Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans.
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.
Landmesser
Ulf
U
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany. Landmesser.Ulf@MH-Hannover.de
Bahlmann
Ferdinand
F
Mueller
Maja
M
Spiekermann
Stephan
S
Kirchhoff
Nina
N
Schulz
Svenja
S
Manes
Costantina
C
Fischer
Dieter
D
de Groot
Kirsten
K
Fliser
Danilo
D
Fauler
Günter
G
März
Winfried
W
Drexler
Helmut
H
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
D000924:Anticholesteremic Agents; D001384:Azetidines; D008055:Lipids; D017382:Reactive Oxygen Species; D019821:Simvastatin; D013482:Superoxide Dismutase; D000069438:Ezetimibe; D001205:Ascorbic Acid