title: Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial.
abstract: OBJECTIVE
  No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles.
  
  
  OBJECTIVE
  To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS).
  
  
  METHODS
  AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated.
  
  
  METHODS
  Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily.
  
  
  METHODS
  The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function.
  
  
  RESULTS
  The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased.
  
  
  CONCLUSIONS
  Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01042769.
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
authors.affiliation: Montreal Heart Institute Coordinating Center, Université de Montréal, Montreal, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: South Australian Health and Medical Research Institute, University of Adelaide, Adelaide.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rydén
authors.affiliation: George Institute for Global Health, University of Sydney, Sydney, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Neal
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden7F. Hoffman-La Roche Ltd, Basel, Switzerland.
authors.forename: Klas
authors.initials: K
authors.lastname: Malmberg
authors.affiliation: Nordic School of Public Health, Frolunda, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Wedel
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: University of California San Diego, San Diego.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: F. Hoffman-La Roche Ltd, Basel, Switzerland.
authors.forename: Arlette
authors.initials: A
authors.lastname: Weichert
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
authors.forename: Ruth
authors.initials: R
authors.lastname: Cannata
authors.affiliation: F. Hoffman-La Roche Ltd, Basel, Switzerland.
authors.forename: Anders
authors.initials: A
authors.lastname: Svensson
authors.affiliation: F. Hoffman-La Roche Ltd, Basel, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Volz
authors.affiliation: Julius Center for Health Sciences and Primary Care and Julius Clinical, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
mesh_terms: D054058:Acute Coronary Syndrome / Q000150:complications*; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010080:Oxazoles / Q000627:therapeutic use*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D012306:Risk; D020521:Stroke; D016019:Survival Analysis; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D013876:Thiophenes; C542437:aleglitazar