title: Synergistic relationship between hyperglycaemia and inflammation with respect to clinical outcomes in non-ST-elevation acute coronary syndromes: analyses from OPUS-TIMI 16 and TACTICS-TIMI 18.
abstract: OBJECTIVE
  To investigate the relationship between diabetes and inflammation and the potentially synergistic relationship between hyperglycaemia and inflammation on clinical outcomes in non ST-elevation ACS.
  
  
  RESULTS
  The principal analysis was conducted in 2200 patients in OPUS-TIMI 16 with C-reactive protein data available and then validated in the invasive arm of TACTICS-TIMI 18 (n = 929). In addition, two further inflammatory markers [monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF)] were assessed in OPUS-TIMI 16. Diabetic patients had higher C-reactive protein and MCP-1 levels vs. non-diabetic patients in OPUS-TIMI 16 (9 vs. 7.8 mg/L, P = 0.002, and 190.6 vs. 170.8 pg/mL, P = 0.04, respectively), higher C-reactive protein levels in TACTICS-TIMI 18 (6.6 vs. 5.2 mg/L, P = 0.0005), and as expected higher glucose levels in both trials. Stratifying by the median C-reactive protein and diabetes in OPUS-TIMI 16, diabetic patients with C-reactive protein greater than or equal to the median were the highest risk group vs. non-diabetic patients with C-reactive protein less than the median (adjusted HR 1.63, 95% CI 1.20-2.23, P = 0.002). Directionally, similar findings were observed for MCP-1 and vWF in OPUS-TIMI 16 and for C-reactive protein in TACTICS-TIMI 18. After adjustment for diabetes, the risk associated with a 1 mmol/L increase in glucose was greater among those with a C-reactive protein greater than or equal to the median (HR 1.07, 95% CI 1.03-1.11) vs. those with a C-reactive protein less than the median (HR 1.02, 95% CI 0.97-1.06). After multivariable adjustment, the synergistic relationship between glucose and C-reactive protein and clinical outcomes remained statistically significant (P = 0.01). A similar pattern was observed in TACTICS-TIMI 18.
  
  
  CONCLUSIONS
  Among ACS patients, diabetes was associated with both greater inflammation and higher glucose levels and patients with both hyperglycaemia and inflammation had worse outcomes. Better control of both inflammation and hyperglycaemia should be assessed in future ACS trials as a means to reduce the cardiovascular risk among diabetics.
authors.affiliation: The TIMI Study Group and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 350 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Ray
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
authors.forename: Ajay J
authors.initials: AJ
authors.lastname: Kirtane
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Buros
authors.forename: Nader
authors.initials: N
authors.lastname: Rifai
authors.forename: Carolyn H
authors.initials: CH
authors.lastname: McCabe
authors.forename: C Michael
authors.initials: CM
authors.lastname: Gibson
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000368:Aged; D000409:Alanine / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000209:etiology* / Q000378:metabolism; D009205:Myocarditis / Q000150:complications* / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D007004:Hypoglycemic Agents; D011759:Pyrrolidines; D014841:von Willebrand Factor; D002097:C-Reactive Protein; C120234:orbofiban; D000409:Alanine