Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia.
BACKGROUND
While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia.


RESULTS
Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1+/-0.6% to 3.6+/-0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study.


CONCLUSIONS
In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only.
Hermann
Frank
F
University Hospital Zurich, Zurich, Switzerland.
Enseleit
Frank
F
Spieker
Lukas E
LE
Périat
Daniel
D
Sudano
Isabella
I
Hermann
Matthias
M
Corti
Roberto
R
Noll
Georg
G
Ruschitzka
Frank
F
Lüscher
Thomas F
TF
D000577:Amides; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D004952:Esters; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D000577:Amides; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D013438:Sulfhydryl Compounds; D014280:Triglycerides; C411602:dalcetrapib