Ezetimibe And Cancer Link Still Not Clear Say Experts

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Main Category: Cancer / Oncology
Also Included In: Cholesterol;  Clinical Trials / Drug Trials;  Cardiovascular / Cardiology
Article Date: 03 Sep 2008 - 2:00 PDT

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The link between cholesterol-lowering drug ezetimibe (marketed as Vytorin) and cancer is still not clear, wrote the editors of the leading medical journal New England Journal of Medicine (NEJM). More time is needed to assess the drug, they said, and in the meantime patients and doctors will have to live with the uncertainty.

The editorial appears in the online first 2nd September issue of NEJM, along with a report of the SEAS clinical trial of lipid-lowering therapy which tested the combination of simvastatin and ezetimibe compared with placebo on the incidence of cardiovascular events in older people with aortic-valve stenosis (abnormal narrowing of the heart valve that lets blood into the aorta).

While the trial found that the treatment did not halt aortic stenosis or show impact on cardiovascular events in general (apart from one or two exceptions), it showed an unexpected result in adverse events, where there appeared to be a rise in cancer incidence and cancer deaths in the treatment group compared to the placebo group.

This would make sense, since the way ezetimibe works is to reduce the absorption of cholesterol in the gut, which could also interfere with the absorption of other substances that affect cancer growth.

However, the SEAS researchers suggested that the higher incidence of cancer in the treatment group could be due to chance, but agreed further studies should look into it. A group of epidemiologists from Oxford University did look into it by using the SEAS data and supplementing it with data from two other ongoing studies on ezetimibe, SHARP and IMPROVE-IT, which although had shorter follow ups than the four years in the SEAS trial, were much larger and gave more cancer data. They then examined the three sets of data to see if the imbalance in incident cancers and cancer deaths from the SEAS trial was replicated in the other two trials.

The Oxford group's analysis failed to confirm the increase in incident cancer found in the SEAS trial, but it did confirm the non-significant increase in cancer deaths. Their study is also reported in the 2nd September issue of NEJM.

The editors pointed out that it was important to note that while cancer mortality is an end point that one would expect to be reliable, none of the trials was designed to assess this as a primary outcome.

When the Oxford group combined the data on cancer deaths from the three trials (SEAS, SHARP, and IMPROVE-IT), they found an increase in risk of cancer death in the combined ezetimibe groups (134 versus 92 deaths in controls, showing a risk ratio of 1.45 and an uncorrected P=0.007).

But the Oxford group said it believed this finding was purely due to chance and could not be a real rise in cancer death risk because if that were the case then there should have been a corresponding rise in cancer incidence.

Again, the editors cautioned that because the test of statistical significance, P, comes from an analysis that combines data from studies with different objectives, it should be interpreted carefully. They wrote that although the Oxford researchers may ultimately be proved correct, patients and doctors should be cautious because it is not clear whether the increased risk of death is due to chance or not. Because of the way it affects absorption of chemicals in the gut, ezetimibe may well affect the balance of cancer altering substances too.

"The fact that the combined data from all three trials showed an increase in cancer mortality with ezetimibe should not be assumed to be a chance finding until further data are in," wrote the editors.

The editors said the SHARP and IMPROVE-IT trials must go on and there should be careful follow up of the patients. These and other trials yielding data on ezetimibe treatments should be analyzed for cancer-related results, they wrote, and mentioned that the US Food and Drug Administration (FDA) had plans to carry out its own analysis.

"Ezetimibe and Cancer -- An Uncertain Association."
Drazen, Jeffrey M., D'Agostino, Ralph B., Ware, James H., Morrissey, Stephen, Curfman, Gregory D.
N Engl J Med 2008 0: NEJMe0807200; published online first 2 September 2008.

Click here for the full Editorial.

Sources: NEJM.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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