Dalcetrapib: Another HDL-Raising CETP Inhibitor Bites The Dust

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 andsimultaneous 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.

Here is the AHA press release:

“Good” cholesterol drug doesn’t reduce risks in heart patients

Study Highlights:
  • A drug that raises high-density lipoprotein (HDL – “good”) cholesterol levels didn’t help reduce the risk for another heart event or stroke in patients who had recently experienced an acute coronary syndrome.
  • Researchers question whether HDL cholesterol is still an important factor in patients who are already taking medicines to reduce “bad” cholesterol and other cardiovascular risk factors.
LOS ANGELES, Nov. 5, 2012 — Among patients who had a recent heart attack External link or hospitalization for chest pain External link, a drug that boosts high-density lipoprotein (HDL)cholesterol External link levels, the so-called “good” cholesterol, failed to reduce the risk of further cardiovascular events, according to a late-breaking clinical trial presented at the American Heart Association’s Scientific Sessions 2012.
The Effects of the Cholesteryl Ester Transfer Protein Inhibitor Dalcetrapib in Patients with Recent Acute Coronary Syndrome (dal OUTCOMES) is also published in the New England Journal of Medicine.
Dalcetrapib increased levels of HDL cholesterol by about 30 percent. However, among nearly 16,000 patients followed for an average of about 2 ½ years, this HDL cholesterol boost didn’t reduce patients’ risk of death, another heart attack, hospitalization for heart-related chest pain, or stroke.
Researchers ended the study in May, when an interim analysis showed that the drug neither provided the expected benefit, nor caused harm.
Many studies have shown that low levels of HDL in the bloodstream are associated with a higher risk of heart disease and stroke. However, the role, if any, for drugs that raise HDL is less certain. “Sometimes a study advances scientific knowledge even though it does not advance therapeutic options,” said Gregory Schwartz, M.D., Ph.D., lead study author. “I believe this study did just that by providing an unexpected answer to an important scientific question.”
Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor. Drugs in this class block the transfer of cholesterol from HDL to low-density lipoprotein (LDL, or “bad” cholesterol), thereby raising the levels of HDL in the bloodstream.
Researchers will undoubtedly debate why the treatment didn’t work, which may have a bearing on other drugs in the CETP class that remain under investigation, said Schwartz, chief of the Cardiology Section at Denver VA Medical Center and Professor of Medicine at the University of Colorado in Denver.
Most of the patients studied were also being treated with statin drugs to lower LDL cholesterol, as well as other medications to reduce risk after heart attack, such as aspirin, clopidogrel, and beta blockers.
“It’s possible that when patients are treated with all these risk-reducing drugs, HDL cholesterol level is no longer a risk factor,” said Schwartz. “It’s also possible that HDL is protective in healthy persons, but is altered in patients with heart disease so that it no longer serves the same protective function. Or, it may be that the specific way that dalcetrapib raises HDL is not advantageous.”
Researchers randomly assigned 15,871 patients age 45 and older in 27 countries to take either 600 milligrams of dalcetrapib or a placebo daily. Ninety-seven percent also took aspirin and statins, and 87 percent took beta blockers to reduce the risk of heart complications.
Launched in 2008, the study had average follow-up of 31 months. Although patients taking dalcetrapib had higher HDL levels, 8.3 percent had a major cardiovascular event, compared with 8 percent of the placebo group.Factors such as gender, age, smoking status, medical history, geographical location or body mass index didn’t influence the results, researchers said.
More research is needed to better understand how HDL functions in healthy people compared with patients who have cardiovascular disease, and to learn how CETP inhibitors affect the composition and function of HDL.
In the meantime, there has been no medicine to date that has shown improved outcomes by raising HDL in patients such as these.
“Perhaps the focus should be not so much on raising the level of HDL cholesterol, but on modifying or eliminating the risk factors that are associated with low HDL cholesterol, such as smoking, obesity, diabetes, and sedentary lifestyle.”
Study co-authors are Anders G. Olsson, M.D., Ph.D.; Markus Abt, Ph.D.; Christie M. Ballantyne, M.D.; Philip Barter, M.D., Ph.D.; Jochen Brumm, Ph.D.; Bernard R. Chaitman, M.D.; Ingar M. Holme, Ph.D.; David Kallend, M.B.B.S.; Lawrence A. Leiter, M.D.; Eran Leitersdorf, M.D.; John J.V. McMurray, M.D.; Hardi Mundl, M.D.; Stephen J. Nicholls, M.B.B.S., Ph.D.; Prediman K. Shah, M.D.; Jean-Claude Tardif, M.D.; and R. Scott Wright, M.D.
F. Hoffmann-La Roche, Ltd. funded the study.
Follow news from the American Heart Association’s Scientific Sessions 2012 via Twitter:@HeartNews. External link
Visit heart.org External link for more about cholesterol External link and reducing heart risk External link.


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