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More controversial findings for ezetimibe
  May 19, 2011 | Sue Hughes
Charlottesville, VA - Whereas statins appeared to halt atherosclerosis, ezetimibe (Zetia, Merck/Schering-Plough) was associated with an increase in plaque volume in peripheral arterial disease (PAD) patients in a new study [1]. The findings add to other similar results from the ENHANCE and ARBITER-6 studies, suggesting that although ezetimibe effectively lowers LDL it does not seem to have a favorable effect on atherosclerosis.
Senior author Dr Christopher Kramer (University of Virginia Health System, Charlottesville, VA) commented to heartwire: "While our results are by no means conclusive, they do add some fuel to the fire regarding the controversy over ezetimibe and the lack of benefit on atherosclerosis seen in imaging studies. Clearly, ezetimibe is not as beneficial as a statin in this regard, despite effectively lowering LDL. This is the third study to have shown this." But Dr Steven Nissen (Cleveland Clinic Foundation, OH) said the study had too many limitations to draw any definite conclusions. He commented to heartwire: "While I remain skeptical about the benefits of ezetimibe, it is important to recognize that this study has major limitations. The study was small and used MRI to measure plaque, a largely untested method."
In the current study, published online April 16, 2011 in Atherosclerosis, the authors, led by Dr Amy West (University of Virginia Health System), investigated whether lowering LDL by adding ezetimibe to statin therapy would regress atherosclerosis measured by MRI in the superficial femoral artery in patients with PAD.
The study involved 67 PAD patients. Those who were not already taking statins were randomized to simvastatin 40 mg (n=16) or simvastatin 40 mg plus ezetimibe 10 mg (n=18). Patients already on statins but with LDL-C above 80 mg/dL were given open-label ezetimibe 10 mg on top of their statin therapy (n=33). Atherosclerotic plaque volume was measured in the superficial femoral artery at baseline and after one and two years.
Results showed no increase in progression of atherosclerosis in statin-naive patients randomized to simvastatin or simvastatin plus ezetimibe. There was also no difference in the change in plaque volume between these two groups, despite greater initial LDL lowering in the simvastatin/ezetimibe group. In contrast, patients previously on a statin with ezetimibe added at study enrollment demonstrated plaque progression despite a significant reduction in LDL. In this group, the extent of LDL lowering correlated with plaque progression, an observation that was also seen in the ARBITER-6 trial. The authors say this "raises questions regarding the utility of ezetimibe when added to patients previously on long-standing statin therapy."


On the observation that atherosclerosis progression was halted in statin-naive patients given simvastatin and ezetimibe, but not in patients already taking long-term statins to which ezetimibe was added, the authors suggest: "The effect of ezetimibe on peripheral atherosclerosis may depend upon relative timing of statin therapy." But Nissen said this idea did not seem biologically plausible. He added: "There is no reason to expect the order in which drugs are administered to strongly affect outcome."
To heartwire, Kramer said: "We saw a 4% progression of atherosclerosis per year over two years when ezetimibe was added to long-term statins. However, in statin-naive patients, simvastatin alone or simvastatin plus ezetimibe both halted atherosclerosis, with the suggestion of regression. So clearly the statins are effective at halting plaque growth."
He added that what can't be ascertained for certain from this study is whether the ezetimibe in the long-term-statin group is actually detrimental or whether the favorable effect of the statin has just started to wear off. "We would have needed to include a placebo group in this part of the trial to answer this question. However, when we started this study back in 2006, it was before there were any question marks about ezetimibe, and we thought that every mechanism that reduces LDL would have a favorable effect on atherosclerosis. But it doesn't look like that is the case, because we saw a progression of disease with ezetimibe when added onto long-term statins, despite achieving a 22% reduction in LDL."
Nissen pointed out that the effect of ezetimibe on outcomes will not be known until the IMPROVE-IT trial completes, but these results will not be available for several years. "Unfortunately, ezetimibe was not appropriately studied in a timely fashion, leaving the medical community with more questions than answers," he added.
1. West AM, Anderson JD, Meyer CH, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis 2011; DOI:10.1016/j.atherosclerosis.2011.04.005. Available at:
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