title: Serial Measurement of High-Sensitivity Troponin I and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care).
abstract: BACKGROUND
  We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes.
  
  
  METHODS
  The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point.
  
  
  RESULTS
  At baseline, hsTnI was detectable (≥1.9 ng/L) in 93% of patients and >99thpercentile upper reference limit in 16%. There was a strong relationship between increasing hsTnI, both at baseline and 6 months, and the incidence of cardiovascular events through 24 months (P<0.001 for each). Patients with undetectable hsTnI at baseline and 6 months were at the lowest risk of future cardiovascular events. Stable patients with hsTnI ≥99th percentile upper reference limit at 6 months were at increased risk of cardiovascular death, myocardial infarction, or stroke compared with patients with hsTnI <99 percentile upper reference limit irrespective of whether hsTnI was newly elevated (28.1% versus 8.8%; adjusted hazard ratio, 2.65; 95% confidence interval, 1.64-4.28;P<0.001) or persistently so (22.5% versus 8.8%; adjusted hazard ratio, 1.90; 95% confidence interval, 1.33-2.70;P<0.001). Alogliptin neither increased nor decreased the risk of cardiovascular events compared with placebo in patients with high baseline hsTnI (22.3% versus 23.0%; hazard ratio, 0.87; 95% confidence interval, 0.60-1.25;P=0.44).
  
  
  CONCLUSIONS
  Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00968708.
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.). matt.cavender@unc.edu.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: William B
authors.initials: WB
authors.lastname: White
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: William C
authors.initials: WC
authors.lastname: Cushman
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Stuart
authors.initials: S
authors.lastname: Kupfer
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Cyrus R
authors.initials: CR
authors.lastname: Mehta
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: From University of North Carolina, Chapel Hill (M.A.C.); Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington (W.B.W.); Department of Pathology (P.J.) and TIMI Study Group (D.A.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; University of Chicago, IL (G.L.B.); Memphis Veterans Affairs Medical Center, University of Tennessee College of Medicine (W.C.C.); Takeda Development Center Americas, Inc., Deerfield, IL (S.K.); Baim Institute for Clinical Research, Boston, MA (Q.C., C.P.C.); Harvard School of Public Health, Boston, MA (C.R.M.); and Inserm 1143, Université de Lorraine, Nancy, France (F.Z.).
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D000368:Aged; D015415:Biomarkers / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000628:therapy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D059039:Standard of Care / Q000639:trends; D016896:Treatment Outcome; D019210:Troponin I / Q000097:blood*; D014498:Uracil / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D010880:Piperidines; D019210:Troponin I; D014498:Uracil; C520853:alogliptin
keywords: acute coronary syndrome; cardiac biomarkers; secondary prevention; troponin; type 2 diabetes mellitus