Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for ‘pleiotropic’ functions of statin therapy

AIMS: Statin therapy is associated with improved endothelial vasodilator function. The clinical availability of ezetimibe, a potent novel cholesterol absorption inhibitor, enables to differentiate lipid-lowering effects from potential non-lipid-lowering (pleiotropic) mechanisms of statins. METHODS AND RESULTS: Forearm blood flow (FBF) responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were measured by venous occlusion plethysmography in four prospectively defined groups of patients with stable coronary artery disease (CAD) before and after 4 weeks of lipid-lowering therapy. Group A (n=15): de novo monotherapy with 10 mg/day ezetimibe; Group B (n=15): 10 mg/day ezetimibe as an add-on to chronic simvastatin therapy with 20 mg/day; Group C (n=15): dose escalation from chronic 10 to 40 mg/day atorvastatin; and Group D (n=15): de novo monotherapy with 40 mg/day atorvastatin. After 4 weeks of therapy, LDL cholesterol levels were significantly reduced in all four groups. Neither ezetimibe monotherapy (Group A) nor ezetimibe combined with 20 mg simvastatin (Group B) was associated with an increase in ACH-mediated FBF responses after 4 weeks. In contrast, dose escalation of atorvastatin from 10 to 40 mg/day (Group C) or de novo therapy with 40 mg atorvastatin/day (Group D) was associated with a significant increase in ACH-mediated FBF responses (P<0.013). CONCLUSION: Thus, both statins and ezetimibe effectively lower LDL-levels within 4 weeks of therapy. However, only statin therapy is associated with improved endothelial vasodilator function, disclosing the relevance of pleiotropic effects of statins during short-term treatment of patients with CAD.