Endothelial Effects of Basal Insulin: Detemir Versus Glargine

Summary

Endothelial progenitor cell (EPC) level represents a surrogate marker of cardiovascular risk and an indicator of the ongoing vascular damage. Moreover, EPCs are involved in the pathogenesis of virtually all diabetic complications. Therefore, ways to modulate EPCs are currently considered of utmost importance, especially in high-risk subjects. While many drugs with pleiotropic vasculoprotective effects have shown ability to positively modulate EPCs, there is no data on the effects of specific insulin formulations. This is a human randomised cross-over comparison trial. The purpose is to compare the effects of two basal insulin analogues (detemir and glargine) added to oral antidiabetic therapy in poorly-controlled type 2 patients with cardiovascular disease on endothelial function and EPC levels. The aim is to test whether optimized glycemic control with add-on basal insulin analogues improves endothelial damage and regeneration in type 2 diabetes with macroangiopathy and to compare the effects of glargine vs detemir on markers of endothelial damage and regeneration. EPC level is the most innovative outcome measure of this study and represents the primary endpoint. Endothelial dysfunction/damage, evaluated using soluble markers, will be the secondary outcome. Given the supposed inverse correlation between EPC and endothelial damage, it is expected that EPC increase reflects amelioration in endothelial biology, a result that may have significant clinical implications in this cohort of high-risk patients.

Timeline

Start

2008-05

Primary completion

2010-03

Completion

2010-03

Publications

• Background Fadini GP. An underlying principle for the study of circulating progenitor cells in diabetes and its complications. Diabetologia. 2008 Jul;51(7):1091-4. doi: 10.1007/s00125-008-1021-0. No abstract available.
• Background Fadini GP, Agostini C, Avogaro A. Endothelial progenitor cells and vascular biology in diabetes mellitus: current knowledge and future perspectives. Curr Diabetes Rev. 2005 Feb;1(1):41-58. doi: 10.2174/1573399052952640.
• Background Fadini GP, Baesso I, Agostini C, Cuccato E, Nardelli GB, Lapolla A, Avogaro A. Maternal insulin therapy increases fetal endothelial progenitor cells during diabetic pregnancy. Diabetes Care. 2008 Apr;31(4):808-10. doi: 10.2337/dc07-1996. Epub 2007 Dec 27. No abstract available.
• Background Fadini GP, Pucci L, Vanacore R, Baesso I, Penno G, Balbarini A, Di Stefano R, Miccoli R, de Kreutzenberg S, Coracina A, Tiengo A, Agostini C, Del Prato S, Avogaro A. Glucose tolerance is negatively associated with circulating progenitor cell levels. Diabetologia. 2007 Oct;50(10):2156-63. doi: 10.1007/s00125-007-0732-y. Epub 2007 Jun 20.
• Background Fadini GP, Sartore S, Agostini C, Avogaro A. Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care. 2007 May;30(5):1305-13. doi: 10.2337/dc06-2305. Epub 2007 Feb 2. No abstract available.
• Background Fadini GP, Sartore S, Schiavon M, Albiero M, Baesso I, Cabrelle A, Agostini C, Avogaro A. Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats. Diabetologia. 2006 Dec;49(12):3075-84. doi: 10.1007/s00125-006-0401-6. Epub 2006 Oct 27.
• Background Fadini GP, de Kreutzenberg SV, Coracina A, Baesso I, Agostini C, Tiengo A, Avogaro A. Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J. 2006 Sep;27(18):2247-55. doi: 10.1093/eurheartj/ehl198. Epub 2006 Aug 15.
• Background Fadini GP, Coracina A, Baesso I, Agostini C, Tiengo A, Avogaro A, de Kreutzenberg SV. Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke. 2006 Sep;37(9):2277-82. doi: 10.1161/01.STR.0000236064.19293.79. Epub 2006 Jul 27.
• Background Avogaro A, Fadini GP, Gallo A, Pagnin E, de Kreutzenberg S. Endothelial dysfunction in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2006 Mar;16 Suppl 1:S39-45. doi: 10.1016/j.numecd.2005.10.015. Epub 2006 Feb 8.
• Background Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol. 2005 May 3;45(9):1449-57. doi: 10.1016/j.jacc.2004.11.067.
• Background Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2140-6. doi: 10.1161/01.ATV.0000237750.44469.88. Epub 2006 Jul 20.
• Background Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005 Sep 8;353(10):999-1007. doi: 10.1056/NEJMoa043814.
• Background Humpert PM, Neuwirth R, Battista MJ, Voronko O, von Eynatten M, Konrade I, Rudofsky G Jr, Wendt T, Hamann A, Morcos M, Nawroth PP, Bierhaus A. SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes. Diabetes Care. 2005 Apr;28(4):934-6. doi: 10.2337/diacare.28.4.934. No abstract available.
• Fadini GP, Albiero M, Vigili de Kreutzenberg S, Avogaro A. Hypoglycemia affects the changes in endothelial progenitor cell levels during insulin therapy in type 2 diabetic patients. J Endocrinol Invest. 2015 Jul;38(7):733-8. doi: 10.1007/s40618-015-0247-1. Epub 2015 Feb 27.
• Fadini GP, Iori E, Marescotti MC, Vigili de Kreutzenberg S, Avogaro A. Insulin-induced glucose control improves HDL cholesterol levels but not reverse cholesterol transport in type 2 diabetic patients. Atherosclerosis. 2014 Aug;235(2):415-7. doi: 10.1016/j.atherosclerosis.2014.05.942. Epub 2014 Jun 4.
• Fadini GP, Mancuso P, Bertolini F, de Kreutzenberg S, Avogaro A. Amelioration of glucose control mobilizes circulating pericyte progenitor cells in type 2 diabetic patients with microangiopathy. Exp Diabetes Res. 2012;2012:274363. doi: 10.1155/2012/274363. Epub 2012 Feb 28.

Drugs

Indications