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

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) or=70 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.