FDA Says Simvastatin & Ezetimibe Unlikely to Cause Cancer

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In December 2009, the FDA completed its review of final data from the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial and interim data from the SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) studies and concluded that the cholesterol-lowering drugs simvastatin (Zocor), ezetimibe (Zetia), and Vytorin (ezetimibe/simvastatin) are not likely to increase cancer risk. In a statement, the FDA said a relationship between these agents and cancer cannot be ruled out, however, and it will continue to assess safety data from the SHARP and IMPROVE-IT trials, which are expected to conclude in 2010 and 2012, respectively.

In August 2008, the FDA warned of a possible association between simvastatin, ezetimibe, and Vytorin and an increased cancer risk based on preliminary data from the SEAS trial. The agency had not identified a causal relationship between the drugs and cancer risk, however, nor did it advise healthcare providers to stop prescribing them.

About the trials

SEAS was a 4-year, double-blind trial that randomized 1873 patients with mild to moderate asymptomatic aortic stenosis to receive Vytorin (10 mg of ezetimibe and 40 mg of simvastatin) or placebo daily. The study’s primary endpoint was reduction in major cardiovascular events. Investigators observed an increased cancer incidence in the Vytorin cohort, with 105 cases (11.1%) reported compared with 70 (7.5%) in the placebo group (P = .01). The cancers observed in the Vytorin group were not clustered at any particular site. The Vytorin group also experienced an increased number of cancer deaths compared with the placebo group (39 vs 23, respectively).

The SHARP trial is an international, doubleblind, placebo-controlled study that randomized ~9400 patients with chronic kidney disease to Vytorin (10 mg ezetimibe and 20 mg simvastatin) or placebo. The study is seeking to determine whether Vytorin is associated with any major vascular complications in patients with chronic kidney disease.

The IMPROVE-IT trial, which is still accruing patients, is a multisite, randomized double blind trial enrolling up to 18,000 moderate- to high-risk patients with chronic coronary artery disease and acute coronary syndromes. Patients are receiving Vytorin (10 mg of ezetimibe and 40 mg of simvastatin) or 40 mg of simvastatin alone to determine whether adding ezetimibe improves cardiovascular outcomes.

Assessing cancer risk

The FDA weighed several factors in evaluating a possible relationship between use of simvastatin, ezetimibe, or Vytorin and cancer risk. The agency cited several reasons for concluding that such a relationship is unlikely, including the fact that most long-term clinical data on simvastatin have shown no increased risk of cancer. The FDA acknowledged that long-term clinical data on ezetimibe is insufficient to rule out an association between the drug and cancer but noted that preclinical animal studies found no increased cancer risk. In addition, longer use of Vytorin in the SEAS trial was not associated with an increased rate of cancer, which would be expected if it caused cancer or promoted the growth of pre-existing cancers. Finally, the cancers were not clustered at a particular point or of a specific type. A single carcinogenic drug rarely increases the risk of multiple cancer types, making a cancer association unlikely.

While analyses of interim cancer data from SHARP and IMPROVE-IT, which enrolled a cumulative 20,617 patients, found no increased risk of cancer with Vytorin, more cancer-related deaths were observed in treatment arms than in the control groups (97 vs 72, respectively). This finding, however, did not reach statistical significance. An assessment of all three trials showed no consistent pattern of increased cancer risk among patients treated with Vytorin. The SEAS trial was not designed to evaluate cancer risk, making the true statistical significance of the cancer imbalance observed in this trial unclear.

The FDA will continue to monitor cancer data from SHARP and IMPROVE-IT. In the meantime, the agency urges healthcare professionals and consumers to report adverse effects from the use of simvastatin, ezetimibe, or Vytorin to the FDA’s MedWatch Adverse Event Reporting program, which can be accessed online at www.fda.gov/safety/MedWatch/default.htm.

US 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) - FDA Investigates a Report from the SEAS Trial (8/21/08). http://tinyurl.com/yedgfyu. Accessed January 6, 2010.