Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: The ACCENTUATE trial


      • Addition of evacetrapib to statin therapy produces favorable effects on atherogenic and protective lipid measures.
      • Increases in apolipoproteins C-III and E, in addition to C-reactive protein, may exert adverse cardiovascular effects.
      • These findings may provide mechanistic rationale for the lack of efficacy of evacetrapib in large outcomes trials.
      • It remains to be determined whether CETP inhibition is useful in secondary prevention.


      Background and aims

      The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters.


      366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured.


      Addition of evacetrapib significantly reduced LDL-C (−33%) compared with ezetimibe (−27%, p=0.045), increasing statin dose (−6%) and statin alone (0%, p<0.001). Evacetrapib also decreased apoB by 23% compared to 19% with ezetimibe (p=0.06) and 7% with increased statin dose (p<0.001), and reduced Lp(a) by 29% (p<0.001 vs. other groups). Evacetrapib increased HDL-C (+125%), apoA-I (+46%), apoC-III (+50%) and apoE (+28%) (p<0.001 vs. other groups). Non-ABCA1-mediated efflux increased by 53% (p<0.001 vs. other groups) with evacetrapib. ABCA1-mediated efflux also increased by 13% with evacetrapib (p<0.001 vs. ezetimibe, p=0.002 vs. increasing statin dose, and p=0.004 vs. statin alone). Addition of evacetrapib to atorvastatin produced an increase in hsCRP compared with ezetimibe (p=0.02).


      While evacetrapib improved traditional atherogenic and putative protective lipid measures compared with ezetimibe and increasing statin dose in patients with ASCVD and/or diabetes, it also adversely affected novel atherogenic risk factors. These findings may contribute to the lack of clinical benefit observed in the ACCELERATE trial.


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