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Antiatherothrombotic Effects of Dipeptidyl Peptidase Inhibitors

  • Vascular Biology (RS Rosenson, Section Editor)
  • Published:
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Abstract

Atherothrombotic cardiovascular events are a leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). A number of factors beyond hyperglycemia contribute to this increased risk of cardiovascular events in T2D, including elevated blood pressure, dyslipidemia, inflammation, endothelial dysfunction, and enhanced platelet activation. Importantly, most currently available antihyperglycemic treatments for T2D do not address these additional mechanisms. Indeed, we posit that this may explain why more intensive treatment of hyperglycemia has not contributed to a reduced incidence of cardiovascular events in subjects with T2D. Incretin-targeted therapies, such as dipeptidyl peptidase 4 inhibitors, are a relatively new class of antidiabetic treatments, and preclinical as well as small mechanistic clinical studies suggest that they exert beneficial cardiovascular effects. This review focuses specifically on the potential antiatherothrombotic effects of dipeptidyl peptidase 4 inhibitors.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Stary HC et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994;89(5):2462–78.

    Article  PubMed  CAS  Google Scholar 

  2. McNeill AM et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the Atherosclerosis Risk in Communities study. Diabetes Care. 2005;28(2):385–90.

    Article  PubMed  Google Scholar 

  3. Steinberg HO et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53.

    Article  Google Scholar 

  5. Aronoff S et al. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care. 2000;23(11):1605–11.

    Article  PubMed  CAS  Google Scholar 

  6. Yousefzadeh P, Wang X. The effects of dipeptidyl peptidase-4 inhibitors on cardiovascular disease risks in type 2 diabetes mellitus. J Diabetes Res. 2013;2013:459821.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diabetes Vasc Dis Res. 2012;9(2):95–108.

    Article  Google Scholar 

  8. Alexander RW. Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension. 1995;25(2):155–61.

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  10. Abd El Motteleb DM, Elshazly SM. Renoprotective effect of sitagliptin against hypertensive nephropathy induced by chronic administration of L-NAME in rats: role of GLP-1 and GLP-1 receptor. Eur J Pharmacol. 2013;720(1–3):158–65.

    Article  PubMed  CAS  Google Scholar 

  11. Mistry GC et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592–8.

    Article  PubMed  CAS  Google Scholar 

  12. Marney A et al. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010;56(4):728–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Scirica BM, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. This is one of the first long-term safety studies specifically aimed at addressing the cardiovascular outcomes of saxagliptin treatment. The results of this study showed that treatment with saxagliptin was noninferior, but not superior, to placebo for a composite end point of cardiovascular death, MI, and stroke.

  14. Ogawa S et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. Tohoku J Exp Med. 2011;223(2):133–5.

    Article  PubMed  CAS  Google Scholar 

  15. Kubota A et al. Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients. J Clin Med Res. 2012;4(5):309–13.

    PubMed Central  PubMed  CAS  Google Scholar 

  16. Jagla A, Schrezenmeir J. Postprandial triglycerides and endothelial function. Exp Clin Endocrinol Diabetes. 2001;109(4):S533–47.

    Article  PubMed  CAS  Google Scholar 

  17. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(3):150–9.

    Article  PubMed  CAS  Google Scholar 

  18. Matikainen N et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49(9):2049–57.

    Article  PubMed  CAS  Google Scholar 

  19. Boschmann M et al. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J Clin Endocrinol Metab. 2009;94(3):846–52.

    Article  PubMed  CAS  Google Scholar 

  20. Tremblay AJ et al. Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):366–73.

    Article  PubMed  CAS  Google Scholar 

  21. 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. 2012;55(4):915–25.

    Article  PubMed  CAS  Google Scholar 

  22. Plutzky J, Viberti G, Haffner S. Atherosclerosis in type 2 diabetes mellitus and insulin resistance: mechanistic links and therapeutic targets. J Diabetes Complicat. 2002;16(6):401–15.

    Article  PubMed  Google Scholar 

  23. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.

    Article  PubMed  CAS  Google Scholar 

  24. Alexandraki K et al. Inflammatory process in type 2 diabetes: the role of cytokines. Ann N Y Acad Sci. 2006;1084:89–117.

    Article  PubMed  CAS  Google Scholar 

  25. Sjoholm A, Nystrom T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006;22(1):4–10.

    Article  PubMed  Google Scholar 

  26. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.

    Article  PubMed  CAS  Google Scholar 

  27. Gorrell MD, Gysbers V, McCaughan GW. CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol. 2001;54(3):249–64.

    Article  PubMed  CAS  Google Scholar 

  28. White PC, Chamberlain-Shea H, de la Morena MT. Sitagliptin treatment of patients with type 2 diabetes does not affect CD4+ T-cell activation. J Diabetes Complicat. 2010;24(3):209–13.

    Article  PubMed  Google Scholar 

  29. Matsubara J et al. Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J. 2013;77(5):1337–44.

    Article  PubMed  CAS  Google Scholar 

  30. Lee SA et al. CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98(6):2553–61.

    Article  PubMed  CAS  Google Scholar 

  31. Shah Z et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. 2011;124(21):2338–49.

    Article  PubMed  CAS  Google Scholar 

  32. Dobrian AD et al. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab. 2011;300(2):E410–21.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Shirakawa J et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes. 2011;60(4):1246–57.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Vittone F et al. Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe -/- mice. Diabetologia. 2012;55(8):2267–75.

    Article  PubMed  CAS  Google Scholar 

  35. Noyan-Ashraf MH et al. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013;127(1):74–85.

    Article  PubMed  CAS  Google Scholar 

  36. Dokken BB et al. Oxidative stress-induced insulin resistance in rat skeletal muscle: role of glycogen synthase kinase-3. Am J Physiol Endocrinol Metab. 2008;294(3):E615–21.

    Article  PubMed  CAS  Google Scholar 

  37. Shah Z, et al. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vasc Pharmacol. 2011;55(1–3):2–9. This is an important study demonstrating the beneficial effect of DPP-4 inhibition in atherosclerotis-prone, high-fat-fed, LDLR -/- mice via reduction of inflammatory recruitment and migration of immune cells.

  38. Mason RP et al. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb. 2011;18(9):774–83.

    Article  PubMed  CAS  Google Scholar 

  39. Liu L et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension. 2012;60(3):833–41.

    Article  PubMed  CAS  Google Scholar 

  40. Krijnen PA et al. Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients. Basic Res Cardiol. 2012;107(1):233.

    Article  PubMed  Google Scholar 

  41. Ayaori M et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2(1):e003277.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Vinik AI et al. Platelet dysfunction in type 2 diabetes. Diabetes Care. 2001;24(8):1476–85.

    Article  PubMed  CAS  Google Scholar 

  43. Schneider DJ. Factors contributing to increased platelet reactivity in people with diabetes. Diabetes Care. 2009;32(4):525–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Li Y, Woo V, Bose R. Platelet hyperactivity and abnormal Ca2+ homeostasis in diabetes mellitus. Am J Physiol Heart Circ Physiol. 2001;280(4):H1480–9.

    PubMed  CAS  Google Scholar 

  45. Angiolillo DJ et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol. 2007;50(16):1541–7.

    Article  PubMed  Google Scholar 

  46. Cameron-Vendrig A, Reheman A, Afroze T, Noyan-Ashraf MH, Ni H, Husain M. Abstract 18777: glucagon-like peptide-1 inhibits thrombin-induced human platelet aggregation. Circulation. 2012;126, A18777.

    Google Scholar 

  47. Gupta AK et al. Sitagliptin: anti-platelet effect in diabetes and healthy volunteers. Platelets. 2012;23(8):565–70.

    Article  PubMed  CAS  Google Scholar 

  48. 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. 2012;380(9840):475–83. The results of this study have been some of the most significant in terms of showing cardiovascular benefits of DPP-4 inhibitor (linagliptin) treatment.

  49. Johansen OE et al. 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. 2012;11:3.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Gitt AK et al. Prognostic implications of DPP-4 inhibitor vs. sulfonylurea use on top of metformin in a real world setting—results of the 1 year follow-up of the prospective DiaRegis registry. Int J Clin Pract. 2013;67(10):1005–14.

    PubMed  CAS  Google Scholar 

  51. Monami M et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15(2):112–20.

    Article  PubMed  CAS  Google Scholar 

  52. Frederich R et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122(3):16–27.

    Article  PubMed  Google Scholar 

  53. 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. 2010;10:7.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Engel SS et al. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol. 2013;12:3.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Scheller NM et al. All-cause mortality and cardiovascular effects associated with the DPPIV-inhibitor sitagliptin compared with metformin, a retrospective cohort study on the Danish population. Diabetes Obes Metab. 2014;16(3):231–6.

    Article  PubMed  CAS  Google Scholar 

  56. White WB et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.

    Article  PubMed  CAS  Google Scholar 

  57. Merck Sharp & Dohme. Sitagliptin Cardiovascular Outcome Study (MK-0431-082) (TECOS). National Library of Medicine. 2008–2014. http://clinicaltrials.gov/show/NCT00790205 NLM Identifier: NCT00790205. Accessed 14 Jan 2014.

  58. Boehringer Ingelheim Pharmaceuticals. CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes. National Library of Medicine. 2010–2014. http://clinicaltrials.gov/show/NCT01243424 NLM Identifier: NCT01243424. Accessed 14 Jan 2014.

  59. Oslo University Hospital. Saxagliptin and Atherosclerosis (SAXATH). National Library of Medicine. 2012. http://clinicaltrials.gov/show/NCT01552018 NLM Identifier: NCT01552018. Accessed 14 Jan 2014.

  60. Sheba Medical Center. Effects of Vildagliptin/Metformin Combination on Markers of Atherosclerosis, Thrombosis, and Inflammation in Diabetics with Coronary Artery Disease (VAAST). National Library of Medicine. 2012–2013. http://clinicaltrials.gov/show/NCT01604213 NLM Identifier: NCT01604213. Accessed 14 Jan 2014.

  61. Bristol-Meyers Squibb. Risk of Cardiovascular Events in Patients with Type 2 Diabetes Initiating Oral Antidiabetic Treatments. National Library of Medicine (US). 2010–2012. http://clinicaltrials.gov/show/NCT01086280 NLM Identifier: NCT01086280. Accessed 14 Jan 2014.

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Conflict of Interest

Alison Cameron-Vendrig and Mansoor Husain report grants from Merck during the duration of the study. Dhanwantee Mundil declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Toronto General Research Institute, TMDT 3-909, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada

    Alison Cameron-Vendrig, Dhanwantee Mundil & Mansoor Husain

  2. Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, ON, Canada

    Alison Cameron-Vendrig

  3. Department of Physiology, University of Toronto, Toronto, ON, Canada

    Dhanwantee Mundil & Mansoor Husain

  4. Department of Medicine and Heart and Stroke Richard Lewar Centre of Excellence, Toronto, ON, Canada

    Mansoor Husain

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  1. Alison Cameron-Vendrig
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  2. Dhanwantee Mundil
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  3. Mansoor Husain
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Correspondence to Mansoor Husain.

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This article is part of the Topical Collection on Vascular Biology

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Cameron-Vendrig, A., Mundil, D. & Husain, M. Antiatherothrombotic Effects of Dipeptidyl Peptidase Inhibitors. Curr Atheroscler Rep 16, 408 (2014). https://doi.org/10.1007/s11883-014-0408-2

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