With the publication of the ACCELERATE trial in the New England Journal of Medicine the long train of bad and disappointing news for the once-promising approach of CETP inhibition remains unbroken.
More than 12,000 high-risk patients were randomized in ACCELERATE to evacetrapib or placebo. In 2015 the trial was prematurely terminated for futility; the main results were presented last year at the American College of Cardiology meeting. After 26 months of follow-up there was no significant difference in the primary endpoint (the composite of CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina): 12.9% in the evacetrapib group versus 12.9% in the placebo group (HR 1.01, CI 0.91-1.11, (P=0.91).
The neutral effect on outcomes occurred despite extremely favorable changes in lipids in the evacetrapib group: LDL decreased by 31% and HDL increased by 133%.
In their paper the ACCELERATE investigators sought to understand the negative results of the trial, which “reinforce the principle that biologic plausibility and beneficial effects on surrogate end points do not obviate the need for adequately powered outcome trials of new therapeutic agents.”
One possibility is that HDL may help prevent the development of cardiovascular disease but is ineffective in people with established disease. An alternative explanation is that CETP may not increase the level of functional HDL particles or may not have an impact on other possible vasoprotective properties.
The investigators also sought to explain the absence of benefit despite the significant reduction in LDL in the evacetrapib group. Similar reductions with moderate-intensity statins and ezetimibe have resulted in a significant reduction in clinical events. The investigators speculated that this might be due to “mechanisms of reduction in the LDL cholesterol level that are specific to CETP inhibition.”
Another possibility is that evacetrapib had “an unmeasured toxic effect that offset the beneficial lipid effects.” They cited a small 1.2 mm Hg increase in systolic blood pressure and a similar small increase in CRP in the evacetrapib group.
“The investigators also sought to explain the absence of benefit despite the significant reduction in LDL in the evacetrapib group. Similar reductions with moderate-intensity statins and ezetimibe have resulted in a significant reduction in clinical events”
How about ‘because changing cholesterol readings is, of itself, no help at all against CVD. Insofar as statins work, they work by some other mechanism’?
‘Another possibility is that evacetrapib had “an unmeasured toxic effect that offset the beneficial lipid effects.”’
I used to amuse myself by coming up with equally fanciful excuses for unexplained phenomena in my own little corner of science. Some of my colleagues would see the joke, some wouldn’t.