Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and therapeutic target for hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Furthermore, research from in-vitro and in-vivo animal models suggest that the inhibition of PCSK9 expression may suppress platelet activation, and systemic inflammation thereby reducing thrombotic risk. Taken together, these data support the lower rates of myocardial infarction, stroke, and coronary revascularization in subjects with increased CVD risk in clinical trials with alirocumab (Praluent) and evolocumab (Repatha) as compared to placebo. The main aim of this single center, exploratory in-vitro evaluation is to investigate the direct role of PCSK9 on platelet activation and aggregation using blood collected from a diverse population of antiplatelet naïve healthy volunteers (n=40) and subjects with CVD risk factors (n=40) between the 18-50 years of age. All procedures including consenting, collection of clinical data, and lab processing will occur at the Sinai Center for Thrombosis Research. The results of this study will provide a better understanding of cardioprotective effects of PCSK9 inhibition beyond lipid lowering.
Healthy subjects (n=40): 18-50 years old male and female subjects without any conditions or taking any agents or food supplements that may influence platelet function as determined by the study principal investigator.
Subjects with Diabetes mellitus, who are on GLP-1 agonists or SGLT2 inhibitors.
Subjects on high dose statin therapy or PCSK9 therapy.
Prior coronary of cerebrovascular event requiring intervention.
Use of any antiplatelet or anticoagulant therapy within 14 days of enrollment.
This trial has been designed to ensure enrollment of healthy volunteers and subjects with CV risk to allow for comparisons across disease states in order to fulfill study objectives. Compared to healthy volunteers, subjects with CV risk factors are highly prothrombotic and exhibit a high platelet reactivity phenotype. Coexistence of at least three risk factors indicate a high risk for future CV events. African Americans and women are inherently at elevated risk for CVD, associated ischemic events, and exhibit higher serum PCSK9 levels. Therefore, equal inclusion of race and genders should provide robust variability in PCSK9 levels for evaluation of platelet related effects of PCSK9.
Cohort
Prospective
PCSK9 Antibody, PCSK9 Enzyme
DrugIn-vitro demonstration of the direct effect if the PCSK9 enzyme on platelets. The study will use commercially available recombinant PCSK9 enzyme to promote platelet activity and the PCSK9 antibody to inhibit activity. In each patient, platelet function testing will occur in the absence of PCSK9 enzyme, after the addition of PCSK9 enzyme, and after the addition of both PCSK9 enzyme and antibody reagent to the blood sample prior to testing.
Difference in ADP-induced platelet aggregation (%) with and without PCSK9 enzyme
Difference in ADP-induced platelet aggregation (%) with and without addition of PCSK9 enzyme in blood collected from healthy volunteers and subjects with cardiovascular risk factors.
Difference in collagen related peptide -induced platelet aggregation (%) with and without PCSK9 enzyme
Difference in collagen related peptide-induced platelet aggregation (%) with and without PCSK9 enzyme in blood collected from healthy volunteers and subjects with cardiovascular risk factors.
Difference in ADP-induced platelet aggregation (%) with PCSK9 enzyme alone and with addition of PCSK9 antibody
Difference in ADP-induced platelet aggregation (%) with PCSK9 enzyme alone and after addition of PCSK9 antibody in blood collected from healthy volunteers and subjects with cardiovascular risk factors
Difference in collagen related peptide-induced platelet aggregation (%) with PCSK9 enzyme alone and with addition of PCSK9 antibody
Difference in collagen related peptide-induced platelet aggregation (%) with PCSK9 enzyme alone and with addition of PCSK9 antibody in blood collected from healthy volunteers and subjects with cardiovascular risk factors.
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LifeBridge Health
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator
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