Abstract
BackgroundThe aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.MethodsPatients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.ResultsDarapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.ConclusionsShort-term treatment (14±4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.Trial Registration InformationName of Registry 1: ClinicalTrials.govRegistry Number 1: NCT01916720Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720 Name of Registry 2: GSK Clinical Study RegisterRegistry Number 2∶480848/010Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F
Highlights
Despite medical and scientific advances over the past 15 years, the burden associated with atherosclerotic cardiovascular (CV)disease remains unacceptably high
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been described as a platelet-activating factor (PAF) acetylhydrolase [3], accumulating evidence suggests that the products of Lp-PLA2, lysophosphatidylcholine and oxidized nonesterified fatty acids, can elicit a broad range of proinflammatory and proapoptotic effects [4]
One subject in the darapladib 80-mg group withdrew from the study prematurely because of an adverse event; this subject experienced a hypertensive crisis while receiving anesthesia in preparation for carotid endarterectomy, 1 day following the completion of study medication
Summary
Despite medical and scientific advances over the past 15 years, the burden associated with atherosclerotic cardiovascular (CV)disease remains unacceptably high. Additional processes within the vessel wall, inflammatory responses, contribute to plaque destabilization, atherothrombosis, and the clinical sequelae. Mediators of these processes represent potential novel treatment targets for reducing CV risk and the burden associated with atherosclerotic CV disease. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging CV risk marker that may play an important pathogenetic role in mediating inflammatory processes that contribute to plaque vulnerability and rupture [2]. A recent analysis of carotid plaque Lp-PLA2 and lysoPC content demonstrated a highly statistically significant correlation of both biomarkers with various plaque M1 macrophage-related proinflammatory cytokines such as IL-6, tumor necrosis factor-a and monocyte chemoattractant protein-1 [11]. The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoproteinassociated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity
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