NEJM: Too Soon To Dismiss Vytorin Cancer Connection

Armen Hareyan's picture
Vytorin and Cancer Link

According to an editorial published in the New England Journal of Medicine, it is too early to rule out concerns about a possible Vytorin cancer connection that was identified in recent study data. The makers of Vytorin had previously sent a letter to healthcare providers dismissing the findings as likely attributed to chance.

Vytorin is a drug which combines ezetimibe (Zetia) and simvastatin (Zocor) to treat high levels of cholesterol in the blood. Although it was once a top seller for the drug’s makers, Merck & Co. and Schering-Plough Corp., sales have dropped sharply in recent months following multiple studies which question whether the medication provides any benefits over cheaper, older cholesterol drugs.

In July, data from a study known as SEAS, Simvastatin and Ezetimibe in Aoritic Stenosis, indicated that users of Vytorin had an increased incidence of cancer. Out of nearly 1,900 patients who were given Vytorin or a placebo, there were 105 reports of cancer among Vytorin users, compared to 70 reports of cancer among those taking the placebo. Although the data indicated an increased risk, the findings did not rise to the level of statistical significance.


After data from the study was released, Merck and Schering Plough sent a letter to healthcare providers dismissing the potential increased risk of cancer with Vytorin. A joint letter from the pharmaceutical companies indicated that they believe the cancer findings among Vytorin users in SEAS was an anomaly, and was not associated with the use of the drug.

Yesterday, the New England Journal of Medicine released a study online, which will be published in the September 25, 2008 issue, which contains an analysis of cancer data from the SEAS study and partial results from two other studies . Researchers concluded longer duration studies were needed to fully evaluate the Vytorin cancer risk, as most of the participants were followed for only a relatively short period of time for risks like cancer to emerge.

“Whether the increased mortality risk is due solely to the play of chance is uncertain,” concluded an editorial which accompanied the New England Journal of Medicine study. “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.”

Last month the FDA issued an early communication to confirm that they are investigating the potential association between Vytorin side effects and cancer. At that time, the FDA indicated that they do not anticipate that their safety review will be complete until spring 2009, at which time they will make any decisions about whether regulator actions are warranted to protect the public.

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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. Gregory D. Pawelski