The Effect of DPP-4i on Endothelial Function and Arterial Stiffness in Patients with Type 2 Diabetes: A Systematic Review of Randomized Placebo-controlled Trials

Author(s): Stavroula A. Paschou, Gerasimos Siasos*, Evanthia Bletsa, Panagiota K. Stampouloglou, Evangelos Oikonomou, Alexios S. Antonopoulos, Konstantinos Batzias, Vasiliki Tsigkou, Konstantinos Mourouzis, Andromachi Vryonidou, Nikolaos Tentolouris, Manolis Vavouranakis, Dimitrios Tousoulis

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 46 , 2020

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We systematically reviewed the literature regarding the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on vascular function, including endothelial function and arterial stiffness, as predictors of atherosclerosis progression and cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). We searched PubMed in order to identify clinical trials that investigated the effect of DPP-4i on vascular function in patients with T2DM when compared with placebo. Although 168 articles were initially found, only 6 studies (total 324 patients) investigated the effect of DPP-4i in comparison with placebo, specifically linagliptin and sitagliptin, and satisfied the inclusion criteria. There are scarce data to indicate that linagliptin may enhance endothelial function and exert a slight beneficial effect on arterial wall properties. Sitagliptin seems to have a neutral effect on these variables. Further trials are needed to elucidate the topic. The standards of reporting were in accordance with the PRISMA guidelines.

Keywords: Type 2 diabetes mellitus, DPP-4 inhibitors, endothelial function, arterial stiffness, cardiovascular health, molecular cardiology.

Avogaro A, de Kreutzenberg SV, Fadini G. Endothelial dysfunction: causes and consequences in patients with diabetes mellitus. Diabetes Res Clin Pract 2008; 82(82)(Suppl. 2): S94-S101.
[] [PMID: 18954919]
Fox CS, Golden SH, Anderson C, et al. American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research; American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2015; 38(9): 1777-803.
[] [PMID: 26246459]
Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287(19): 2570-81.
[] [PMID: 12020339]
Nilsson J, Bengtsson E, Fredrikson GN, Björkbacka H. Inflammation and immunity in diabetic vascular complications. Curr Opin Lipidol 2008; 19(5): 519-24.
[] [PMID: 18769234]
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2018 executive summary. Endocr Pract 2018; 24(1): 91-120.
[] [PMID: 29368965]
Luconi M, Cantini G, Ceriello A, Mannucci E. Perspectives on cardiovascular effects of incretin-based drugs: From bedside to bench, return trip. Int J Cardiol 2017; 241: 302-10.
[] [PMID: 28285800]
Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008; 24(2): 489-96.
[] [PMID: 18182122]
Nyström T, Gutniak MK, Zhang Q, 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 2004; 287(6): E1209-15.
[] [PMID: 15353407]
Ida S, Murata K, Betou K, et al. Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study. Cardiovasc Diabetol 2016; 15(1): 153.
[] [PMID: 27809903]
Ayaori M, Iwakami N, Uto-Kondo H, 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
[] [PMID: 23525426]
Leung M, Leung DY, Wong VW. Effects of dipeptidyl peptidase-4 inhibitors on cardiac and endothelial function in type 2 diabetes mellitus: A pilot study. Diab Vasc Dis Res 2016; 13(3): 236-43.
[] [PMID: 26993495]
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55(13): 1318-27.
[] [PMID: 20338492]
Baltzis D, Dushay JR, Loader J, et al. Effect of Linagliptin on Vascular Function: A Randomized, Placebo-controlled Study. J Clin Endocrinol Metab 2016; 101(11): 4205-13.
[] [PMID: 27583476]
Widlansky ME, Puppala VK, Suboc TM, et al. Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy. Vasc Med 2017; 22(3): 189-96.
[] [PMID: 28145158]
de Boer SA, Heerspink HJL, Juárez Orozco LE, et al. Effect of linagliptin on pulse wave velocity in early type 2 diabetes: A randomized, double-blind, controlled 26-week trial (RELEASE). Diabetes Obes Metab 2017; 19(8): 1147-54.
[] [PMID: 28244635]
Smits MM, Tonneijck L, Muskiet MH, et al. The effects of GLP-1 based therapies on postprandial haemodynamics: Two randomised, placebo-controlled trials in overweight type 2 diabetes patients. Diabetes Res Clin Pract 2017; 124: 1-10.
[] [PMID: 28086201]
Jax T, Stirban A, Terjung A, et al. A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes. Cardiovasc Diabetol 2017; 16(1): 13.
[] [PMID: 28109295]
Hage C, Brismar K, Lundman P, Norhammar A, Rydén L, Mellbin L. The DPP-4 inhibitor sitagliptin and endothelial function in patients with acute coronary syndromes and newly detected glucose perturbations: A report from the BEGAMI study. Diab Vasc Dis Res 2014; 11(4): 290-3.
[] [PMID: 24845072]
Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373(3): 232-42.
[] [PMID: 26052984]
Rosenstock J, Perkovic V, Johansen OE, et al. CARMELINA Investigators 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 2019; 321(1): 69-79.
[] [PMID: 30418475]
Rosenstock J, Kahn SE, Johansen OE, et al. Effect of Linagliptin vs. Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA 2019; 322(12): 1155-66.
Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol 2013; 168(1): 344-51.
[] [PMID: 23041097]
Tousoulis D, Androulakis E, Papageorgiou N, et al. Novel biomarkers assessing endothelial dysfunction: role of microRNAs. Curr Top Med Chem 2013; 13(13): 1518-26.
[] [PMID: 23745803]
Charakida M, de Groot E, Loukogeorgakis SP, et al. Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial. Eur Heart J 2013; 34(45): 3501-7.
[] [PMID: 23821401]
Siasos G, Gouliopoulos N, Moschos MM, et al. Role of endothelial dysfunction and arterial stiffness in the development of diabetic retinopathy. Diabetes Care 2015; 38(1): e9-e10.
[] [PMID: 25538324]
Mitchell GF, Hwang SJ, Vasan RS, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010; 121(4): 505-11.
[] [PMID: 20083680]
Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol 2011; 57(14): 1511-22.
[] [PMID: 21453829]
Chen CC, Hung KC, Hsieh IC, Wen MS. Association between peripheral vascular disease indexes and the numbers of vessels obstructed in patients with coronary artery disease. Am J Med Sci 2012; 343(1): 52-5.
[] [PMID: 21709534]
Koska J, Sands M, Burciu C, Reaven P. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes. Diab Vasc Dis Res 2015; 12(3): 154-63.
[] [PMID: 25852133]
Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol 2013; 10(2): 73-84.
[] [PMID: 23296071]
Takahashi M. Role of the SDF-1/CXCR4 system in myocardial infarction. Circ J 2010; 74(3): 418-23.
[] [PMID: 20118565]
Takahashi A, Ihara M, Yamazaki S, Asanuma H, Asakura M, Kitakaze M. Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure. Int Heart J 2015; 56(4): 372-6.
[] [PMID: 26104180]
Shigeta T, Aoyama M, Bando YK, et al. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. Circulation 2012; 126(15): 1838-51.
[] [PMID: 23035207]
Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275(5302): 964-7.
[] [PMID: 9020076]
Oliver JJ, Webb DJ, Newby DE. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans. Arterioscler Thromb Vasc Biol 2005; 25(12): 2470-9.
[] [PMID: 16210566]

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Article Details

Year: 2020
Page: [5980 - 5987]
Pages: 8
DOI: 10.2174/1381612826666200417153241
Price: $65

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