Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Atherosclerosis Reports
Published in: Current Atherosclerosis Reports 5/2014

01-05-2014 | Vascular Biology (RS Rosenson, Section Editor)

Antiatherothrombotic Effects of Dipeptidyl Peptidase Inhibitors

Authors: Alison Cameron-Vendrig, Dhanwantee Mundil, Mansoor Husain

Published in: Current Atherosclerosis Reports | Issue 5/2014

Login to get access

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.
Literature
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.CrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.CrossRef
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.PubMedCrossRef
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.CrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMed
16.
Jagla A, Schrezenmeir J. Postprandial triglycerides and endothelial function. Exp Clin Endocrinol Diabetes. 2001;109(4):S533–47.PubMedCrossRef
17.
Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 2009;5(3):150–9.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
23.
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.PubMedCrossRef
24.
Alexandraki K et al. Inflammatory process in type 2 diabetes: the role of cytokines. Ann N Y Acad Sci. 2006;1084:89–117.PubMedCrossRef
25.
Sjoholm A, Nystrom T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006;22(1):4–10.PubMedCrossRef
26.
Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
34.
Vittone F et al. Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe -/- mice. Diabetologia. 2012;55(8):2267–75.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
42.
43.
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
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.PubMedCrossRef
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.
47.
Gupta AK et al. Sitagliptin: anti-platelet effect in diabetes and healthy volunteers. Platelets. 2012;23(8):565–70.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
54.
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.PubMedCrossRef
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.PubMedCrossRef
57.
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.
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.
Metadata
Title
Antiatherothrombotic Effects of Dipeptidyl Peptidase Inhibitors
Authors
Alison Cameron-Vendrig
Dhanwantee Mundil
Mansoor Husain
Publication date
01-05-2014
Publisher
Springer US
Published in
Current Atherosclerosis Reports / Issue 5/2014
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-014-0408-2

Other articles of this Issue 5/2014

Current Atherosclerosis Reports 5/2014 Go to the issue

Genetics (AJ Marian, Section Editor)

Pharmacogenetics of Antiplatelet Therapy

Genetics (AJ Marian, Section Editor)

Noncoding RNAs and Atherosclerosis

Vascular Biology(RS Rosenson, Section Editor)

The Endothelium in Diabetic Nephropathy

Coronary Heart Disease (JA Farmer, Section Editor)

The Role of Nonpharmacologic Device Interventions in the Management of Drug-Resistant Hypertension

Cardiovascular Disease and Stroke (P Perrone-Filardi and S. Agewall, Section Editors)

Adiposopathy, “Sick Fat,” Ockham’s Razor, and Resolution of the Obesity Paradox

Genetics (AJ Marian, Section Editor)

Dissecting the Causal Genetic Mechanisms of Coronary Heart Disease
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits