Identical LDL-cholesterol lowering but non-identical effects on NF-κB activity: High dose simvastatin vs combination therapy with ezetimibe.
OBJECTIVE
Lowering LDL-cholesterol by statins has been proven to be associated with reduction of proinflammatory regulators e.g. activation of the transcription factor NF-κB. To our knowledge, anti-inflammatory potential of newer cholesterol lowering agents such as ezetimibe is less intensively studied. Therefore we analyzed the effects of equipotent LDL-lowering therapy with simvastatin alone compared to a combination with ezetimibe on NF-κB activation in peripheral blood mononuclear cells (PBMCs) of patients with type 2 diabetes.


METHODS
Thirty-one patients with type 2 diabetes were included in a double-blind, randomized trial receiving either 80 mg simvastatin (sim80; n = 10) or a combination of 10 mg simvastatin and 10 mg ezetimibe (sim10eze10; n = 11) or placebo (n = 9) for eight weeks. NF-κB binding activity and inflammatory markers (IL-6, hsCRP) were analyzed at baseline and after eight weeks of treatment. NF-κB binding activity was analyzed by electrophoretic mobility shift assay. IL-6 and hsCRP were measured by ELISA.


RESULTS
After eight weeks of treatment LDL-cholesterol was lowered to the same extent in both treatment groups (p = 0.40) but not in placebo. However, patients taking sim80 showed a significant reduction of mononuclear NF-κB binding activity compared to baseline (p = 0.009) while no effect was observed in the sim10eze10 group (p = 0.79). Similar differences in anti-inflammatory effects were also observed when analyzing hsCRP (sim80: p = 0.03; sim10eze10: p = 0.40) and IL-6 levels (sim80: p = 0.15; sim10eze10: p = 0.95).


CONCLUSIONS
High dose simvastatin therapy reduces proinflammatory transcription factor NF-κB binding activity and hsCRP levels, while combination of low dose simvastatin with ezetimibe resulting in a similar LDL-reduction does not affect these inflammatory markers.
Department Medicine I and Clinical Chemistry, University of Heidelberg, Germany. gottfried_rudofsky@med.uni-heidelberg.de
Gottfried
G
Rudofsky
Peter
P
Reismann
Jan B
JB
Groener
Zdenka
Z
Djuric
Thomas
T
Fleming
Cornelia
C
Metzner
Ingo A
IA
Grafe
Angelika
A
Bierhaus
Peter P
PP
Nawroth
D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001384:Azetidines / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004311:Double-Blind Method; D015536:Down-Regulation; D004338:Drug Combinations; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D000069499:Ezetimibe, Simvastatin Drug Combination; D005260:Female; D005858:Germany; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000097:blood*; D019821:Simvastatin / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D001384:Azetidines; D015415:Biomarkers; D008078:Cholesterol, LDL; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D002097:C-Reactive Protein; D019821:Simvastatin