title: Cardiovascular disease in diabetes: where does glucose fit in?
abstract: BACKGROUND
  Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies.
  
  
  METHODS
  The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic.
  
  
  RESULTS
  High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. EPIDEMIOLOGICAL AND COHORT STUDIES: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality.
  
  
  CONCLUSIONS
  Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia.
authors: Denver VA Medical Center, Clermont Street, Denver, Colorado 80220, USA. jane.reusch@ucdenver.edu
authors: Jane E B
authors: JE
authors: Reusch
authors: Cecilia C Low
authors: CC
authors: Wang
references: N Engl J Med. 2011 Mar 3;364(9):818-28
references: 21366473
references: Am J Med. 1983 Nov 30;75(5B):67-80
references: 6424441
references: BMJ. 1998 Mar 14;316(7134):823-8
references: 9549452
references: Cardiovasc Diabetol. 2010 Jul 27;9:31
references: 20663195
references: Eur J Cardiovasc Prev Rehabil. 2010 Feb;17(1):94-9
references: 19940780
references: N Engl J Med. 2009 Jan 8;360(2):129-39
references: 19092145
references: J Intern Med. 2010 Nov;268(5):468-70
references: 20964737
references: N Engl J Med. 2008 Oct 9;359(15):1577-89
references: 18784090
references: Diabetes Care. 2003 Jul;26(7):2181-8
references: 12832332
references: Diabetes Care. 2006 Apr;29(4):877-82
references: 16567831
references: Am J Cardiol. 2010 Sep 1;106(5):754-5
references: 20723660
references: N Engl J Med. 1993 Sep 30;329(14):977-86
references: 8366922
references: Diabetes Care. 2010 May;33(5):983-90
references: 20427682
references: BMJ. 2010 Jan 08;340:b4909
references: 20061358
references: Diabetes Care. 1999 Aug;22(8):1262-5
references: 10480768
references: N Engl J Med. 2005 Dec 22;353(25):2643-53
references: 16371630
references: Circulation. 2004 Jul 13;110(2):227-39
references: 15249516
references: N Engl J Med. 2010 Oct 7;363(15):1410-8
references: 20925543
references: Diabetes. 2004 Nov;53(11):2735-40
references: 15504952
references: Clin Appl Thromb Hemost. 2011 Jun;17(3):288-92
references: 20530060
references: J Cereb Blood Flow Metab. 2008 Feb;28(2):377-86
references: 17684520
references: Am Heart J. 1984 Jul;108(1):31-7
references: 6731279
references: Diabetes Care. 1991 Jul;14(7):537-43
references: 1914792
references: J Appl Physiol (1985). 2005 Oct;99(4):1471-6
references: 16024521
references: Diabetes Obes Metab. 2009 Feb;11(2):150-6
references: 18671796
references: Lancet. 1998 Sep 12;352(9131):837-53
references: 9742976
references: Diabetologia. 2005 Dec;48(12):2667-74
references: 16283236
references: J Exp Med. 2008 Sep 29;205(10):2409-17
references: 18809715
references: Diabetologia. 1996 Dec;39(12):1540-5
references: 8960840
references: Med Electron Microsc. 2001 Jun;34(2):86-91
references: 11685657
references: Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H736-45
references: 20008269
references: BMJ. 2010 Jan 08;340:b5444
references: 20061360
references: Nat Rev Nephrol. 2010 Jun;6(6):332-41
references: 20421885
references: JAMA. 2010 Jun 9;303(22):2291-2
references: 20530784
references: Diabetes Care. 1998 Jul;21(7):1167-72
references: 9653614
references: Am Heart J. 1991 Feb;121(2 Pt 1):586-90
references: 1990765
references: Diabetes Care. 2010 Jul;33(7):1640-6
references: 20424222
references: Circulation. 2002 May 7;105(18):e138-43
references: 11994264
references: N Engl J Med. 2008 Jun 12;358(24):2545-59
references: 18539917
references: Horm Metab Res. 2009 Feb;41(2):109-15
references: 19214920
references: Circulation. 2004 Jul 13;110(2):214-9
references: 15197140
references: N Engl J Med. 1998 Jul 23;339(4):229-34
references: 9673301
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9047-52
references: 18579779
references: Eur J Clin Invest. 1999 Jun;29 Suppl 2:7-11
references: 10383604
references: Arterioscler Thromb Vasc Biol. 1995 Apr;15(4):431-40
references: 7749853
references: Diabetes Care. 1997 Mar;20(3):314-21
references: 9051380
references: Diabetes Care. 1998 Mar;21(3):360-7
references: 9540016
references: Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1400-7
references: 19029021
references: Diabetes Care. 2010 Apr;33(4):721-7
references: 20103550
references: Nat Rev Cardiol. 2010 Jul;7(7):369-75
references: 20404853
references: JAMA. 2009 Dec 2;302(21):2345-52
references: 19952321
references: Diabetes. 2008 May;57(5):1349-54
references: 18299315
references: J Intern Med. 2010 Nov;268(5):471-82
references: 20804517
references: Am J Physiol Cell Physiol. 2008 Jul;295(1):C221-30
references: 18463230
references: Diabetologia. 2004 Dec;47(12):2118-28
references: 15662552
references: N Engl J Med. 2010 Mar 4;362(9):800-11
references: 20200384
references: J Gen Intern Med. 2003 Dec;18(12):1039-52
references: 14687264
references: J Am Coll Cardiol. 2001 May;37(6):1543-50
references: 11345363
references: Br J Nutr. 2009 Jul;102(2):264-72
references: 19222875
references: Lancet. 2010 Jun 26;375(9733):2215-22
references: 20609967
references: Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2):R236-50
references: 21068200
references: N Engl J Med. 2008 Jun 12;358(24):2560-72
references: 18539916
references: Diabetes. 2005 Jun;54(6):1615-25
references: 15919781
references: Diabetes. 2009 Nov;58(11):2642-8
references: 19651816
references: Diabetes Obes Metab. 2007 Jul;9(4):455-63
references: 17587387
references: Acta Diabetol. 2001;38(2):71-6
references: 11757804
references: J Clin Invest. 2003 Oct;112(7):1049-57
references: 14523042
references: Diabetes Res Clin Pract. 2010 Jul;89(1):38-45
references: 20398956
references: Autoimmun Rev. 2010 Oct;9(12):830-4
references: 20678595