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


METHODS
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Hakonarson
Hakon
H
Decode Genetics Inc, Reykjavik, Iceland. hakonh@decode.is
Thorvaldsson
Sverrir
S
Helgadottir
Anna
A
Gudbjartsson
Daniel
D
Zink
Florian
F
Andresdottir
Margret
M
Manolescu
Andrei
A
Arnar
David O
DO
Andersen
Karl
K
Sigurdsson
Axel
A
Thorgeirsson
Gestur
G
Jonsson
Asgeir
A
Agnarsson
Uggi
U
Bjornsdottir
Halldora
H
Gottskalksson
Gizur
G
Einarsson
Atli
A
Gudmundsdottir
Hrefna
H
Adalsteinsdottir
Asdis E
AE
Gudmundsson
Kolbeinn
K
Kristjansson
Kristleifur
K
Hardarson
Thordur
T
Kristinsson
Arni
A
Topol
Eric J
EJ
Gulcher
Jeffrey
J
Kong
Augustine
A
Gurney
Mark
M
Thorgeirsson
Gudmundur
G
Stefansson
Kari
K
D058927:5-Lipoxygenase-Activating Proteins; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018592:Cross-Over Studies; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D009195:Peroxidase / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011804:Quinolines / Q000627:therapeutic use*; D012307:Risk Factors
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D015415:Biomarkers; D002352:Carrier Proteins; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D007975:Leukotriene B4; D017999:Leukotriene E4; D009195:Peroxidase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase