Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial

Jeroen V Koomen, Hiddo J L Heerspink, Ilse C Schrieks, Gregory G Schwartz, A Michael Lincoff, Stephen J Nicholls, Anders Svensson, Hans Wedel, Arlette Weichert, Diederick E Grobbee, Jasper Stevens

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Abstract

Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-alpha gamma agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 mu g or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC(0-24)) of 174.7 ng h/mL (SD: +/- 112.9 ng h/mL) versus 142.2 ng h/mL (SD: +/- 92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002,

Original languageEnglish
Number of pages9
JournalDiabetes obesity & metabolism
Early online date29-Aug-2019
DOIs
Publication statusPublished - 1-Oct-2019

Keywords

  • aleglitazar
  • exposure response
  • peroxisome proliferator-activated receptor
  • PK-PD
  • randomized controlled trial
  • TYPE-2 DIABETES-MELLITUS
  • ACUTE CORONARY SYNDROME
  • ALPHA/GAMMA AGONIST
  • CLOPIDOGREL
  • PHARMACOKINETICS
  • METABOLISM
  • ASPIRIN
  • EVENTS

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