ACCELERATE Shows Third Time’s No Charm for CETP Inhibitors

Lingering hopes for the CETP inhibitor class of lipid-modifying drugs were dealt a major blow last October when the phase 3 ACCELERATE trial of evacetrapib was terminated early due to failure to reduce cardiovascular events after a preliminary analysis. Now ACCELERATE investigators have shared data at ACC.16, the American College of Cardiology’s 65th Annual Scientific Session, showing just how stark the disconnect is between evacetrapib’s effect on lipids and its lack of impact on clinical events.

Among the ACCELERATE findings presented at ACC.16:

• Mean HDL cholesterol levels were raised 130 percent with evacetrapib compared with placebo
• Mean LDL cholesterol levels were reduced by 37 percent with evacetrapib compared with placebo
• The composite primary end point of major cardiovascular events was virtually identical in the evacetrapib and placebo groups out to three years of follow-up (hazard ratio = 1.01; 95% CI, 0.91-1.12)

A case lesson in why outcome trials matter

“Here we’ve got an agent that more than doubles HDL cholesterol and lowers LDL cholesterol as much as many statins, yet it has no effect on clinical events,” says ACCELERATE co-principal investigator Stephen Nicholls, MBBS, PhD, who presented the findings at an April 3 late-breaking clinical trials session. Dr. Nicholls is a professor at the South Australian Health and Medical Research Institute and a consultant to the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which served as the study’s coordinating center.

“We were certainly hoping for different results and are trying to understand why we didn’t see a clinical benefit from this drug,” adds co-principal investigator A. Michael Lincoff, MD, a Cleveland Clinic cardiologist and Director of C5Research. “The trial raises questions about the benefits of raising HDL cholesterol and the future of the CETP inhibitor class of drugs.”

“These findings illustrate the importance of performing large, high-quality outcome trials,” notes ACCELERATE steering committee chair Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic. “Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits.”

ACCELERATE at a glance

ACCELERATE enrolled 12,092 patients at more than 540 sites who were at high cardiovascular risk due to one or more of the following:

• Acute coronary syndrome 30 to 365 days prior to enrollment
• Cerebrovascular atherosclerotic disease
• Peripheral artery disease
• Diabetes with coronary artery disease

Patients were randomized to at least 18 months of therapy with either the CETP inhibitor evacetrapib 130 mg/day or placebo in addition to standard medical therapy, which in a large majority of patients included statins or other cholesterol-lowering drugs. The data reported at ACC.16 reflect an average of 25 months on study drug and follow-up through all patients’ end-of-study visit.

The events included in the composite primary end point were cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina. Notably, there were no significant differences between the evacetrapib and placebo groups on any of these individual end points. Although a reduction in all-cause mortality in the evacetrapib group approached statistical significance (P = .06), it was not driven by a decrease in cardiovascular death.

The study raised no safety concerns with evacetrapib, and no major side effects emerged, but Eli Lilly has announced that it is discontinuing development of the agent.

Three strikes against the CETP inhibitor class

This marks the demise of the third agent to emerge from the class of cholesteryl ester transfer protein (CETP) inhibitors, which act by disrupting the process by which HDL cholesterol is converted to LDL cholesterol. Development of these agents was predicated on the notion, supported by animal and genetic studies, that CETP deficiency is cardioprotective.

Yet the first CETP inhibitor, torcetrapib, was abandoned after it was shown to increase rates of cardiovascular events and death in late-stage trials, and development of the second agent, dalcetrapib, was discontinued after phase 2 clinical testing found it ineffective.

Search for explanations ensues

The ACCELERATE results are particularly disappointing because evacetrapib was believed to offer potent CETP inhibition without the toxicity of torcetrapib. “These findings continue to challenge the hope that CETP inhibition might successfully address residual cardiovascular risk,” says Dr. Nicholls. He notes that while the lack of clinical benefit remains a mystery, at least several theoretical explanations have been posited:

• Statins and other current therapies (which the vast majority of ACCELERATE enrollees were taking) are so effective at improving cardiovascular outcomes in high-risk patients that further improvement is difficult to achieve.
• Evacetrapib’s active ingredient or CETP inhibitors’ biological mechanism simply has no effect on cardiovascular risk.
• Benefit could potentially be limited to low-risk patients (unlike the high-risk patients in ACCELERATE), although testing this would demand an immense sample size and involve different research questions.
• Conventional thinking about HDL cholesterol-related cardioprotection may need to be revisited.

To help sort out these and other theories, the ACCELERATE trial leaders and Eli Lilly are making the trial database available to independent investigators. Review of research proposals and governance will be coordinated by Cleveland Clinic’s C5Research group.

Click here to view more late-breaking trials and clinical research from ACC.16