Torcetrapib does not reduce atherosclerosis beyond atorvastatin and induces more proinflammatory lesions than atorvastatin.
BACKGROUND
Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice.


RESULTS
E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content.


CONCLUSIONS
CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype.
de Haan
Willeke
W
Leiden University Medical Center, Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, 2300 RC Leiden, The Netherlands.
de Vries-van der Weij
Jitske
J
van der Hoorn
José W A
JW
Gautier
Thomas
T
van der Hoogt
Caroline C
CC
Westerterp
Marit
M
Romijn
Johannes A
JA
Jukema
J Wouter
JW
Havekes
Louis M
LM
Princen
Hans M G
HM
Rensen
Patrick C N
PC
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D008815:Mice, Inbred Strains; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use
D053480:Cholesterol Ester Transfer Proteins; D006538:Heptanoic Acids; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin