Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial

JAMA. 2005 May 11;293(18):2245-56. doi: 10.1001/jama.293.18.2245.


Context: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI.

Objective: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.

Design, setting, and patients: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004.

Interventions: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.

Main outcome measures: Changes in levels of biomarkers associated with risk of MI.

Results: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events.

Conclusion: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Proteins
  • Aged
  • Biomarkers / metabolism
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / genetics*
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Cross-Over Studies
  • Epoxide Hydrolases / genetics
  • Female
  • Humans
  • Leukotriene B4 / metabolism
  • Leukotriene E4 / metabolism
  • Lipoxygenase Inhibitors / therapeutic use*
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics*
  • Middle Aged
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / prevention & control
  • Peroxidase / metabolism
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Quinolines / therapeutic use*
  • Risk Factors


  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Biomarkers
  • Carrier Proteins
  • Lipoxygenase Inhibitors
  • Membrane Proteins
  • Quinolines
  • 2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid
  • Leukotriene B4
  • Leukotriene E4
  • Peroxidase
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase