The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Meigs JB. 1.  2003. Epidemiology of cardiovascular complications in type 2 diabetes mellitus. Acta Diabetol 40:Suppl. 2S358–61 [Google Scholar]
  2. 2. Centers for Disease Control and Prevention (CDC) 2014. National diabetes statistics report, 2014. Atlanta, GA: US Dep. Health Hum. Serv., Cent. Dis. Control Prevent http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf [Google Scholar]
  3. 3. UK Prospective Diabetes Study (UKPDS) Group 1998. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS-33). Lancet 352:837–53 [Google Scholar]
  4. 4. ACCORD Study Group 2011. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N. Engl. J. Med. 364:818–28 [Google Scholar]
  5. 5. The ADVANCE Collaborative Group 2008. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358:2560–72 [Google Scholar]
  6. Goldfine AB. 6.  2008. Assessing the cardiovascular safety of diabetes therapies. N. Engl. J. Med. 359:1092–95 [Google Scholar]
  7. Nissen SE, Wolski K. 7.  2007. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356:2457–71 [Google Scholar]
  8. 8. US Food and Drug Administration 2008. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes Silver Spring, MD: US Food and Drug Adm www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf [Google Scholar]
  9. Holst JJ, Deacon CF. 9.  1998. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663–70 [Google Scholar]
  10. Ghatak SB, Patel DS, Shanker N. 10.  et al. 2010. Alogliptin: a novel molecule for improving glycemic control in type II diabetes mellitus. Curr. Diab. Rev. 6:6410–21 [Google Scholar]
  11. Scirica BM, Bhatt DI, Braunwald E. 11.  et al. and the SAVOR-TIMI 53 Steering Committee and Investigators 2013. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369:1317–26 [Google Scholar]
  12. White WB, Cannon CP, Heller SR. 12.  et al. and the EXAMINE Investigators 2013. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369:1327–35 [Google Scholar]
  13. Green JB, Bethel MA, Armstrong PW. 13.  et al. 2015. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373:232–42 [Google Scholar]
  14. Wajchenberg BL. 14.  2007. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev. 28:187–218 [Google Scholar]
  15. Pratley RE, Weyer C. 15.  2001. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia 44:929–45 [Google Scholar]
  16. Baggio LL, Drucker DJ. 16.  2007. Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–57 [Google Scholar]
  17. Orskov C, Wettergren A, Holst JJ. 17.  1993. Biological effects and metabolic rates of glucagonlike peptide-17–36 amide and glucagonlike peptide-17–37 in healthy subjects are indistinguishable. Diabetes 42:658–61 [Google Scholar]
  18. Meier JJ. 18.  2012. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8:728–42 [Google Scholar]
  19. Neumiller JJ. 19.  2015. Incretin-based therapies. Med. Clin. N. Am. 99:107–29 [Google Scholar]
  20. Trujillo JM, Nuffer W, Ellis SL. 20.  2015. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 6:19–28 [Google Scholar]
  21. Eng J, Kleinman WA, Singh L. 21.  et al. 1992. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267:7402–5 [Google Scholar]
  22. Knudsen LB, Nielsen PF, Huusfeldt PO. 22.  et al. 2000. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once-daily administration. J. Med. Chem. 43:1664–69 [Google Scholar]
  23. Elbrønd B, Jakobsen G, Larsen S. 23.  et al. 2002. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diab. Care 25:1398–404 [Google Scholar]
  24. Kieffer TJ, McIntosh CH, Pederson RA. 24.  1995. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585–96 [Google Scholar]
  25. Havale SH, Pal M. 25.  2009. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem. 17:1783–802 [Google Scholar]
  26. Golightly LK, Drayna CC, McDermott MT. 26.  2012. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin. Pharmacokinet. 51:501–14 [Google Scholar]
  27. Amori RE, Lau J, Pittas AG. 27.  2007. Efficacy and safety of incretin therapy in type 2 diabetes. Systematic review and meta-analysis. JAMA 298:194–206 [Google Scholar]
  28. Harris KB, McCarty DJ. 28.  2015. Efficacy and tolerability of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus. Ther. Adv. Endocrinol. Metab. 6:3–18 [Google Scholar]
  29. Sun F, Chai S, Li L. 29.  et al. 2015. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J. Diab. Res. 2015:157201 [Google Scholar]
  30. Deacon CF, Mannucci E, Ahren B. 30.  2012. Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidylpeptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes—a review and meta-analysis. Diab. Obes. Metab. 14:762–67 [Google Scholar]
  31. Eng C, Kramer CK, Zinman B, Retnakaran R. 31.  2014. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 384:2228–34 [Google Scholar]
  32. Liu FP, Dong JJ, Yang Q. 32.  et al. 2015. Glucagon-like peptide 1 receptor agonist therapy is more efficacious than insulin glargine for poorly controlled type 2 diabetics: a systematic review and meta-analysis. J. Diab. 7:322–28 [Google Scholar]
  33. Nauck MA, Heimesat MM, Behle K. 33.  et al. 2002. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J. Clin. Endocrinol. Metab. 87:1239–46 [Google Scholar]
  34. Li L, Shen J, Bala MM. 34.  et al. 2014. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomized and non-randomised studies. BMJ 348g2366 [Google Scholar]
  35. Scheen AJ. 35.  2015. A review of gliptins for 2014. Expert Opin. Pharmacother. 16:43–62 [Google Scholar]
  36. Karagiannis T, Paschos P, Paletas K. 36.  et al. 2012. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344:e1369 [Google Scholar]
  37. Craddy P, Palin HJ, Johnson KI. 37.  2014. Comparative effectiveness of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diab. Ther. 5:1–41 [Google Scholar]
  38. Ussher JR, Drucker DJ. 38.  2012. Cardiovascular biology of the incretin system. Endocr. Rev. 33:187–215 [Google Scholar]
  39. Ussher JR, Drucker DJ. 39.  2014. Cardiovascular actions of incretin-based therapies. Circ. Res. 114:1788–803 [Google Scholar]
  40. Nikolaidis LA, Elahi D, Shen TY, Shannon RP. 40.  2005. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 289:H2401–8 [Google Scholar]
  41. Ban K, Kim H, Cho J. 41.  et al. 2010. GLP-1(9–36) protects cardiomyocytes and endothelial cells from ischemia-reperfusion injury via cytoprotective pathways independent of the GLP-1 receptor. Endocrinology 151:1520–31 [Google Scholar]
  42. Zhao T, Parikh P, Bhashyam S. 42.  et al. 2006. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J. Pharmacol. Exp. Ther. 317:1106–13 [Google Scholar]
  43. Ban K, Noyan-Ashraf MH, Hoefer J. 43.  et al. 2008. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117:2340–50 [Google Scholar]
  44. Nikolaidis LA, Mankad S, Sokos GG. 44.  et al. 2004. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109:962–65 [Google Scholar]
  45. Sokos GG, Nikolaidis LA, Mankad S. 45.  et al. 2006. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J. Card. Fail. 12:694–99 [Google Scholar]
  46. Halbirk M, Nørrelund H, Møller N. 46.  et al. 2010. Cardiovascular and metabolic effects of 48-hour glucagon-like peptide 1 infusion in compensated chronic heart failure patients. Am. J. Physiol. Heart Circ. Physiol. 298:H1096–102 [Google Scholar]
  47. Nyström T, Gutniak MK, Zhang Q. 47.  et al. 2004. 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:E1209–15 [Google Scholar]
  48. Timmers L, Henriques JP, de Kleijn DP. 48.  et al. 2009. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J. Am. Coll. Cardiol. 53:501–10 [Google Scholar]
  49. Kristensen J, Mortensen UM, Schmidt M. 49.  et al. 2009. Lack of cardioprotection from subcutaneously and preischemic administered liraglutide in a close chest porcine ischemia reperfusion model. BMC Cardiovasc. Disord. 9:31 [Google Scholar]
  50. Løngborg J, Vijlstrup N, Kelbaek H. 50.  et al. 2012. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur. Heart J. 33:1491–99 [Google Scholar]
  51. Lønborg J, Kelbaek H, Vejlstrup N. 51.  et al. 2012. Exenatide reduces final infarct size in patients with ST-segment elevation myocardial infarction and short-duration of ischemia. Circ. Cardiovasc. Interv. 5:288–95 [Google Scholar]
  52. Noyan-Ashraf MH, Shikatani EA, Schuiki I. 52.  et al. 2013. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation 127:74–85 [Google Scholar]
  53. Hirata K, Kume S, Araki SI. 53.  et al. 2009. Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem. Biophys. Res. Commun. 380:44–49 [Google Scholar]
  54. Kim M, Platt MJ, Shibasaki T. 54.  et al. 2013. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control blood pressure. Nat. Med. 19:567–75 [Google Scholar]
  55. Wang B, Zhong J, Lin H. 55.  et al. 2013. Blood pressure–lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diab. Obes. Metab. 15:737–49 [Google Scholar]
  56. Kotout M, Zhu H, Rutsky J. 56.  et al. 2014. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am. J. Hypertens. 27:130–39 [Google Scholar]
  57. Matheeussen V, Baerts L, De Meyer G. 57.  et al. 2011. Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries. Biol. Chem. 392:189–98 [Google Scholar]
  58. Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. 58.  2015. DPP4 in cardiometabolic disease. Recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ. Res. 116:1491–504 [Google Scholar]
  59. Sauve M, Ban K, Momen A. 59.  et al. 2010. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes following myocardial infarction in mice. Diabetes 59:1063–73 [Google Scholar]
  60. Huisamen B, Genis A, Marais E, Lochner A. 60.  2011. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc. Drugs Ther. 25:13–20 [Google Scholar]
  61. McCormick LM, Kydd AC, Read PA. 61.  et al. 2014. Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease. Circ. Cardiovasc. Imaging 7:274–81 [Google Scholar]
  62. dos Santos L, Salles TA, Arruda-Junior EF. 62.  et al. 2013. Circulating dipeptidyl peptidase IV activity correlates with cardiac dysfunction in human and experimental heart failure. Circ. Heart Fail. 6:1029–38 [Google Scholar]
  63. Gomez N, Touihri K, Matheeussen V. 63.  et al. 2012. Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur. J. Heart Fail. 14:14–21 [Google Scholar]
  64. Takahashi A, Asakura M, Ito S. 64.  et al. 2013. Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice. Am. J. Physiol. Heart Circ. Physiol. 304:H1361–69 [Google Scholar]
  65. Shah Z, Pineda C, Kampfrath T. 65.  et al. 2011. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vasc. Pharmacol. 55:2–9 [Google Scholar]
  66. Ishii M, Shibata R, Kondo K. 66.  et al. 2014. Vildagliptin stimulates endothelial cell network formation and ischemia-induced revascularization via an endothelial nitric-oxide synthase-dependent mechanism. J. Biol. Chem. 298:27235–45 [Google Scholar]
  67. Aroor AR, Sowers JR, Bender SB. 67.  et al. 2013. Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. Endocrinology 154:2501–13 [Google Scholar]
  68. Mistry GC, Maes AL, Lasseter KC. 68.  et al. 2008. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J. Clin. Pharmacol. 48:592–98 [Google Scholar]
  69. Monami M, Ahren B, Dicembrini I, Mannucci E. 69.  2013. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diab. Obes. Metab. 15:112–20 [Google Scholar]
  70. Jackson EK, Mi Z, Tofovic SP, Gillespie EG. 70.  2015. Effect of dipeptidyl peptidase 4 inhibition on arterial blood pressure is context dependent. Hypertension 65:238–49 [Google Scholar]
  71. Nissen SE. 71.  2012. Cardiovascular effects of diabetes drugs: emerging from the dark ages. Ann. Intern. Med. 157:671–72 [Google Scholar]
  72. Nissen SE, Wolski K, Topol EJ. 72.  2005. Effect of muraglitizar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294:2581–86 [Google Scholar]
  73. Hiatt WR, Kaul S, Smith RJ. 73.  2013. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N. Engl. J. Med. 369:1285–87 [Google Scholar]
  74. Sager PT, Seltzer J, Turner JR. 74.  et al. 2015. Cardiovascular safety outcome trials: a meeting report from the Cardiac Safety Research Consortium. Am. Heart J. 169:486–95 [Google Scholar]
  75. Mahaffey KW, Hafley G, Dickerson S. 75.  et al. 2013. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am. Heart J. 166:240–49.e1 [Google Scholar]
  76. Dormandy JA, Charbonnet B, Eckland DJ. 76.  et al. and the PROactive Investigators 2005. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study: a randomized clinical trial. Lancet 366:1279–89 [Google Scholar]
  77. Robinson LE, Holt TA, Rees K. 77.  et al. 2013. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 24:3 [Google Scholar]
  78. Ferdinand KC, White WB, Calhoun DA. 78.  et al. 2014. Effects of the once weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension 64:731–37 [Google Scholar]
  79. Pfeffer MA. 79.  2015. The evaluation of lixisenatide in acute coronary syndrome—the results of the ELIXA trial Symp. Sci. Sessions Am. Diab. Assoc., 75th, Boston, MA, June 8 [Google Scholar]
  80. White WB, Kupfer S, Nissen SE. 80.  et al. 2014. Mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. J. Am. Coll. Cardiol. 63:12SA116 (Abstr.) [Google Scholar]
  81. Scirica BM, Braunwald E, Raz I. 81.  et al. 2014. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 130:181579–88 [Google Scholar]
  82. Zannad F, Cannon CP, Cushman WC. 82.  et al. 2015. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicenter, randomized, double-blind trial. Lancet 385:99822067–76 [Google Scholar]
  83. Gilbert TE, Krum H. 83.  2015. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet 385:2107–17 [Google Scholar]
  84. Marney A, Kunchakarra S, Byrne L, Brown NJ. 84.  2010. Interactive hemodynamic effects of dipeptidyl peptidase IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 56:728–33 [Google Scholar]
  85. 85. Astra-Zeneca 2015. Saxagliptin Advisory Committee meeting slide CS-41. Presented at Apr. 14 meet. Endocrinol. Metab. Drugs Advis. Comm. (EMDAC). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM444146.pdf [Google Scholar]
  86. 86. Takeda Development Center Americas, Inc 2015. EXAMINE: Cardiovascular outcome trial of alogliptin slide CE-28. Presented at Apr. 14 meet. Endocrinol. Metab. Drugs Advis. Comm. (EMDAC). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM444148.pdf [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error