Recent publications on Residual Risk

Treatment with evacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, did not reduce cardiovascular events, despite substantially raising high-density lipoprotein cholesterol (HDL-C, increase by 130%) and lowering low-density lipoprotein cholesterol (LDL-C, decrease by 37%).
 
ACCELERATE was a phase 3, multicenter randomized, double-blind trial involving 12,092 patients (mean age 65 years, 23% female, mean body mass index 30.2 kg/m2 and 68% with diabetes) with either an acute coronary syndrome, cerebrovascular atherosclerotic disease, peripheral vascular disease or diabetes with coronary artery disease. Patients were randomized 1:1 to evacetrapib 130 mg daily (n=6,038) or placebo (n=6,054) in addition to standard medical therapy. Almost all (96%) patients were treated with a statin at baseline, although only 46% were treated with high-intensity statin. The total duration of follow-up was 30 months (following termination due to futility). At baseline, mean HDL-C was 45 mg/dl and mean LDL-C was 81 mg/dl.
 
The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization and unstable angina. There was no difference in the incidence of the primary outcome over the follow-up period (12.8% for the evacetrapib group vs. 12.7% for placebo, p = 0.85). Similarly, there was no significant effect for any of the individual components of the primary outcome. All-cause mortality was lower in the evacetrapib group but this was not significant (3.8% vs. 4.1% on placebo, p = 0.06).
 
In terms of lipids, mean HDL-C at the end of follow-up was 104 mg/dl vs. 46 mg/dl on placebo (p<0.001); mean LDL-C was 55 mg/dl vs. 84 mg/dl (p < 0.001).
 
There was no difference between the two groups with respect to treatment discontinuation due to adverse events (8.6% in the evacetrapib group vs. 8.7% on placebo, p = 0.86).
 
The reasons for the lack of benefit of evacetrapib in ACCELERATE are so far unclear. The functionality of HDL particles generated by CETP inhibition was also questioned with respect to reverse cholesterol transport and/or other beneficial characteristics. The accumulating evidence suggests that CETP inhibition may not be a good strategy to mitigate residual cardiovascular risk; results are awaited from the ongoing outcomes trial with anacetrapib (REVEAL).