title: Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans.
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.
  
  
  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 (DeltaFDD-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%; P=NS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (Deltamevalonate-simvastatin, -1.04+/-0.62 versus Deltamevalonate-ezetimibe, 1.79+/-0.94 ng/mL; P<0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5+/-0.6% versus 5.1+/-0.7%; P<0.01) but not after ezetimibe treatment (5.6+/-0.5% versus 5.8+/-0.6%; P=NS). DeltaFDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by >100% (P<0.05) 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 humans.
authors.affiliation: Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany. Landmesser.Ulf@MH-Hannover.de
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Bahlmann
authors.forename: Maja
authors.initials: M
authors.lastname: Mueller
authors.forename: Stephan
authors.initials: S
authors.lastname: Spiekermann
authors.forename: Nina
authors.initials: N
authors.lastname: Kirchhoff
authors.forename: Svenja
authors.initials: S
authors.lastname: Schulz
authors.forename: Costantina
authors.initials: C
authors.lastname: Manes
authors.forename: Dieter
authors.initials: D
authors.lastname: Fischer
authors.forename: Kirsten
authors.initials: K
authors.lastname: de Groot
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.forename: Günter
authors.initials: G
authors.lastname: Fauler
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000069438:Ezetimibe; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D017534:Radial Artery / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008055:Lipids; D017382:Reactive Oxygen Species; D019821:Simvastatin; D013482:Superoxide Dismutase; D000069438:Ezetimibe; D001205:Ascorbic Acid