Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

The New England Journal of Medicine
(NEJM) published results online from one study and an analysis of partial
results from two others.  They also were presented at the European Cardiology conference in Munich.

What we do know so far?  The results from three studies of the cholesterol-lowering drug
Vytorin are not enough to prove or rule out a possible link to a higher
risk of cancer, so the drug should be used with caution until more is

Vytorin is a combination of Merck's Zocor, a long-sold statin drug, and Schering-Plough's Zetia, a newer type of medicine that lowers cholesterol in a different way.

The possible cancer risk unexpectedly arose in July, when Dr. Terje Pedersen of Oslo, Norway, announced preliminary results from a study testing whether Vytorin could prevent damage to the heart's aortic valve from worsening.

The drug exerted no difference in heart attacks,
strokes or surgeries related to the valve problem but surprisingly, they noticed a higher number of cancer cases in those taking it compared to those given placebo.

Pedersen's study involved 1,873 people in Europe and the United States who were starting to have problems with their aortic valves.  They were either given Vytorin or a placebo with a view that lowering cholesterol would ward off future heart problems.

Of those given Vytorin, 105 developed cancer, compared with 70 among
those on placebo. That is higher than the 93 cases among Vytorin users
and 65 in the others that scientists reported on a conference call in
July when the issue first became known.

Cancer-related deaths were higher in all three studies.

When the results were combined, it was that found 134 among
Vytorin users and 92 in the others, a result the NEJM Editors said the increase cannot simply be
chalked up to chance. An interim analysis of the results of two other ongoing studies of Vytorin was performed by Sir Richard Peto and epidemiologists at Oxford University in England.
Their review, reported in the NEJM, found higher rates of cancer deaths among Vytorin users,
but the number of cancer cases did not significantly differ.

The accompanying NEJM editorial was brisk:

"When the cancer mortality data from the SEAS, SHARP, and IMPROVE-IT trials were combined, there was an increase in cancer mortality risk in the combined ezetimibe groups (134 deaths, as compared with 92 deaths in controls; risk ratio, 1.45; 95% CI, 1.02 to 2.05; uncorrected P=0.007).  Because this P value was obtained from one of several data-driven analyses rather than from a test of a single prespecified hypothesis, it should be interpreted cautiously.  The Oxford researchers believe that this finding is due entirely to the play of chance rather than to a true increase in cancer mortality.  They argue that an increase in the risk of cancer death, if real, should be paralleled by an increase in the risk of cancer incidence, which was not found in the combined analysis, and that there is no plausible mechanism for such an effect."

It should be noted that whether the increased mortality risk is due solely to the play of chance remains uncertain at this stage and the data is still immature and preliminary.

Zetia interferes with the gastrointestinal absorption of cholesterol and also of other molecular entities that could conceivably affect the growth of cancer cells.  The combined data from all three trials showed an increase in cancer mortality with ezetimibe may not be assumed to be a chance finding until further data are in. 

We must therefore wait until more data from the ongoing trials are available, leaving doctors and patients uncertain about the drugs effects.

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2 Responses to “Vytorin and Cancer – is there a link?”

  1. Gregory D. Pawelski

    The New England Journal of Medicine (NEJM) editorial blasted the analysis by Oxford University statistician, Richard Peto that dismissed Vytorin’s possible link to cancer. The SEAS study found that Vytorin patients had higher rates of cancer and cancer deaths. The results for cancer incidence was clearly significant, as well as the results for cancer death.
    The NEJM editorial on ezatimibe accompanied the publication of the SEAS trial and a statistical analysis of cancer incidence and deaths in SEAS and two other ezetimibe trials conducted by Richard Peto and the Clinical Trials Service Unit of Oxford University.
    Vytorin is a combination of cholesterol-lowering Zetia (ezetimibe) and the statin Zocor (simvastin). As mentioned in the NEJM editorial, some have theorized that Zetia could cause cancer because it blocks chemicals called plant sterols, which may cause heart disease but could also have some anti-cancer effect.
    Plant sterols (phytosterols) resemble cholesterol in structure but are found exclusively in plant-based foods like fruits, vegetables, nuts and whole grains. A number of tissue culture studies have exposed various types of human cancer cells to plant sterols and have found a slowing of the progression of cells from one stage to another, something that is abnormal in cancer cells.
    In addition, plant sterols have been found to cause apoptosis and shown to inhibit changes in cells that take place when tumor cells metastasize. Also, it has been shown an increase in growth of cells that are part of the human immune system, such as natural killer cells, which could be protective against cancer.
    Ezetimibe inhibits cholesterol absorption, as opposed to removing cholesterol from the blood like statins. But ezetimibe also inhibits absorpotion of dietary plant sterols and there is a plausible theory that the reduction in sterol absorption in patients in the SEAS trial may have increased risk of contracting cancer.
    The SEAS trial found an increase in cancer cases and deaths in the group that received ezetimibe. The Peto analysis of two ongoing ezetimibe trials found no increase in cancer cases, but did find more cancer deaths (97 vs. 72 in the control group), although the increase in cancer deaths did not reach statistical significance (p = .07).
    When all three trials (SEAS, IMPROVE-IT and SHARP) were combined, there was a significant excess of cancer deaths among the patients assigned to ezetimibe (134 vs. 92; risk ratio, 1.45; p = 0.007). The Oxford group believes this is a statistical fluke, noting that there was no trend in the relative risk of death from cancer over time in SHARP and IMPROVE-IT alone or in all three trials combined.
    Several lines of evidence suggest that plant sterols may have anti-cancer effects. The New York Tiimes interviewed Peter Bradford, a pharmacologist at SUNY Buffalo who has extensively studied plant sterols. Bradford explained that in laboratory tests plant sterols promote cell death in a way that could make them valuable anti-cancer agents as weapons against tumors. But by blocking plant sterol absorption, ezetimibe could be promoting cancer, he said.
    More data is urgently needed before patients can again feel comfortable taking ezetimibe. It would be useful for the SEAS investigators to test the levels of plant sterols and carotenoids in blood samples from participants in the SEAS trial.
    Until more information is available, ezetimibe use should be limited to patients in clinical trials. Zetia should not be used in clinical medicine until the justifiable and substantial cloud of uncertainty over it is resolved.

  2. FEMA Corp

    Plant sterols have been shown to lower cholesterol too. So it seems to me that that would be worth a try for a few months before going on a potentially dangerous med.

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