, S. B., Topp, B. G., Siler, S. Q. & Alexander, C. M. Treatment with sitagliptin or metformin does not increase body weight despite predicted reductions in urinary glucose excretion. J. Diabetes Sci. Technol. 3, 68–82 (2009).

    PubMed  PubMed Central  Google Scholar 

  60. Foley, J. E. & Jordan, J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc. Health Risk Manag. 6, 541–548 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Russell-Jones, D. et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 35, 252–258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bergenstal, R. M. et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376, 431–439 (2010).

    PubMed  Google Scholar 

  63. Horton, E. S., Silberman, C., Davis, K. L. & Berria, R. Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care 33, 1759–1765 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Brown, N. J. Cardiovascular effects of antidiabetic agents: focus on blood pressure effects of incretin-based therapies. J. Am. Soc. Hypertens. 6, 163–168 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Marney, A., Kunchakarra, S., Byrne, L. & Brown, N. J. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 56, 728–733 (2010).

    CAS  PubMed  Google Scholar 

  66. Mistry, G. C. et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J. Clin. Pharmacol. 48, 592–598 (2008).

    CAS  PubMed  Google Scholar 

  67. Jackson, E. K. Dipeptidyl peptidase IV inhibition alters the hemodynamic response to angiotensin-converting enzyme inhibition in humans with the metabolic syndrome. Hypertension 56, 581–583 (2010).

    CAS  PubMed  Google Scholar 

  68. Ogawa, S. et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. J. Exp. Med. 223, 133–135 (2011).

    CAS  Google Scholar 

  69. Gutzwiller, J. P. et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J. Clin. Endocrinol. Metab. 89, 3055–3061 (2004).

    CAS  PubMed  Google Scholar 

  70. Tanaka, T., Nangaku, M. & Nishiyama, A. The role of incretins in salt-sensitive hypertension: the potential use of dipeptidyl peptidase-IV inhibitors. Curr. Opin. Nephrol. Hypertens. 20, 476–481 (2011).

    CAS  PubMed  Google Scholar 

  71. Rieg, T. et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am. J. Physiol. Renal Physiol. 303, F963–F971 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Chaudhuri, A. & Dandona, P. Effects of insulin and other antihyperglycaemic agents on lipid profiles of patients with diabetes. Diabetes Obes. Metab. 13, 869–879 (2011).

    CAS  PubMed  Google Scholar 

  73. Ansar, S., Koska, J. & Reaven, P. D. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc. Diabetol. 10, 61 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Farr, S. & Adeli, K. Incretin-based therapies for treatment of postprandial dyslipidemia in insulin-resistant states. Curr. Opin. Lipidol. 23, 56–61 (2012).

    CAS  PubMed  Google Scholar 

  75. Tremblay, A. J., Lamarche, B., Deacon, C. F., Weisnagel, S. J. & Couture, P. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes. Metab. 13, 366–373 (2011).

    CAS  PubMed  Google Scholar 

  76. Matikainen, N. et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 49, 2049–2057 (2006).

    CAS  PubMed  Google Scholar 

  77. Boschmann, M. et al. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 94, 846–852 (2009).

    CAS  PubMed  Google Scholar 

  78. Eliasson, B. et al. Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study. Diabetologia 55, 915–925 (2012).

    CAS  PubMed  Google Scholar 

  79. Hsieh, J. et al. The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia 53, 552–561 (2010).

    CAS  PubMed  Google Scholar 

  80. Monami, M., Lamanna, C., Desideri, C. M. & Mannucci, E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv. Ther. 29, 14–25 (2012).

    CAS  PubMed  Google Scholar 

  81. Shah, Z. et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124, 2338–2349 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ta, N. N., Schuyler, C. A., Li, Y., Lopes-Virella, M. F. & Huang, Y. DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J. Cardiovasc. Pharmacol. 58, 157–166 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Derosa, G. et al. Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients. Metabolism 59, 887–895 (2010).

    CAS  PubMed  Google Scholar 

  84. Hattori, S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr. J. 58, 69–73 (2011).

    CAS  PubMed  Google Scholar 

  85. Makdissi, A. et al. Sitagliptin exerts an antinflammatory action. J. Clin. Endocrinol. Metab. 97, 3333–3341 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 

  87. Klempfner, R., Leor, J., Tenenbaum, A., Fisman, E. Z. & Goldenberg, I. Effects of a vildagliptin/metformin combination on markers of atherosclerosis, thrombosis, and inflammation in diabetic patients with coronary artery disease. Cardiovasc. Diabetol. 11, 60 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ceriello, A. et al. The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an “endothelial resistance” to glucagon-like peptide 1 in diabetes. Diabetes Care 34, 697–702 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Koren, S. et al. The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients. Diabetes Technol. Ther. 14, 561–567 (2012).

    CAS  PubMed  Google Scholar 

  90. Cersosimo, E. & DeFronzo, R. A. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab. Res. Rev. 22, 423–436 (2006).

    CAS  PubMed  Google Scholar 

  91. Motta, A. J., Koska, J., Reaven, P. & Migrino, R. Q. Vascular protective effects of diabetes medications that mimic or increase glucagon-like peptide-1 activity. Recent Pat. Cardiovasc. Drug Discov. 7, 2–9 (2012).

    CAS  PubMed  Google Scholar 

  92. Nystrom, T. et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am. J. Physiol. Endocrinol. Metab. 287, E1209–E1215 (2004).

    PubMed  Google Scholar 

  93. Mannucci, E. & Dicembrini, I. Incretin-based therapies and cardiovascular risk. Curr. Med. Res. Opin. 28, 715–721 (2012).

    CAS  PubMed  Google Scholar 

  94. van Poppel, P. C., Netea, M. G., Smits, P. & Tack, C. J. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care 34, 2072–2077 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Fadini, G. P. & Avogaro, A. Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul. Pharmacol. 55, 10–16 (2011).

    CAS  PubMed  Google Scholar 

  96. Gupta, A. K., Verma, A. K., Kailashiya, J., Singh, S. K. & Kumar, N. Sitagliptin: anti-platelet effect in diabetes and healthy volunteers. Platelets 23, 565–570 (2012).

    CAS  PubMed  Google Scholar 

  97. Sokos, G. G. et al. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am. J. Cardiol. 100, 824–829 (2007).

    CAS  PubMed  Google Scholar 

  98. Read, P. A., Khan, F. Z., Heck, P. M., Hoole, S. P. & Dutka, D. P. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ. Cardiovasc. Imaging 3, 195–201 (2010).

    PubMed  Google Scholar 

  99. Ghadge, S. K., Muhlstedt, S., Ozcelik, C. & Bader, M. SDF-1α as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol. Ther. 129, 97–108 (2011).

    CAS  PubMed  Google Scholar 

  100. Post, S. et al. Reduced CD26 expression is associated with improved cardiac function after acute myocardial infarction: Insights from the REPERATOR study. J. Mol. Cell. Cardiol. 53, 899–905 (2012).

    CAS  PubMed  Google Scholar 

  101. Theiss, H. D. et al. Safety and efficacy of SITAgliptin plus Granulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial)—rationale, design and first interim analysis. Int. J. Cardiol. 145, 282–284 (2010).

    PubMed  Google Scholar 

  102. Sokos, G. G., Nikolaidis, L. A., Mankad, S., Elahi, D. & Shannon, R. P. 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).

    CAS  PubMed  Google Scholar 

  103. Khan, M. A., Deaton, C., Rutter, M. K., Neyses, L. & Mamas, M. A. Incretins as a novel therapeutic strategy in patients with diabetes and heart failure. Heart Fail. Rev. http://dx.doi.org/10.1007/s10741-012-9318-y.

  104. Vanderheyden, M. et al. Dipeptidyl-peptidase IV and B-type natriuretic peptide. From bench to bedside. Clin. Chem. Lab. Med. 47, 248–252 (2009).

    CAS  PubMed  Google Scholar 

  105. Goldfine, A. B. Assessing the cardiovascular safety of diabetes therapies. N. Engl. J. Med. 359, 1092–1095 (2008).

    CAS  PubMed  Google Scholar 

  106. Anagnostis, P. et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes. Metab. 13, 302–312 (2011).

    CAS  PubMed  Google Scholar 

  107. Monami, M., Dicembrini, I., Martelli, D. & Mannucci, E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr. Med. Res. Opin. 27 (Suppl. 3), 57–64 (2011).

    CAS  PubMed  Google Scholar 

  108. Williams-Herman, D. 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. 10, 7 (2010).

    PubMed  PubMed Central  Google Scholar 

  109. Schweizer, A. et al. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population. Diabetes Obes. Metab. 12, 485–494 (2010).

    CAS  PubMed  Google Scholar 

  110. Frederich, R. et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad. Med. 122, 16–27 (2010).

    PubMed  Google Scholar 

  111. Cobble, M. E. & Frederich, R. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc. Diabetol. 11, 6 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. White, W. B. et al. Cardiovascular events in patients receiving alogliptin: a pooled analysis of randomized clinical trials [abstract]. Diabetes 59 (Suppl.), 391-PP (2010).

    Google Scholar 

  113. Johansen, O. E., Neubacher, D., von Eynatten, M., Patel, S. & Woerle, H. J. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc. Diabetol. 11, 3 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gallwitz, B. et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 380, 475–483 (2012).

    CAS  PubMed  Google Scholar 

  115. Fonseca, V. A. Ongoing clinical trials evaluating the cardiovascular safety and efficacy of therapeutic approaches to diabetes mellitus. Am. J. Cardiol. 108 (Suppl. 3), 52B–58B (2011).

    CAS  PubMed  Google Scholar 

  116. Scirica, B. M. et al. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am. Heart J. 162, 818–825.e6 (2011).

    CAS  PubMed  Google Scholar 

  117. White, W. B. et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am. Heart J. 162, 620–626.e1 (2011).

    PubMed  Google Scholar 

  118. Rosenstock, J. et al. Rationale and design of the CAROLINA trial: An Active Comparator CARdiOvascular Outcome Study of the DPP-4 Inhibitor LINAgliptin in Patients With Type 2 Diabetes at High Cardiovascular Risk [abstract 1103-P]. Diabetes 60 (Suppl. 1), A303 (2011).

    Google Scholar 

  119. Bethel, M., Green, J., Califf, R. & Holman, R. Rationale and design of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) [abstract]. Diabetes 58 (Suppl. 1), 2152 (2009).

    Google Scholar 

  120. van Genugten, R. E., van Raalte, D. H. & Diamant, M. Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence. Diabetes Obes. Metab. 14, 101–111 (2012).

    CAS  PubMed  Google Scholar 

  121. Drucker, D. J. Dipeptidyl peptidase 4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30, 1335–43 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  123. Shah, Z. et al. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul. Pharmacol. 55, 2–9 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Kröller-Schön, S. et al. Glucose Independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition. Cardiovasc. Res. 96, 140–149 (2012).

    PubMed  Google Scholar 

  125. Matsubara, J. et al. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J. Am. Coll. Cardiol. 59, 265–276 (2012).

    CAS  PubMed  Google Scholar 

  126. Shen, M. et al. The synergistic effect of valsartan and LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] on vascular oxidative stress and inflammation in type 2 diabetic mice. Exp. Diabetes Res. 2012, 146194 (2012).

    PubMed  PubMed Central  Google Scholar 

  127. Matsui, T., Nishino, Y., Takeuchi, M. & Yamagishi, S. Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axis. Pharmacol. Res. 63, 383–388 (2011).

    CAS  PubMed  Google Scholar 

  128. Chaykovska, L. et al. Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy. PLoS ONE 6, e27861 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Huisamen, B., Genis, A., Marais, E. & Lochner, A. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc. Drugs Ther. 25, 13–20 (2011).

    CAS  PubMed  Google Scholar 

  130. Lenski, M., Kazakov, A., Marx, N., Böhm, M. & Laufs, U. Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J. Mol. Cell. Cardiol. 51, 906–918 (2011).

    CAS  PubMed  Google Scholar 

  131. Ferreira, L. et al. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm. 2010, 592760 (2010).

    PubMed  PubMed Central  Google Scholar 

  132. Gomez, N. et al. Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur. J. Heart Fail. 14, 14–21 (2012).

    CAS  PubMed  Google Scholar 

  133. Chinda, K. et al. Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia–reperfusion injury. Int. J. Cardiol. 9, 256–269 (2012).

    Google Scholar 

  134. Apaijai, N., Pintana, H., Chattipakorn, S. C. & Chattipakorn, N. Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet. Endocrinology 153, 3878–3885 (2012).

    CAS  PubMed  Google Scholar 

  135. Yin, M., Sillje, H. H., Meissner, M., van Gilst, W. H. & de Boer, R. A. Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure. Cardiovasc. Diabetol. 10, 85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu, L. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension 60, 833–841 (2012).

    CAS  PubMed  Google Scholar 

  137. Pacheco, B. P. et al. Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats. J. Hypertens. 29, 520–528 (2011).

    CAS  PubMed  Google Scholar 

  138. Vaghasiya, J., Sheth, N., Bhalodia, Y. & Manek, R. Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes. Regul. Pept. 166, 48–54 (2011).

    CAS  PubMed  Google Scholar 

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  1. Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU Sart Tilman (B35), University of Liège, Liège 1, B-4000, Belgium

    André J. Scheen

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A. J. Scheen has received consultancy fees or honoraria from the following companies: AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi–Aventis, and Servier.

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Scheen, A. Cardiovascular effects of gliptins. Nat Rev Cardiol 10, 73–84 (2013). https://doi.org/10.1038/nrcardio.2012.183

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