Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions.
BACKGROUND
Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis.


RESULTS
This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was approximately 200 mm3, and the least squares mean change at end of treatment was 0.7 mm3 for placebo and 7.7, 4.1, and 4.8 mm3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 [unadjusted P=0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (P<0.05 in all groups).


CONCLUSIONS
Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.
Tardif
Jean-Claude
JC
Montreal Heart Institute, 5000 Belanger St, Montreal, H1T 1C8, Canada. jean-claude.tardif@icm-mhi.org.
Grégoire
Jean
J
L'Allier
Philippe L
PL
Anderson
Todd J
TJ
Bertrand
Olivier
O
Reeves
Francois
F
Title
Lawrence M
LM
Alfonso
Fernando
F
Schampaert
Erick
E
Hassan
Alita
A
McLain
Richard
R
Pressler
Milton L
ML
Ibrahim
Reda
R
Lespérance
Jacques
J
Blue
John
J
Heinonen
Therese
T
Rodés-Cabau
Josep
J
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000368:Aged; D001055:Apolipoproteins B / Q000097:blood; D015415:Biomarkers; D002097:C-Reactive Protein / Q000032:analysis; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D018084:Ultrasonography, Interventional; D000097587:Sterol O-Acyltransferase 2
D000081:Acetamides; D000085:Acetates; D001055:Apolipoproteins B; D015415:Biomarkers; D002097:C-Reactive Protein; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D002785:Sterol O-Acyltransferase; D013449:Sulfonamides; D013451:Sulfonic Acids; D000097587:Sterol O-Acyltransferase 2; C423185:avasimibe; C493492:sterol O-acyltransferase 1