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-PLA2 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 daraplaclib 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/di. Plasma Lp-PLA2 was higher in older patients ( >= 75 years), in men, in those taking atorvastatin 20 mg, at LDL-C 70 mg/di 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-PLA2 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 (>= 70 vs. <70 mg/di) and HDL-C (<40 vs. >= 40 mg/dl). At 12 weeks, darapladib 160 mg decreased interieukin (IL)-6 by 12.3% (95% confidence interval [Cl] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% Cl -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA2 inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B-2). No major safety concerns were noted. Conclusions Daraplaclib produced sustained inhibition of plasma Lp-PLA2 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-PLA2 inhibition is associated with favorable effects on CV events.