Alogliptin and Gliclazide Similarly Increase Circulating Endothelial Progenitor Cells in Type 2 Diabetes Patients

Abstract

Aim We investigated the effect of alogliptin and gliclazide on endothelial progenitor cells (EPCs) in type 2 diabetes.

Methods Eighty patients with type 2 diabetes and HbA1c between 7.5% and 8.5% were randomized to receive either alogliptin (25 mg/daily) or gliclazide extended-release (30 mg/daily for HbA1c 7.5-8.0% and 60 mg/daily for HbA1c 8.0-8.5%) in combination with metformin for 4 months. At baseline and 4 months, clinical and laboratory parameters of EPCs were determined.

Results After 4 months of treatment, alogliptin and gliclazide resulted in a similar significant reduction in HbA1c (%) (8.0±0.3 vs. 7.1±0.2, and 8.0±0.3 vs. 7.0±0.2, respectively; P<0.05) and a similar and significant increase in EPC count (cells/10⁶ WBC) (CD45⁻CD133⁺KDR⁺ : 2.2±1.2 vs. 3.7±1.6, CD45⁻CD34⁺KDR⁺: 3.3±1^.8 vs. 4.9±1.8; P<0.05 for alogliptin; CD45⁻CD133⁺KDR⁺: 2.3±1.3 vs. 3^.6±1.5, CD45⁻CD34⁺KDR⁺: 3.1±1.3 vs. 4^.6±1.7; P<0.05 for gliclazide).

Conclusions Both alogliptin and gliclazide demonstrated a beneficial effect in increasing EPCs in poorly controlled type 2 diabetes. As alogliptin and gliclazide exhibit different mechanisms of action, the observed increase in EPCs seems to be due to their glucose-lowering effect.

Key words

diabetes - DPP4 inhibitors - endothelial progenitor cells - alogliptin - gliclazide - metformin

• References

• 1 Asahara T, Murohara T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967
• 2 Werner N, Priller J, Laufs U. et al. Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: Effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arteriosclerosis, Thrombosis, and Vascular Biology 2002; 22: 1567-1572
• 3 Tepper OM, Capla JM, Galiano RD. et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 2005; 105: 1068-1077
• 4 Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arteriosclerosis, Thrombosis, and Vascular Biology 2008; 28: 1584-1595
• 5 Aragona CO, Imbalzano E, Mamone F. et al. Endothelial progenitor cells for diagnosis and prognosis in cardiovascular disease. Stem Cells Int 2016; 2016: 8043792 Review
• 6 Werner N, Kosiol S, Schiegl T. et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999-1007
• 7 Rigato M, Avogaro A, Fadini GP. Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies. Circ Res 2016; 118: 1930-1939
• 8 Haffner SM, Lehto S, Rönnemaa T. et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229-234 1998;
• 9 Spigoni V, Picconi A, Cito M. et al. Pioglitazone improves in vitro viability and function of endothelial progenitor cells from individuals with impaired glucose tolerance. PLoS One 2012; 7: e48283
• 10 Oikonomou D, Kopf S, von Bauer R. et al. Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: A partially double-blind, randomized, three-arm unicenter study. Cardiovasc Diabetol 2014; 13: 137
• 11 Lin LY, Huang CC, Chen JS. et al. Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: A pilot prospective, double-blind, randomized study. Cardiovasc Diabetol 2014; 13: 111
• 12 Raptis AE, Markakis KP, Mazioti MC. et al. Effect of aliskiren on circulating endothelial progenitor cells and vascular function in patients with type 2 diabetes and essential hypertension. Am J Hypertens 2015; 28: 22-29
• 13 Duan L, Rao X, Xia C. et al. The regulatory role of DPP4 in atherosclerotic disease. Cardiovasc Diabetol 2017; 16: 76
• 14 Fadini GP, Avogaro A. Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis 2013; 229: 23-29
• 15 Schmidt-Lucke C, Fichtlscherer S, Aicher A. et al. Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol. PLoS One 2010; 5: e13790
• 16 Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood 2005; 106: 1525-1531
• 17 Fadini GP, Boscaro E, Albiero M. 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-1alpha. Diabetes Care 2010; 33: 1607-1609
• 18 Fadini GP, Bonora BM, Cappellari R. et al. Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes. J Clin Endocrinol Metab 2016; 101: 748-756
• 19 Aso Y, Jojima T, Iijima T. et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, increases the number of circulating CD34+ CXCR4+ cells in patients with type 2 diabetes. Endocrine 2015; 50: 659-664
• 20 Dei Cas A, Spigoni V, Cito M. et al. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: A 12-month randomized controlled trial in patients with type 2 diabetes. Cardiovasc Diabetol 2017; 16: 27
• 21 Li F, Chen J, Leng F. et al. Effect of Saxagliptin on Circulating Endothelial Progenitor Cells and Endothelial Function in Newly Diagnosed Type 2 Diabetic Patients. Exp Clin Endocrinol Diabetes 2017; 125: 400-407
• 22 Fadini GP, Rigato M, Cappellari R. et al. Long-term prediction of cardiovascular outcomes by circulating CD34+ and CD34+CD133+ stem cells in patients with type 2 diabetes. Diabetes Care 2017; 40: 125-131
• 23 Scirica BM, Bhatt DL, Braunwald E. et al. SAVOR-TIMI 53 Steering Committee and Investigators et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-1326
• 24 White WB, Cannon CP, Heller SR. et al. EXAMINE Investigators et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-1335
• 25 Green JB, Bethel MA, Armstrong PW. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232-242
• 26 Assmus B, Leistner DM, Schächinger V. et al. Long-term clinical outcome after intracoronary application of bone marrow-derived mononuclear cells for acute myocardial infarction: Migratory capacity of administered cells determines event-free survival. Eur Heart J 2014; 35: 1275-1283
• 27 Schächinger V, Erbs S, Elsässer A. et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: Final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775-2783
• 28 Chen LL, Yu F, Zeng TS. et al. Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes. Eur J Pharmacol 2011; 659: 296-301
• 29 Chen LL, Liao YF, Zeng TS. et al. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine 2010; 38: 266-275