Simvastatin Versus Ezetimibe

Abstract

Background-Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function. Methods and Results-Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (⌬FDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; PϭNS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (⌬mevalonate-simvastatin, Ϫ1.04Ϯ0.62 versus ⌬mevalonate-ezetimibe, 1.79Ϯ0.94 ng/mL; PϽ0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5Ϯ0.6% versus 5.1Ϯ0.7%; PϽ0.01) but not after ezetimibe treatment (5.6Ϯ0.5% versus 5.8Ϯ0.6%; PϭNS). ⌬FDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by Ͼ100% (PϽ0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect. Conclusions-Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in

Clinical Significance of Statin Pleiotropic Effects

“…3 In this issue of Circulation, Landmesser et al report that with equal lowering of LDL-cholesterol by simvastatin or ezetimibe, only simvastatin improved endothelial function (as measured by flow-dependent dilation in the radial artery) in patients with congestive heart failure (CHF). 4 This study supports the view that statins provide clinical cardiovascular benefits beyond lipid modification.…”

Biologic Effects of Simvastatin in Patients with Aneurysmal Subarachnoid Hemorrhage: A Double-Blind, Placebo-Controlled Randomized Trial

“…However, the impact of pleiotropic effects for clinical benefit is a matter of intense debate. Although data from meta-analyses of lipid-lowering trials suggest that lipid modification alone accounts for the clinical benefits associated with statin therapy, recent studies have implied that statin-induced LDL cholesterol reduction may in fact be more beneficial compared with non-statin-induced LDL cholesterol reduction (Brouilette et al, 2007;Landmesser et al, 2005;Fichtlscherer et al, 2006;Rossebø et al, 2008). These pleiotropic effects have even been suggested to contribute to neuroprotection (Kivipelto et al, 2005).…”

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

“…40 Mevalonic acid was converted to the corresponding lactone, extracted into ethyl acetate, purified via silica gel chromatography, and eluted with dichloromethane:methanol (95:5 v/v). After derivatization with N-methyl-N-trimethylsilyltrifluoro-acetamide (containing 1% trimethylchlorosilane)/pyridine (2:1 v/v) at room temperature, samples were analyzed via electron ionization gas chromatography/mass spectrometry in single-ion-monitoring mode using ions at m/z 233 for the target and m/z 237 for the internal standard ion.…”