Obesity and Inflammation and Altered Clopidogrel Pharmacokinetics and Pharmacodynamics.

Abstract

Clopidogrel is a key antiplatelet drug that has substantial interpatient variability in pharmacodynamic response. Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction. A number of reports have demonstrated that obesity is a risk factor for a reduced clopidogrel pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion, a number of mechanisms that increase platelet reactivity, suppress cytochrome P450 enzyme activity, and increase platelet turnover, all contributing to a poor clopidogrel response. Comprehensive understanding of the mechanisms underlying obesity-related high onclopidogrel platelet reactivity will help in the optimization of antithrombotic therapy in this patient population.