title: Peripheral artery disease, biomarkers, and darapladib.
abstract: OBJECTIVE
  Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor.
  
  
  METHODS
  This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA(2) inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787).
  
  
  RESULTS
  After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10-31], P < .01), myeloperoxidase (12% [2-20], P = .01), interleukin-6 (13% [4-21], P = .01), adiponectin (17% [7-26], P < .01), intercellular adhesion molecule-1 (7% [2-11], P < .01), osteoprotegrin (6% [1-10], P = .02), CD40 ligand (15% [1-28], P = .04), high-sensitivity C-reactive protein (17% [1-31], P = .04), and triglycerides (11% [0.2-21], P = .05). No significant difference was detected for Lp-PLA(2) activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA(2) activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD.
  
  
  CONCLUSIONS
  Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA(2) inhibitor, was equally effective in reducing Lp-PLA(2) activity levels in subjects with and without PAD.
authors.affiliation: New York University School of Medicine, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Berger
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Michael H
authors.initials: MH
authors.lastname: Davidson
authors.forename: Joel L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tarka
authors.forename: Denise
authors.initials: D
authors.lastname: Lawrence
authors.forename: Trupti
authors.initials: T
authors.lastname: Trivedi
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalewski
authors.forename: Emile R
authors.initials: ER
authors.lastname: Mohler
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000097:blood; D000368:Aged; D001547:Benzaldehydes / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000008:administration & dosage / Q000627:therapeutic use*; D058729:Peripheral Arterial Disease / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D015415:Biomarkers; D010091:Oximes; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides