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Exposure to Ezetimibe and LDL cholesterol reduction related to paradoxical progression of atherosclerosis


Ezetimibe ( Ezetrol, Zetia ) 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.
Resaerchers have explored the relationship between treatment effects and cumulative exposure to Ezetimibe, with its effects on carotid intima–media thickness ( CIMT ) in ARBITER 6-HALTS.

The analysis has included the 159 patients randomized to Ezetimibe within ARBITER 6-HALTS that have completed the final imaging endpoint assessment.
Eligibility criteria for ARBITER 6-HALTS included known coronary artery disease or high risk for coronary heart disease, and treatment with a statin with LDL-C less than 100 mg/dL and high-density lipoprotein cholesterol less than 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.

Investigators have 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 has 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 less than 0.001 ).

Change in CIMT also had univariate associations with baseline LDL-C, triglycerides, high-sensitive C-reactive protein ( hsCRP ), and systolic blood pressure and was directly associated with the change in triglycerides and inversely associated with the change in high-sensitive C-reactive protein.

Multivariable models controlling for change in LDL cholesterol, 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.

In conclusion, among coronary artery disease and high-risk patients on statin therapy in the ARBITER-6 trial, Ezetimibe leads to paradoxical progression of carotid intima–media thickness in association with both greater LDL cholesterol reduction and cumulative drug exposure.
These findings may suggest the presence of off-target actions of Ezetimibe. ( Xagena )

Taylor AJ et al, Eur Heart J 2012; 33: 2939-2945

XagenaMedicine_2012



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