Performance of CETP inhibitors vexing

PHILADELPHIA — While cholesterol ester transfer protein inhibitors raise HDL and some lower LDL, they have so far not shown any impact on CV outcomes and their future is unclear, an expert said at the National Lipid Association Scientific Sessions.

Peter H. Jones, MD, FNLA, associate professor at Methodist DeBakey Heart and Vascular Center, Baylor College of Medicine, Houston, said that while there is strong epidemiologic evidence for an inverse relationship between HDL levels and CV risk, studies of CETP inhibitors and other mechanisms of raising HDL have not demonstrated an effect on CV outcomes.

“The question remains: Is HDL a mediator of atherosclerosis and hence a target of therapy, or is it just a marker of risk, such as a disturbed triglyceride metabolism system?” he asked.

Peter H. Jones

It was believed that inhibiting CETP would make cholesterol go through the HDL pathway to the liver (reverse cholesterol transport), helping HDL stimulate anti-inflammatory and other positive responses, he said.

This led to the development of CETP inhibitors, but none have been successful so far, Jones, who is also chief science officer of the NLA, said.

The ILLUMINATE study of torcetrapib (Pfizer) was stopped because of harm, he said, despite the agent increasing HDL and lowering LDL, because torcetrapib was associated with more all-cause mortality and CV death vs. placebo, he said.

Dalcetrapib (Roche) had a different mechanism to raise HDL and had no effect on LDL, but the dal-OUTCOMES study showed “no hint anywhere of any benefit, and the trial was stopped for futility,” Jones said.

“The likely explanation at this point was torcetrapib had an off-target effect, a significant change in the renin-angiotensin-aldosterone system resulting in increased BP, and dalcetrapib, being a weaker drug, led to a modest increase in HDL, not enough to have an effect,” Jones said. “There was still hope that a CETP inhibitor that no harmful effect on BP but good effect on HDL and LDL would help.”

Evacetrapib (Eli Lilly) raised HDL and lowered LDL by large amounts, but the ACCELERATE trial was stopped in October 2015 for futility. The primary outcome of major vascular events was almost identical between evacetrapib and placebo, Jones said, noting there was a nonsignificant trend toward reduced all-cause mortality in the evacetrapib group.

The DEFINE trial of anacetrapib (Merck) showed it raised HDL and lowered LDL, but also reduced lipoprotein(a), which could be a positive sign, Jones said.

However, “[a potential] problem with anacetrapib is the drug accumulation,” he said. “You take the drug, it’s stored in fat and slowly released over time. You can still detect plasma levels 3 to 4 years after stopping the drug. The LDL and HDL effects persisted for several months after stopping the drug. Having a long half-life is a potential downside.”

The REVEAL outcomes trial of anacetrapib is now underway. More than 30,000 patients on background atorvastatin therapy have been randomly assigned to anacetrapib 100 mg or placebo, he said.

The last CETP inhibitor in development is AM-8995 (Amgen), he said, noting it performs similarly to anacetrapib and evacetrapib, but at lower doses.

The results so far have raised a number of questions, according to Jones.

“Cholesterol content of HDL is not an accurate measure for these drugs, and cholesterol efflux capacity probably is. But as clinicians, measuring efflux is not easy to do, and it’s probably not an appropriate surrogate for the FDA [to evaluate benefit],” he said. “What about the reduction in LDL observed with some of these drugs? Evacetrapib should have improved CVD risk, but didn’t. To get answers, we have to wait for the REVEAL trial, and studies of the last one [AM-8995].

“HDL may have protective effects on atherosclerosis, but the cholesterol content of HDL is probably not the correct measurement any benefit,” Jones concluded. “The quality of HDL function is more likely where the focus of benefit should be, and a clinical method to estimate or measure this is needed. The mechanism for reduced LDL from CETP inhibition is not clear. This makes it difficult to explain the failure of evacetrapib to decrease CVD events despite a 37% reduction in LDL.” – by Erik Swain

Reference:

Jones PH. CETP Outcomes Studies. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Jones is chief science officer for the NLA and reports being a scientific advisory consultant for Amgen, Merck and Sanofi/Regeneron.