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Frequently Asked Questions

Is the use of the combination of ezetimibe/simvastatin associated with causing cancer?

SEAS Results Alarming
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial randomized 1873 patients to ezetimibe/simvastatin (Vytorin) 10 mg/40 mg or placebo for a mean of 4.1 years.1 The trial results were alarming because a statistically significantly increased incidence in new onset of cancer was observed in patients randomized to ezetimibe/simvastatin (101 patients) compared with placebo (65 patients, uncorrected p=0.006).1,2 The cancers were not clustered in any one particular area, with increases seen in prostate, skin, gastrointestinal, and other types of cancers.

SHARP and IMPROVE-IT Analyzed
These results prompted Richard Peto, Oxford University, and colleagues to compare the incidence of cancer from the SEAS trial with the combined incidence observed in 2 currently on-going trials: the Study of Heart and Renal Protection (SHARP) trial and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).2 The analysis was published on-line on September 2nd in the New England Journal of Medicine. In the SHARP trial, 9264 patients were randomized to ezetimibe/simvastatin 10 mg/20 mg or placebo and followed for a mean of 2.7 years, and in IMPROVE-IT, 11,353 patients were randomized to ezetimibe/simvastatin 10 mg/40 mg or simvastatin 40 mg and followed for a mean of 1 year.

Combined results from the SHARP and IMPROVE-IT studies did not find an increased incidence of cancer in patients randomized to ezetimibe/simvastatin (313 cases) compared to those not given the drug (326 cases, p=0.61).2 In addition, no specific trend towards one type of cancer was noted in the SHARP and IMPROVE-IT studies, and a non-significant increase in cancer deaths in the ezetimibe/simvastatin group was observed in these 2 trials (97 deaths versus 72 in the control group, p=0.07). The investigators did note; however, that the number of cancer deaths became significant in the ezetimibe/simvastatin group when data from all 3 trials were combined (134 deaths versus 92 in the control group, uncorrected p=0.007). They attributed this finding to chance, stating that an increased risk of cancer death with ezetimibe/simvastatin should have been matched with an increase in the risk of cancer, which was not observed in their analysis. The investigators concluded that there is no credible evidence to link ezetimibe/simvastatin to cancer.

In an accompanying editorial also published on-line in the same journal, Jeffery Drazen and colleagues cautioned clinicians that the current finding of increased cancer deaths may not be due to chance.3 They stated that ezetimibe inhibits the absorption of “molecular entities that could conceivably affect the growth of cancer cells.” They also pointed to the fact that the combined analysis of all 3 trials resulted in increased cancer-related mortality. The editorial concluded that further data with longer follow-up times are needed before sound safety conclusions about ezetimibe/simvastatin can be drawn.

FDA Investigating
The Food and Drug Administration (FDA) is currently conducting its own safety analysis on the risk of cancer with ezetimibe/simvastatin, with findings to be released sometime in 2009.4 The FDA noted that most large prospective studies of statin drugs have reported no difference in cancer incidence between active therapy and placebo. For example, the incidence rate for cancer in the Heart Protection Study (n=20,000) was 7.9% in patients randomized to simvastatin 40 mg/day compared with 7.8% in patients given placebo. The FDA recommends that patients talk to their healthcare provider if they have questions surrounding the safety of ezetimibe/simvastatin. Patients are advised NOT to stop their lipid-lowering therapy before discussing any changes with their prescriber. Until additional data become available, clinicians should follow the current recommendation of treating patients with maximally tolerated doses of statins alone as first-line therapy to lower low-density lipoprotein (LDL) cholesterol.

References

  1. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. http://content.nejm.org/cgi/reprint/NEJMoa0804602.pdf. Accessed September 24, 2008.
  2. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. http://content.nejm.org/cgi/reprint/NEJMsa0806603.pdf. Accessed September 24, 2008.
  3. Drazen JM, D’Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and cancer-an uncertain association. http://content.nejm.org/cgi/reprint/NEJMe0807200.pdf. Accessed September 24, 2008.
  4. Food and Drug Administration. Early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia). http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin_SEAS.htm. Accessed September 24, 2008.