Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.
OBJECTIVE
Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib.


METHODS
Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models.


RESULTS
Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats.


CONCLUSIONS
Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.
Forrest
M J
MJ
Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. mike_forrest@merck.com
Bloomfield
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D
Briscoe
R J
RJ
Brown
P N
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Cumiskey
A-M
AM
Ehrhart
J
J
Hershey
J C
JC
Keller
W J
WJ
Ma
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McPherson
H E
HE
Messina
E
E
Peterson
L B
LB
Sharif-Rodriguez
W
W
Siegl
P K S
PK
Sinclair
P J
PJ
Sparrow
C P
CP
Stevenson
A S
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Sun
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Tsai
C
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Vargas
H
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Walker
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West
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White
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Woltmann
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D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects; D000450:Aldosterone / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D003345:Corticosterone / Q000097:blood; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D023303:Oxazolidinones / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; D011804:Quinolines; D000450:Aldosterone; C483909:torcetrapib; C530884:anacetrapib; D003345:Corticosterone