CETP Inhibitor Evacetrapib’s Disappointments Extend to Diabetics Too

Despite significant and sustained elevations in HDL and reductions in LDL cholesterol levels, the CETP inhibitor evacetrapib failed to reduce cardiovascular events among the subgroup of 8,236 ACCELERATE trial enrollees with diabetes mellitus (DM) at baseline.

So concludes a substudy of the large multicenter ACCELERATE trial presented at the European Society of Cardiology (ESC) Congress 2017 in Barcelona on Aug. 28. The substudy results mirror findings of the primary ACCELERATE analysis, which was published in the New England Journal of Medicine this past May. The primary analysis showed that evacetrapib failed to reduce cardiovascular events relative to placebo in the overall study population — consisting of patients at high risk for cardiovascular events — despite raising HDL cholesterol levels 133 percent from baseline and reducing LDL cholesterol levels 31 percent from baseline.

“We were unpleasantly surprised,” says Cleveland Clinic cardiologist Venu Menon, MD, who presented the findings in the diabetic subset at the ESC Congress. “All genetic and epidemiological data suggested that raising HDL would reduce cardiovascular risk in this vulnerable population. The high prevalence of low HDL levels in the setting of diabetic dyslipidemia gave investigators the additional hope that the diabetic population would especially benefit from potent CETP inhibition.”

Dr. Menon is Associate Director of the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which has overseen the 543-site, 36-nation ACCELERATE trial.

The substudy in brief

The new substudy focused on the 8,236 enrollees in the 12,092-patient ACCELERATE trial who had established DM prior to randomization to either evacetrapib or placebo (on top of background statin therapy in over 96 percent of patients).

The analysis found that, similar to the overall population, patients with DM who received evacetrapib had a 38 percent median reduction in LDL cholesterol and a 132 median increase in HDL cholesterol from baseline after four months. Despite these favorable lipid effects, at median follow-up of 26 months, the composite clinical end point (cardiovascular death, MI, stroke, revascularization or hospitalization for unstable angina) occurred at comparable rates among diabetic patients regardless of whether they were randomized to evacetrapib (14.5 percent) or placebo (16.0 percent) (P = .38).

This absence of a favorable effect on clinical outcomes was seen despite the fact that in another subanalysis, which focused on glycemic control, exposure to evacetrapib was also associated with an early and sustained improvement in glycemic profile relative to placebo in all subjects, regardless of diabetic status.

Dr. Menon recaps the subanalyses’ findings this way: “Despite favorable changes in lipid profile and glycemic control, it was clear that evacetrapib had no impact on cardiovascular outcomes in over two years of follow-up.”

The upshot for clinical practice is that another potential novel therapy for selectively conferring cardiovascular benefit in patients with DM has fizzled out. “There’s a pressing need to find interventions that will reduce residual cardiovascular risk for this vulnerable subgroup of patients,” says Dr. Menon. He notes that a diagnosis of diabetes in the fifth decade of life remains associated with a six- to seven-year decrease in longevity that’s mainly mediated through cardiovascular morbidity.

Story not yet over for CETP agents

As noted in earlier coverage of the ACCELERATE trial, evacetrapib is the third CETP inhibitor to fail to translate its significant HDL-raising effects to improved clinical outcomes.

“Additional subanalyses of ACCELERATE are underway to help understand the lack of clinical benefit despite favorable changes in lipid profile,” notes Dr. Menon. “We are preparing five or six of them for presentation at the American Heart Association meeting in November.”

Furthermore, with speculation about possible positive findings coming out of the pivotal REVEAL trial of a fourth CETP inhibitor, anacetrapib, at the ESC Congress, writing off the entire class may still prove premature.