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Cholesteryl ester transfer protein (CETP) inhibitors are a drug class targeting the enzyme CETP (1). The first CETP inhibitor, torcetrapib, was discontinued because of increased cardiovascular events that were attributed to off-target adverse effects (increased aldosterone and blood pressure) (2). The development program of another CETP inhibitor, dalcetrapib, which did not have the off-target adverse effects of torcetrapib, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes (3). Recently, the results of the ACCELERATE trial, that examined the effects of the CETP inhibitor evacetrapib, were published. ACCELERATE was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, that randomly assigned 12,092 patients with high cardiovascular risk to receive either evacetrapib (130 mg/d) or matching placebo on top of standard medical treatment (4). Evacetrapib treatment resulted in a substantial improvement of lipid profile; after 3 months, a 37.1% absolute decrease in the mean low-density lipoprotein (LDL) cholesterol levels and a 131.6% absolute increase in the mean high-density lipoprotein (HDL) cholesterol concentration compared with placebo were observed. Despite this lipid profile improvement, the primary end-point (the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) did not differ between evacetrapib and placebo after a median of 26 months (12.9% in the evacetrapib group and 12.8% in the placebo group; hazard ratio 1.01, 95% confidence interval, 0.91–1.11; P=0.91), leading the data and safety monitoring board to terminate the trial early because of a lack of efficacy (4).
The failure of the ACCELERATE trial may be attributed to certain on-target and off-target adverse effects:
Thus, the lack of efficacy of evacetrapib in the ACCELERATE trial may be associated with many on-target and off-target adverse effects. Many of these effects are common characteristics between CETP inhibitors pointing to the possibility that may be class-specific. However, it was recently announced that the REVEAL outcomes trial of the CETP inhibitor anacetrapib met its primary cardiovascular end-point (21). The final results, which will be revealed in the next few months, will show if this positive result concerning the primary cardiovascular end-point is due to better efficacy or less on-target/off-target adverse effects of anacetrapib compared with other CETP inhibitors.
Provenance: This is an invited Editorial commissioned by Section Editor Dr. Hai-Long Dai (Department of Cardiology, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, China).
Conflicts of Interest: This editorial was conducted independently. MS Elisaf reports personal fees from Astra-Zeneca, grants and personal fees from MSD, personal fees from PFIZER, ABBOTT, Sanofi-Aventis, Boehringer Ingelheim, Eli-Lilly and GSK. TD Filippatos has given talks and attended conferences sponsored by various pharmaceutical companies, including Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, Teva and MSD.