Background The 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. Methods Patients 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. Results Darapladib 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. Conclusions Short-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 Information Name of Registry 1: ClinicalTrials.gov Registry Number 1: NCT01916720 Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916？720 Name of Registry 2: GSK Clinical Study Register Registry Number 2:480848/010 Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result？_detail.jsp?protocolId=480848%2F010&stud？yId=74F5DB65-4661-4FA8-91D4-EBF78D769F24？&compound=darapladib&type=Compound&lette？rrange=A-F
References
[1]
Dembowski E, Davidson MH (2009) A review of lipid management in primary and secondary prevention. J Cardiopulm Rehabil Prev 29: 2–12. doi: 10.1097/hcr.0b013e318192754e
[2]
Zalewski A, Macphee C (2005) Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 25: 923–931. doi: 10.1161/01.atv.0000160551.21962.a7
Ferguson JF, Hinkle CC, Mehta NN, Bagheri R, Derohannessian SL, et al. (2012) Translational studies of lipoprotein-associated phospholipase A2 in inflammation and atherosclerosis. J Am Coll Cardiol 59: 764–772. doi: 10.1016/j.jacc.2011.11.019
[7]
Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, et al. (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res 108: 985–995. doi: 10.1161/circresaha.110.233775
[8]
Kolodgie FD, Burke AP, Skorija KS, Ladich E, Kutys R, et al. (2006) Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 26: 2523–2529. doi: 10.1161/01.atv.0000244681.72738.bc
[9]
Mannheim D, Herrmann J, Versari D, G？ssl M, Meyer FB, et al. (2008) Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke 39: 1448–1455. doi: 10.1161/strokeaha.107.503193
Gon？alves I, Edsfeldt A, Ko NY, Grufman H, Berg K, et al. (2012) Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol 32: 1505–1512. doi: 10.1161/atvbaha.112.249854
[12]
Thompson A, Gao P, Orfei L, Watson S, Di Angelantonio E, et al. (2010) Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 375: 1536–1544. doi: 10.1016/s0140-6736(10)60319-4
[13]
Wilensky RL, Shi Y, Mohler ER III, Hamamdzic D, Burgert ME, et al. (2008) Inhibition of lipoprotein-associated phospholipase A 2 reduces complex coronary atherosclerotic plaque development. Nat Med 14: 1059–1066. doi: 10.1038/nm.1870
[14]
Wang W, Zhang J, Wu W, Li J, Ma Y, et al. (2011) Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice. PLoS ONE 6(8): e23425 doi:10.1371/journal.pone.0023425.
[15]
Serruys PW, García-García HM, Buszman P, Erne P, Verheye S, et al. (2008) Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118: 1172–1182. doi: 10.1161/circulationaha.108.771899
[16]
White H, Held C, Stewart R, Watson D, Harrington R, et al. (2010) Study design and rationale for the clinical outcomes of the STABILITY trial (STabilization of atherosclerotic plaque by initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J 160: 655–661. doi: 10.1016/j.ahj.2010.07.006
[17]
O’Donoghue ML, Braunwald E, White HD, Serruys P, Steg PG, et al. (2011) Study design and rationale for the stabilization of pLaques usIng darapladib-thrombolysis in myocardial infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J 162: 613–619. doi: 10.1016/j.ahj.2011.07.018
[18]
Johnson A, Zalewski A, Janmohamed S, Sawyer J, Rolfe T, et al.. (2004) Lipoprotein-associated phospholipase A2 activity, an emerging CV risk marker, can be inhibited in atherosclerotic lesions and plasma by novel pharmacologic intervention: the results of a multicenter clinical study. Circulation 110(suppl III): III-590. Abstract.
[19]
Oei HH, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, et al. (2005) Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 111: 570–575. doi: 10.1161/01.cir.0000154553.12214.cd
[20]
Carpenter KL, Dennis IF, Challis IR, Osborn DP, Macphee CH, et al. (2001) Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidized LDL on human monocyte-macrophages. FEBS Lett. 505: 357–363. doi: 10.1016/s0014-5793(01)02840-x
[21]
Davis B, Koster G, Douet LJ, Scigelova M, Woffendin G, et al. (2008) Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. J Biol Chem 283: 6428–6437. doi: 10.1074/jbc.m709970200
[22]
Mohler ER III, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, et al. (2008) 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 51: 1632–1641. doi: 10.1016/j.jacc.2007.11.079
[23]
Sluijter JPG, Pulskens WPC, Schoneveld AH, Velema E, Strijder CF, et al. (2006) Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 37: 235–239. doi: 10.1161/01.str.0000196986.50059.e0
[24]
Fiotti N, Moretti ME, Bussani R, Altamura N, Zamolo F, et al. (2011) Features of vulnerable plaques and clinical outcome of UA/NSTEMI: relationship with matrix metalloproteinase functional polymorphisms. Atherosclerosis 215: 153–159. doi: 10.1016/j.atherosclerosis.2010.12.010
[25]
Vickers KC, Maguire CT, Wolfert R, Burns AR, Reardon M, et al. (2009) Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis. J Lipid Res 50: 1735–1743. doi: 10.1194/jlr.m800342-jlr200
[26]
Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111: 245–259. doi: 10.1161/circresaha.111.261388
