DEFINE: grote effecten op LDL-c en HDL-c met anacetrapib

DEFINE: Large effects on LDL and HDL cholesterol with CETP inhibitor anacetrapib

November 17, 2010

N Engl J Med 2010; DOI:10.1056/NEJMoa1009744 (PDF).

Chicago, IL - Boldly attempting to go where one drug has gone before, researchers presented new data this week on a new cholesteryl ester transfer protein (CETP) inhibitor, showing the drug had a resounding effect on LDL- and HDL-cholesterol levels, all without the adverse safety profile that plagued its predecessor.

Researchers, led by Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA), showed that anacetrapib (Merck, Whitehouse Station, NJ) significantly decreased LDL-cholesterol levels by 36% and increased HDL-cholesterol levels by 138% when compared with placebo. Importantly, there was no increase in systolic blood pressure, an off-target effect that troubled torcetrapib, an earlier CETP inhibitor that was later pulled from clinical testing after a large morbidity and mortality trial revealed an increased risk of mortality and cardiovascular events.

"I think the very exciting thing is that we're entering an era where we have medications that raise HDL cholesterol," Cannon told the media during a morning press conference. "We know from epidemiological studies that it's good to have high HDL cholesterol, but [in terms of] current medications, we have just one that raises HDL, that's niacin, and we have to push that to a high dose where there are a lot of side effects. . . . It's been a very difficult lipid parameter to affect."

While investigators were impressed with the "striking" increase in HDL-cholesterol levels, they were also equally pleased with a prespecified safety analysis showing anacetrapib was not associated with an increased risk of death or cardiovascular events. Over the course of the 76-week study, known as Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE), cardiovascular events—a composite of death from cardiovascular causes, MI, hospitalization for unstable angina, or stroke—occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients treated with placebo (2.6%), a nonsignificant difference.

Presenting the results of the study during the late-breaking clinical-trials session at the American Heart Association 2010 Scientific Sessions—which were published simultaneously in the November 17, 2010 issue of the New England Journal of Medicine—Cannon said the safety and adverse-event data provide reassurance that the inhibition of CETP, when not accompanied by the off-target effects linked with torcetrapib, does not appear to cause adverse cardiovascular events.

Dr Steven Nissen (Cleveland Clinic, OH), who was involved in clinical trials with torcetrapib but was not involved in the DEFINE trial, called the anacetrapib data a good result for the new CETP inhibitor.

"First of all, it's important to understand what DEFINE tells us and what it doesn't," he told heartwire. "Nobody knew after torcetrapib failed whether or not the entire class was doomed. Merck, appropriately, did a medium-sized safety trial with DEFINE to find out whether anacetrapib would show the same increase in adverse cardiovascular events that was seen with torcetrapib. And it did not. Now, the study is too small to show definitive benefit, but the major adverse cardiovascular events trended in the right direction."

It's game changer, but because we don't have hard clinical events, we can't say that it's a home run. The data were impressive enough that Merck is moving forward into a large morbidity and mortality trial. The REVEAL HPS-3 TIMI-55 trial, launched in collaboration with Oxford and Harvard researchers, will include 30 000 coronary heart disease patients treated with statin therapy and will take at least four years to complete.

Finding some light in the shadow of torcetrapib

The death knell for torcetrapib came in December 2006 when Pfizer announced the increased risk of death and cardiovascular events among patients treated with the CETP inhibitor. The signal emerged from the ILLUMINATE study, a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin (Lipitor, Pfizer) vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 subjects with coronary heart disease or risk equivalents.

The safety risk with torcetrapib surprised some, although others had raised concerns about the off-target blood-pressure effects with the drug. Later analyses showed that torcetrapib stimulates aldosterone, and this possibly accounted for its adverse outcomes.

In the DEFINE trial, investigators randomized 1623 patients to treatment with anacetrapib 100 mg or to placebo. Patients included in the trial had known coronary heart disease or were at high risk for coronary heart disease and had a baseline LDL-cholesterol level between 50 mg/dL and 100 mg/dL while taking a statin medication and an HDL-cholesterol level <60 mg/dL. The primary end point of the study was the change in LDL-cholesterol levels at 24 weeks, which investigators chose because it is a surrogate marker that is strongly correlated with cardiovascular events, and the safety and side-effect profile at 76 weeks. The change in HDL-cholesterol level was a secondary end point.

LDL-cholesterol levels decreased from 81 mg/dL at baseline to 45 mg/dL after 24 weeks of treatment with anacetrapib, a statistically significant difference compared with placebo. HDL-cholesterol levels increased from 40.5 mg/dL at baseline to 101 mg/dL at 24 weeks and to 102 mg/dL at 76 weeks, also a statistically significant difference.

There was no observed change in blood pressure, electrolytes, or aldosterone levels among the anacetrapib-treated patients. As noted, mortality and cardiovascular events were not significantly different in the two treatment arms, and there was a trend toward a reduction in revascularization, mainly PCI, among patients treated with the CETP inhibitor. Cannon told the media that when he saw the raw revascularization numbers moving in the right direction—28 coronary revascularizations in the placebo arm compared with eight in the anacetrapib arm—he sent a text message to Dr Eugene Braunwald (Brigham and Women's Hospital, Boston, MA), saying this drug might just work.

Putting the results into clinical context

Numerous experts spoke with heartwire, and all were upbeat, if not cautiously optimistic, about the fate of the anacetrapib. Nissen said his interpretation of the data is that there is a high probability the "drug is not like torcetrapib, and whether it reduces morbidity and mortality will have to be determined in a large outcomes trial, but the odds of that trial succeeding are good."

We've gone as far with statins as we can go, and HDL cholesterol is a very promising target. Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) said DEFINE is a "solid double, maybe even a triple."

"It's game changer, but because we don't have hard clinical events, we can't say that it's a home run," he told heartwire. "Still, in this short time, we see a decrease in total events and total revascularizations, and we weren't expecting that at all. We just wanted to see the safety of the drug. So, it's really exciting. With torcetrapib, we saw the rise in aldosterone levels, which led to the hypertension in susceptible patients. With anacetrapib, there is no rise in aldosterone or blood pressure. There are no adverse effects that we can see at all."

Also speaking with heartwire, Dr Eliot Antman (Brigham and Women's Hospital) focused on the dramatic reduction in LDL cholesterol with anacetrapib and called the concept of pushing the LDL-cholesterol levels beyond what is achievable with aggressive statin therapy a "fascinating idea, one that is important to explore." He noted that in neonates, or even very young children, LDL-cholesterol levels are around 40 mg/dL, so it's important to study whether such a significant reduction in LDL-cholesterol levels can translate into clinical benefit.

Cannon said the researchers are now in a position to study whether LDL cholesterol might be too low and that the DEFINE investigators "played it safe" by taking patients with LDL-cholesterol levels lower than 25 mg/dL off the study drug. "It's an ongoing question in every lipid trial—could we get too low?—but we haven't seen it yet," said Cannon.

Antman and Blumenthal said they are less concerned about the very, very low levels of LDL-cholesterol levels, around 45 mg/dL, achieved in this trial, with Blumenthal noting that an analysis of PROVE-IT showed that patients with LDL-cholesterol levels less than 40 mg/dL fared best with statin therapy.

Functionality of HDL cholesterol

We can make arguments that we know what we're doing, and then we can be wrong. Raising HDL-cholesterol levels for the reduction of cardiovascular events is not as straightforward as lowering LDL-cholesterol level's effect, according to the experts. With the disastrous fate of torcetrapib looming large with CETP inhibition, Dr Eliot Brinton (University of Utah, Salt Lake City), a member of the DEFINE steering committee, told heartwire that humility is needed.

"We can make arguments that we know what we're doing, and then we can be wrong," said Brinton.

The data suggest that the HDL cholesterol produced by inhibiting CETP is functional, said Brinton. The only true way to see whether the HDL is functional is if it reduces cardiovascular morbidity and mortality, added Nissen, although imaging studies, such as an intravascular ultrasound (IVUS) trial that measures plaque progression or regression, would also provide some hints. The Oxford/Harvard REVEAL trial with anacetrapib might yet include some imaging studies within the larger trial, although that has not yet been finalized, according to Cannon. Another CETP inhibitor, dalcetrapib (Roche, Pleasanton, CA), is also in development, with imaging studies planned, including IVUS and CT/MRI analyses.

Nissen said a drug that raises HDL cholesterol and is effective would be a big deal for patients and clinicians. Moreover, the first statin that was ever studied failed, and when that happened many researchers were pessimistic about the fate of the drug class. With that in mind, he believes pushing forward with other CETP-inhibitor trials should be done.

"We've gone as far with statins as we can go, and HDL cholesterol is a very promising target," he said. "It's going to take a few years to answer all the questions, but what this study does is that it opens the door to another CETP inhibitor. If you're a physician who has to deal with patients that have low HDL cholesterol, that's good news."