This Article Free upon publication Full Text Full Text (PDF) CME: Take the course for this article: Circulation: December 9, 2008, Volume 118, Number 24 Data Supplement All Versions of this Article: 118/24/2506    most recent CIRCULATIONAHA.108.790733v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nicholls, S. J. Articles by Nissen, S. E. Search for Related Content PubMed PubMed Citation Articles by Nicholls, S. J. Articles by Nissen, S. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ATORVASTATIN HEPTANOIC ACID POTASSIUM PYRROLE SODIUM Medline Plus Health Information Coronary Artery Disease Related Collections Secondary prevention Risk Factors Imaging Coronary imaging: angiography/ultrasound/Doppler/CC Lipid and lipoprotein metabolism Related Article

(Circulation. 2008;118:2506-2514.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Cholesteryl Ester Transfer Protein Inhibition, High-Density Lipoprotein Raising, and Progression of Coronary Atherosclerosis

Insights From ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)

Stephen J. Nicholls, MBBS, PhD; E. Murat Tuzcu, MD; Danielle M. Brennan, MS; Jean-Claude Tardif, MD; Steven E. Nissen, MD

From the Departments of Cardiovascular Medicine (S.J.N., E.M.T., D.M.B., S.E.N.) and Cell Biology (S.J.N.), Cleveland Clinic, Cleveland, Ohio; and Montreal Heart Institute (J.-C.T.), Montreal, Quebec, Canada.

Correspondence to Stephen Nicholls, Department of Cardiovascular Medicine, Cleveland Clinic, Mail Code JJ-65, 9500 Euclid Ave, Cleveland, OH 44195. E-mail nichols1{at}ccf.org

Received May 5, 2008; accepted September 12, 2008.

Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis.

Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P=0.02), and lowered serum potassium (0.11±0.02 mmol/L, P<0.0001). Despite substantial increases in HDL-C, no effect was found of torcetrapib on percent atheroma volume. In torcetrapib-treated patients, an inverse relationship was observed between changes in HDL-C and percentage atheroma volume (r=–0.17, P<0.001). Participants with regression had greater increases in HDL-C (mean±SE, 62.9±37.4% versus 54.0±39.1%, P=0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (–0.31±0.27 versus 0.88±0.27%, P=0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (–0.69±0.27%, P=0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression (P=0.001).

Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.

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