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Dalcetrapib boosted HDL with no ill effects.


PARIS -- The investigational cholesteryl ester transfer protein inhibitor dalcetrapib increased HDL cholesterol without the toxic effects that have raised safety concerns over the use of CETP inhibitors as a cardiovascular therapy.

Dalcetrapib reduced CETP activity by 49% and increased HDL cholesterol by 31% without affecting LDL cholesterol among patients with or at risk of coronary heart disease in the randomized phase II dal-VESSEL trial.

Dalcetrapib did not cause endothelial dysfunction nor did it improve it. Unlike the CETP inhibitor torcetrapib, dalcetrapib did not raise blood pressure, providing further reassurance regarding the safety of the compound, Dr. Thomas Luscher said.

"I think we can say it's safe and has no untoward effects like the others, and it does the job as far as the lipid profile is concerned," he told reporters. "It's a bit less potent than torcetrapib, which increased HDL by about 60%-70%, but [it] may be that's even an advantage. We'll see."

Dr. Luscher said it was a bit disappointing that dalcetrapib (manufactured by Hoffmann-La Roche) did not improve vascular function, but noted that it wa not worsened either.

Whether the novel CETP inhibitor will have an effect on cardiovascular events will be determined by the phase III dal-OUTCOMES trial, with results expected sometime in 2013, said Dr. Luscher, professor and chair of cardiology at University Hospital Zurich, Switzerland.

A total of 15,872 patients with stable heart disease following a recent acute coronary event have been enrolled, according to the drug maker's web site.

Invited discussant Dr. Keith A.A. Fox of the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science said the positive dal-VESSEL data represent a "clear advance," but urged caution because of the limited size of the trial.

"We need to know whether the modest changes in blood pressure are real or have an impact on outcomes," he said.

The recent DEFINE trial of Merck's CETP inhibitor anacetrapib, however, illustrates the very real difficulties in achieving this goal. Anacetrapib raised HDL cholesterol 138% and reduced LDL cholesterol by 40% compared with placebo, but did not reduce cardiovascular events in 1,623 patients with or at high risk for coronary heart disease (N. Engl. J. Med. 2010;363:2406-15).

Torcetrapib, the first CTEP to be tested, increased HDL cholesterol by 61% and decreased LDL cholesterol by 20%, but was associated with a roughly 4.6-mm Hg increase in blood pressure (N. Engl. J. Med. 2007;356:1304-16). Development of the agent came to a screeching halt, however, when the ILLUMINATE trial subsequently reported that torcetrapib also increased the risk of cardiovascular events by 25% and all-cause mortality by 58% in patients at high cardiovascular risk (N. Engl. J. Med. 2007:357:2109-22).

The dal-VESSEL study was conducted at 19 centers in Europe and randomized 476 patients with coronary heart disease or CHD risk equivalents and HDL cholesterol of less than 50 mg/dL to dalcetrapib 600 mg/day or placebo plus their standard medication for a total of 36 weeks. Endothelial function was measured at 12 weeks using brachial flow-mediated dilation (FMD), a validated marker of endothelial dysfunction. Their mean age was 62 years, and roughly 97% were on statins.

The mean change in HDL cholesterol from baseline at week 4 was 2.7% for placebo and 27.5% for dalcetrapib; at week 36 it was -0.14% vs. 30.7%, respectively (P less than .0001 for both), Dr. Luscher said.

At 36 weeks lipoprotein A-1 levels were significantly increased with dalcetrapib, but lipoprotein B levels were not affected.

There was no significant change with dalcetrapib in the co-primary safety end points of 24-hour ambulatory BP at week 4 and FMD at week 12.

The trial was sponsored by Hoffmann-La Roche. Dr. Luscher reports receiving research grants from Pfizer, Eli Lilly, and Merck and consultancy or lecture fees from CSL, Merck, Pfizer, and F. Hoffmann-La Roche.

To view an interview with Dr. Luscher, scan the QR code with a smartphone or go to
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Title Annotation:high-density lipoprotein; CARDIOVASCULAR MEDICINE
Author:Wendling, Patrice
Publication:Family Practice News
Date:Sep 15, 2011
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