A randomised placebo-controlled double-blind trial to evaluate lipid-lowering pharmacotherapy on proteolysis and inflammation in abdominal aortic aneurysms.
OBJECTIVE
Modulation of abdominal aortic aneurysm (AAA) expansion by HMG-CoA reductase inhibitors (statins) might be linked to reducing IL-6 and MMP-9, which may be consequent on reducing plasma cholesterol. Ezetimibe is a novel cholesterol absorption inhibitor used in combination with statins. This pilot study compared the biological effects of ezetimibe combination therapy with simvastatin alone on parameters relevant to aneurysm expansion including cytokines and proteolytic enzymes.


METHODS
Randomised placebo-controlled double-blind trial.


METHODS
Eighteen patients scheduled for elective open AAA repair were randomised to simvastatin 40 mg plus ezetimibe 10 mg (n = 9), or simvastatin 40 mg plus placebo (n = 9), for 32.5 days (IQR 28-50.5) until the day of surgery. Total concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10, MMPs-1, -2, -3, -8, -9, -12, -13, TIMP-1 and -2 were measured in plasma, aortic wall homogenates and tissue culture explants.


RESULTS
Two patients in the placebo arm did not undergo open repair precluding aortic samples. Ezetimibe was associated with a significant reduction in aortic wall MMP-9 (p = 0.02) and aortic wall IL-6 (p = 0.02), associated with a reduction in plasma lipids.


CONCLUSIONS
These results suggest that ezetimibe combination therapy reduces aortic wall proteolysis and inflammation, key processes that drive AAA expansion. A larger RCT is justified focussing on aneurysm growth rates in small AAA.
Dawson
J A
JA
St George's Vascular Institute, 4th Floor St James Wing, St George's Hospital, London SW17 0QT, UK. mrjoedawson@yahoo.co.uk
Choke
E
E
Loftus
I M
IM
Cockerill
G W
GW
Thompson
M M
MM
D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017544:Aortic Aneurysm, Abdominal / Q000628:therapy*; D001384:Azetidines / Q000627:therapeutic use; D001706:Biopsy; D002097:C-Reactive Protein / Q000032:analysis; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010865:Pilot Projects; D019821:Simvastatin / Q000627:therapeutic use; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D007378:Interleukins; D008055:Lipids; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D002097:C-Reactive Protein; D019821:Simvastatin; D020782:Matrix Metalloproteinases; D000069438:Ezetimibe