The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study

J Am Coll Cardiol. 2008 Apr 29;51(17):1632-41. doi: 10.1016/j.jacc.2007.11.079.

Abstract

Objectives: This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk.

Background: Elevated Lp-PLA(2) levels are associated with an increased risk of CV events.

Methods: Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers.

Results: Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (>or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-C >or=70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (>or=70 vs. <70 mg/dl) and HDL-C (<40 vs. >or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted.

Conclusions: Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

Trial registration: ClinicalTrials.gov NCT00269048.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / blood
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / drug effects
  • Aged
  • Anti-Inflammatory Agents / therapeutic use*
  • Anticholesteremic Agents / therapeutic use*
  • Atorvastatin
  • Benzaldehydes / administration & dosage
  • Benzaldehydes / pharmacology*
  • Biomarkers / blood
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / enzymology*
  • Double-Blind Method
  • Female
  • Heptanoic Acids / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Inflammation / enzymology
  • Interleukins / blood
  • Male
  • Middle Aged
  • Oximes / administration & dosage
  • Oximes / pharmacology*
  • Prognosis
  • Pyrroles / therapeutic use
  • Recurrence
  • Risk Factors

Substances

  • Anti-Inflammatory Agents
  • Anticholesteremic Agents
  • Benzaldehydes
  • Biomarkers
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Interleukins
  • Oximes
  • Pyrroles
  • Atorvastatin
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • darapladib

Associated data

  • ClinicalTrials.gov/NCT00269048