November 5th, 2012
Dalcetrapib: Another HDL-Raising CETP Inhibitor Bites the Dust
Larry Husten, PHD
Another HDL-raising CETP inhibitor has failed to demonstrate cardiovascular benefit in a large clinical trial. With the presentation of the dal-OUTCOMES trial at the American Heart Association in Los Angeles and simultaneous publication in the New England Journal of Medicine, dalcetrapib joins torceptrapib on the list of once-promising CETP inhibitors.
In dal-OUTCOMES, 15,871 patients with a recent acute coronary syndrome were randomized to dalcetrapib or placebo. At a prespecified interim analysis after a median follow-up of 31 months, the Data and Safety Monitoring Board recommended termination of the trial for futility. The primary endpoint — a composite of death from CHD, nonfatal MI, ischemic stroke, unstable angina, or cardiac arrest with resuscitation — occurred in 8.3% of dalcetrapib recipients and 8.0% of placebo recipients (HR, 1.04; 95% CI, 0.93-1.16; P=0.52).
As expected, dalcetrapib raised HDL (by about 30%) and had little effect on LDL. However, there was no correlation between baseline HDL level and clinical outcome. Furthermore, dalcetrapib treatment resulted in mean increases of 18% in CRP level and of 0.6 mm Hg in systolic blood pressure.
The chair of the trial, Gregory Schwartz, said that the small increases in blood pressure and CRP might explain the results. The discussant for the trial, Alan Tall, said that the decision to stop the trial prematurely was rational. In addition to the changes in blood pressure and CRP, he offered several additional possible reasons for the drug’s failure to improve outcomes:
- Moderate HDL elevation in patients who are already well treated may have little impact. It is possible that much larger elevations in HDL will be required to alter the course of disease.
- CETP inhibitors may produce a form of HDL that does not enhance reverse cholesterol transport.
- Dalcetrapib is only a partial CETP inhibitor. Phase 3 trials of more-potent CETP inhibitors, such as anacetrapib and evacetrapib, may still demonstrate benefit.
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3 Responses to “Dalcetrapib: Another HDL-Raising CETP Inhibitor Bites the Dust”
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Lipid Theory is dead… yet – we hear it again – “Long Live the Lipid Theory”.
Keeping it alive – on a life support of endless excuses and modifications that made it essentially unrecognizable – is becoming simply inhumane to the good old theory… Please let it die with dignity, and find its place among “great medical delusions of the past”. Please do not let it’s disintegrating body become an impediment to the development of new directions and ideas in our understanding of atherothrombosis/CV events.
Let us admit to the obvious: we cannot predict the effect of metabolic poisons (AKA – pharmaceuticals) in accordance with lipid theory on athrosclerotic/atherothrombotic events, – except for statins (we just got lucky there).
For all the billions of dollars and billions of work hours spent in the last 10-15 years – what does “modern lipidology” has to show us for the result of outcome trials guided by contemporary “lipid theory”? I would say -close to nothing.
Thus:
RIP Honorable Surrogate Markers.
RIP Honorable Lipid Theory.
It is time for us to move on.
I think that many of the failures of drugs developed to modify the lipid profile result from the fact that they are developed under the lipid hypothesis and in particular that cholesterol is the cause of heart disease. This is has diverted the attention from the true line of attack on the problem of heart disease. The scientific literature shows that heart disease occurs regardless of cholesterol level (see for instance references: 1-3 ) Let me make a comparison: In a city where many fires happen we see a large number of local firefighters in fires. Therefore we find a strong correlation between the number of firefighters and the number of fires, so someone thought that reducing the number of firefighters would also fewer fires. It’s statistic stupid!
(1) Amit Sachdeva et al., Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines, American Heart Journal, Volume 157, Number 1 (2009)
(2) Keaven M. Anderson, PhD; William P. Castelli, MD; Daniel Levy, MD, Cholesterol and Mortality: 30 Years of Follow-up From the Framingham Study, JAMA, April 24,Vol. 257, nº6, (1987)
(3) Naoki Nago1, Shizukiyo Ishikawa2, Tadao Goto3, and Kazunori,Low Cholesterol is Associated With Mortality,From Stroke, Heart Disease, and Cancer:The Jichi Medical School Cohort Study, J Epidemiol (2011);21(1):67-74
Questions about raising HDL are more and more present… The moderate degree of HDL raising (30%) with dalcetrapib didn’t impact outcomes. We are collaborating with Oxford on the REVEAL trial of anacetrapib, an agent that increases HDL by 140% and reduces LDL by 30-40%. Thus, with an HDL more than 4 times greater, and with some LDL reduction, could this agent work? Possibly – we will have to see what the trial shows. As of August, we had enrolled over 20,000 patients (http://www.ctsu.ox.ac.uk/research/mega-trials/hps3-reveal/reveal-press-release-260812-v2).
Steve Nissen is leading a trial called ACCELERATE with evactrapib.(NCT01105975) It is using a new dose of the drug – 130 mg, so I don’t know what LDL or HDL reduction it could achieve. the 100 mg dose about doubled HDL and reduced LDL by about 25%.
Although this is the second big failure (although on a streak – first trial adverse, second one neutral, will the third one be positive?
only our trials will tell!