BARCELONA, SPAIN — The first major trial to show a significant reduction in outcomes with a cholesteryl ester transfer protein (CETP) inhibitor has shown a 9% relative risk reduction in major coronary events with anacetrapib when added to intensive statin therapy[1].
But the question remains as to whether this is enough for the drug to continue in development and reach the market.
The REVEAL trial was presented here at the European Society of Cardiology (ESC) 2017 Congress today and simultaneously published in the New England Journal of Medicine.
“The REVEAL trial has shown for the first time that adding a CETP inhibitor to intensive statin therapy reduces the incidence of cardiovascular events in high-risk patients,” said co–lead investigator Prof Martin Landray (University of Oxford, UK).
He suggested the benefit appeared to be mediated by LDL reduction rather than an increase in HDL, the mechanism behind the development of this class of drugs.
“The reductions in LDL, [apolipoprotein B] apo B, and non-HDL cholesterol all line up with what you would expect in terms of the event-rate reductions seen, and we don’t seem to be seeing anything over and above this, even though there was a doubling of HDL cholesterol. But how exactly the drug is bringing about the event reduction is impossible to say.”
Landray said the positive result in REVEAL “was in marked contrast to the disappointing results of previous trials with CETP inhibitors, which were stopped early due to unexpected hazards or apparent lack of efficacy. The REVEAL trial was much larger than the other CETP-inhibitor trials with double the number of patients, events, and treatment time than any of the other studies, and the benefit did not start to be seen until 2 years of treatment. This may help explain why a positive result was achieved,” he said.
While the study is groundbreaking in this regard, the results were not greeted with huge enthusiasm by experts at the ESC conference, with the clinical benefit described as “modest.”
And although the drug appears to have a relatively benign side-effect profile, with a small increase in blood pressure and a small reduction in kidney function, the fact that it accumulates in adipose tissue and stays in the body for up to 5 years is seen as a concern.
Nissen Unimpressed
Commenting for the theheart.org / Medscape Cardiology, Dr Steve Nissen (Cleveland Clinic, OH) said: “The purpose of clinical trials like REVEAL is not to show a statistically significant P value but rather to determine whether a therapy produces a clinically meaningful benefit to patients. The effect of anacetrapib on the primary end point, a 9% reduction in risk, was too small to provide a clinically important benefit. In a trial of more than 30,000 patients, there were only 163 fewer primary events during more than 4 years of follow-up.”
He added: “A weak therapy studied in enough patients for long enough can produce a statistically significant P value that falls below the threshold necessary for a successful launch of a product. The drug also has important downsides, including a persistence in tissues that continues for several years. This raises safety questions that would be troubling for regulators. So the combination of a small treatment effect with a very long biological persistence makes anacetrapib unlikely to be submitted for approval.”
Dr Stephen Nicholls (University of Adelaide, Australia) said: “The results certainly suggest if you treat a lot of people for a long time with anacetrapib then you will see some benefit. But in the context of other results here at this meeting with the potential to change practice, it’s hard to see that this will prove to be the case for anacetrapib, although this may open the CETP field up again.”
Dr John Claude Tardif (Montreal Heart Institute, QC) suggested that further analysis of the data may identify a subgroup in which the drug had a larger effect, as has happened with dalcetrapib.
Although the major dalcetrapib trial—dal-OUTCOMES—did not show a benefit on cardiovascular events, Tardif genotyped the trial population and found that patients with a certain genetic profile (those homozygous for a variant in the ADCY9 gene, which account for 20% of the population) actually showed a large benefit of the drug. He is now leading a trial (dal-GENE) exclusively in patients with this genotype to try to confirm a benefit of the drug, and he suggests that a similar strategy may be possible for the other CETP inhibitors too.
He commented to theheart.org / Medscape Cardiology: “Lilly has now also conducted a genotype analysis of its data on evacetrapib, and they are presenting their results at the AHA meeting in November. I would suggest that Merck and the REVEAL investigators will do the same thing.
“What the genetic results seem to suggest is that humans respond better to CETP inhibition in terms of HDL particles taking up cholesterol from the vessel wall if they have this certain genotype,” Tardif added.
Landray, however, believes there is already a case for anacetrapib to be made available.
“If you look at hypertension there are four or more standard classes of agents available. There are good reasons to use one or another in certain patient groups. We are used to using them in various combinations and tailoring them to the needs of individual patients. We could eventually see a similar thing happening in lipidology.”
Another presentation of genetic data from a Mendelian randomization study at the ESC meeting suggested that CETP inhibitors may work better as monotherapy and statins may actually negate their effects.
On this idea, Landray said: “All I can say is that in REVEAL everyone was on intense-dose statins already and they had very low LDL levels (mean 61 mg/dL) at baseline, and still we saw some benefit. So we set ourselves the hardest possible test. It is not unreasonable to extrapolate that if these people weren’t on statins the CETP inhibitor may have had more effect as their baseline LDL would have been higher.”
He added: “There is certainly a group that can’t take statins and there is an argument for having an armamentarium of drugs available that can be used clinically depending on the context, and the context can be driven by the risk of vascular disease, the lipid profile, family history, side effects, costs, and what people feel is convenient and acceptable.”
Study Details REVEALed
The REVEAL study randomized 30,449 patients with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy (baseline mean LDL-C 61 mg/dL; HDL-C 40 mg/dL) to anacetrapib 100 mg once daily or placebo.
During 4.1 years of follow-up, the primary outcome of coronary death, MI, or coronary revascularization occurred in 10.8% of the anacetrapib group vs 11.8% of those on placebo (rate ratio 0.91, 95% CI 0.85–0.97; P=0.004).
At the trial midpoint, HDL was 43-mg/dL higher in the anacetrapib group (a relative difference of 104%) and non-HDL cholesterol was 17 mg/dL lower (a relative difference of -18%).
There was no effect of anacetrapib on mortality, fatal or nonfatal cancer, or any major category of serious or nonserious adverse event. There was a slight reduction in new-onset diabetes (5.3% vs 6%; P=0.049) and slightly higher blood pressure (0.7 mm Hg systolic/0.3 mm Hg diastolic). In addition, the risk of developing an estimated glomerular filtration rate of less than 60 mL/minute/1.73 m2 was slightly higher (11.5% vs 10.6%; P=0.04).
The REVEAL trial was sponsored by Merck. Landray reports grants from Merck during the conduct of the study and from Novartis and Pfizer outside the submitted work. Disclosures for the coauthors are listed on the journal website.
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