Dalcetrapib increased HDL, did not reduce risk for CV events

Issue: December 2012

LOS ANGELES — New data from the dal-OUTCOMES trial reveal that dalcetrapib, a cholesterol ester transfer protein inhibitor, increased HDL levels by about 30% during the study period, but did not reduce risk for recurrent CV events in patients with recent ACS.

Perspective from Alan Tall, MD; Harlan M. Krumholz, MD

The dal-OUTCOMES trial included 15,871 patients (baseline mean HDL: 42 mg/dL; mean LDL: 76 mg/dL; triglycerides: 134 mg/dL) with ACS who were randomly assigned to dalcetrapib (F. Hoffmann-La Roche) 600 mg per day or placebo, plus evidence-based care. The patients received evidence-based background therapies, with 97% receiving aspirin and statins, 89% receiving an additional anti-platelet agent, and 87% receiving beta-blockers.

The trial was terminated in May, after interim analysis showed no benefit or harm with dalcetrapib on the composite primary endpoint of death from CHD, nonfatal MI, ischemic stroke, unstable angina or cardiac arrest with resuscitation. Mean follow-up was 31 months.

Gregory G. Schwartz

According to results presented by Gregory G. Schwartz, MD, PhD, from the VA Medical Center and University of Colorado in Denver, dalcetrapib increased HDL levels by approximately 30% at 3 years, with minimal effect on LDL levels. However, compared with placebo, dalcetrapib did not reduce the risk for the primary end point at 3 years (9.2% vs. 9.1%; HR=1.04; 95% CI, 0.93-1.16). Schwartz also reported no significant changes in any component of the composite endpoint, all-cause mortality or unanticipated coronary revascularization.

Further, “HDL concentration did not predict risk in this study population,” Schwartz said at a press conference.

Dalcetrapib was generally well tolerated. However, patients assigned to treatment with dalcetrapib had slightly higher C-reactive protein levels that were 18% higher and mean systolic BP levels compared with patients assigned to placebo (differences of 0.2 mg/L and 0.6 mm Hg, respectively; P<.001 for both). The slightly higher systolic BP and CRP levels with dalcetrapib might mark an adverse effect of inhibiting CETP, Schwartz said. – by Samantha Costa

For more information:

Schwartz GG. Late breaking clinical trials: Novel treatments for managing lipid disorders. Presented at: the American Heart Association Scientific Sessions; Nov. 3-7, 2012; Los Angeles.

Schwartz GG. N Engl J Med. 2012;doi:10.1056/NEJMoa1206797.

Disclosure: Schwartz reports receiving research grants from Anthera Pharmaceuticals, Resverlogix and Roche, and other support from Sanofi. The study was funded by F. Hoffman-La Roche.

Perspective

Alan Tall, MD

This was a well-conducted study with a disappointing outcome. I believe that the decision to stop the trial prematurely was rational. In moderate HDL elevation, patients already optimally treated with statins and other agents may not have an impact on coronary disease. This explanation is supported by the lack of relationship of HDL concentration to clinical outcomes in the present study. This would also be consistent with one of the major theories in basic science that [the benefit of] HDL really is to reverse the effects of an atherogenic stimulus. CTEP elevation may produce a form of HDL that doesn’t work properly.

Overall, the impact of CTEP elevation by dalcetrapib on HDL function remains uncertain and the results of dal-OUTCOMES suggest any benefit was, at best, modest. Delcetrapib is only a partial, relatively weak CTEP inhibitor and may have been insufficiently potent to provide benefit in this particular setting. Ongoing phase 3 clinical studies with potent CTEP inhibitors will test the hypothesis that high level CTEP inhibition reduces atherosclerotic CV risk.

Alan Tall, MD

Tilden Weger Bieler Professor of Medicine

Department of Medicine

Columbia University

New York

Disclosures: Tall reports no relevant financial disclosures.

Perspective

Harlan M. Krumholz, MD

The dal-OUTCOMES study was a terrific study, but a disappointing result. Moreover, because the development of the drug was stopped as a result of the trial, there are no direct clinical implications. However, the findings emphasize so strongly the need for us to conduct studies with outcomes. Here’s a drug that in so many ways looked so promising. We had hoped that this drug would success where torcetrapib had failed — that it might be safer and more effective and produce large benefits for patients. This study describes its failure to achieve that promise

We do not know yet why these drugs have failed. These studies have also influenced by view of the other compounds that are emerging to treat lipid disorders and have tempered my enthusiasm for the phase 2 trials. I believe it is important to wait for the phase 3 outcomes trials. Also, for drugs that have yet to have phase 3 trials are yet are being sold, such as ezetimibe, I am also more cautious than ever about assuming that they provide a benefit for patients. This study adds to others that show us that changing risk factors does not always change risk.

Harlan M. Krumholz, MD

Professor of Medicine in Cardiology

Yale School of Medicine

Disclosures: Krumholz reports no relevant financial disclosures.