UZH-Logo

Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia


Hermann, F; Enseleit, F; Spieker, L; Periat, D; Sudano, I; Hermann, M; Corti, R; Noll, G; Ruschitzka, F; Luscher, T F (2009). Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia. Thrombosis Research, 123(3):460-465.

Abstract

Introduction: 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.
Methods and 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.
Conclusion: 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.

Introduction: 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.
Methods and 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.
Conclusion: 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.

Citations

32 citations in Web of Science®
41 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:January 2009
Deposited On:09 Dec 2008 11:52
Last Modified:05 Apr 2016 12:39
Publisher:Elsevier
ISSN:0049-3848
Publisher DOI:10.1016/j.thromres.2008.06.022
PubMed ID:18789492

Download

Full text not available from this repository.View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations