title: Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes.
abstract: BACKGROUND
  Insulin-resistant states, including type 2 diabetes (T2D) and prediabetes, are associated with elevated cardiovascular (CV) risk. Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions, favorable effects on blood lipids, and an acceptable safety profile in short-time studies. Therefore, it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes (defined as glycosylated hemoglobin ≥5.7% to <6.5%) with previous CV complications.
  
  
  METHODS
  ALEPREVENT was a phase III, multicenter, randomized, double-blind, trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established, stable CV disease. The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events. However, the trial was halted prematurely after 1,999 patients had been randomized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar.
  
  
  RESULTS
  At study termination after 58 ± 38 days of treatment, data had been collected from 1,996 patients (1,581 with T2D and 415 with pre-T2D). Despite the brief duration of treatment, aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids, similar for participants with T2D or prediabetes. However, compared with placebo, aleglitazar increased the incidence of hypoglycemia (86 vs 166; P < .0001), and muscular events (3 vs12; P = .012).
  
  
  CONCLUSIONS
  Even within a short duration of exposure, aleglitazar was associated with excess adverse events, corroborating the findings of a larger and longer trial in T2D. Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators, this class now holds little promise for CV therapeutics.
authors.affiliation: Herzzentrum der Universität zu Köln, Cologne, Germany.
authors.forename: Erland
authors.initials: E
authors.lastname: Erdmann
authors.affiliation: Department of Medicine, Duke University, Durham, NC.
authors.forename: Robert
authors.initials: R
authors.lastname: Califf
authors.affiliation: Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
authors.affiliation: Department of Medicine, Karolinska Institutet, Stockholm, Sweden; F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Klas
authors.initials: K
authors.lastname: Malmberg
authors.affiliation: Unidad de Hipertensión, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Ruilope
authors.affiliation: University of Colorado School of Medicine, Denver, CO.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
authors.affiliation: Nordic School of Public Health, Frolunda, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Wedel
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Volz
authors.affiliation: Former, F Hoffmann-La Roche Ltd; Current, Astra Zeneca, Mölndal, Sweden.
authors.forename: Marc
authors.initials: M
authors.lastname: Ditmarsch
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Anders
authors.initials: A
authors.lastname: Svensson
authors.affiliation: F Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Monica
authors.initials: M
authors.lastname: Bengus
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000150:complications / Q000517:prevention & control*; D002561:Cerebrovascular Disorders / Q000150:complications; D003327:Coronary Disease / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D063806:Myalgia / Q000139:chemically induced; D009203:Myocardial Infarction / Q000150:complications / Q000517:prevention & control; D009220:Myositis / Q000139:chemically induced; D010080:Oxazoles / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D058729:Peripheral Arterial Disease / Q000150:complications; D011236:Prediabetic State / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000517:prevention & control; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D013876:Thiophenes; C517652:hemoglobin A1c protein, human; C542437:aleglitazar