Paradoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe

Aims Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) but has complex actions on cholesterol transport and metabolism, and thus, LDL-C reduction may not solely define its overall effects. We explored the relationship between treatment effects and cumulative exposure to ezetimibe, with its effects on carotid intimamedia thickness (CIMT) in ARBITER 6-HALTS. Methods and results This analysis includes the 159 patients randomized to ezetimibe within ARBITER 6-HALTS that completed the final imaging endpoint assessment. Eligibility criteria for ARBITER 6-HALTS included known coronary artery disease (CAD) or high risk for coronary heart disease, and treatment with a statin with LDL-C 100 mg/dL and high-density lipoprotein cholesterol 50 or 55 mg/dL for men and women, respectively. The mean CIMT was measured in the far wall of the distal common carotid artery. We analysed the univariate and multivariate relationships of the change in CIMT with baseline characteristics, on-treatment effects, and cumulative ezetimibe exposure (treatment duration dose adherence). Ezetimibe reduced LDL-C from 84 23 to 66 20 mg/dL. No net effect on CIMT was observed (baseline CIMT 0.898 0.151 mm; net change 0.002 mm; P 0.52). There was an inverse relationship between LDL-C and change in CIMT such that greater reductions in LDL-C were associated with greater CIMT progression (r 0.266; P 0.001). Change in CIMT also had univariate associations with baseline LDL-C, triglycerides (TG), high-sensitive C-reactive protein, and systolic blood pressure and was directly associated with the change in TG and inversely associated with the change in high-sensitive C-reactive protein. Multivariable models controlling for change in LDL-C, cumulative ezetimibe exposure, and baseline and on-treatment variables showed that both increased LDL-C reduction (P 0.005) and cumulative drug exposure (P 0.02) were associated with ezetimibe-associated CIMT progression. Conclusion Among CAD and high-risk patients on statin therapy in the ARBITER-6 trial, ezetimibe leads to paradoxical progression of CIMT in association with both greater LDL-C reduction and cumulative drug exposure. These findings may suggest the presence of off-target actions of ezetimibe.