Does Ezetimibe Cause Cancer?

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: The available results from three ezetimibe/simvastatin trials did not provide credible evidence of any adverse effects of ezetimibe on the rate of cancer association with ezetimibe administration at the present time.

Source: Peto R, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-1366.

The spectacular benefits of statin drug therapy have been clearly demonstrated by the proven ability to reduce the incidence of heart attacks, strokes, and revascularization procedures by about one-fifth for each 40 mg/dL reduction of low-density lipoprotein (LDL).1 Concerns have been raised about whether lipid-lowering drugs might produce an excess of cancers even though at least 14 statin trials involving 90,000 patients1 have not demonstrated any significant excess of any particular type of cancer2,3; however, it should be clearly recognized that ezetimibe has been studied far less extensively than have the statin drugs.

The concern about whether lipid-lowering drugs might produce an excess of cancers was addressed by Rossebo and her colleagues who conducted a randomized, double-blind trial involving 1873 patients to test whether hyperlipidemia might be a risk factor for stenosis of the aortic valve.4 Patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. Study results revealed that the combination drug regimen did not reduce the composite outcome of the combined aortic valve events or ischemic events in patients with aortic stenosis; however, it did reduce the incidence of ischemic cardiovascular events, but not events related solely to aortic valve stenosis. In addition, the study results did find a significantly higher incidence of cancers, which occurred in 105 (11.1%) patients in the drug therapy group and in only 70 (7.5%) patients in the placebo group (P = 0.01).


Unexpected and often extreme findings in the results of a particular study can be statistically misleading and should always be confirmed by independently testing the findings using a separate database that is larger than the one that generated the unexpected results in the first place.5,6 Responding to the results of the Rossebo study,4 Peto and colleagues7 analyzed the results and then compared them to two large ongoing trials comparing ezetimibe/simvastatin to matching placebo.8,9 These studies demonstrated that there was no overall excess of cancer and no significant excess at any particular site in the drug therapy groups. Among patients assigned to ezetimibe, there were more, although not significantly more, deaths from cancer but also, there were fewer although not significantly fewer, other cases of cancer in the control groups. Also, there was no evidence of a trend in the risk ratio for incidence of death from cancer with increasing duration of follow-up. The results of the data analysis from the three trials revealed that although there was a nominally significant excess of death from cancer among patients assigned to receive ezetimibe as compared with the controls, these findings were statistically insignificant and did not provide credible evidence of any adverse affect of ezetimibe on cancer rates. Therefore, Peto and colleagues concluded that the available results from the three trials did not provide significant evidence of any adverse effect of ezetimibe on cancer rates and that follow-up of longer duration, which will permit an appropriate balance of risks and benefits, is necessary to properly assess whether ezetimibe administration is related to an increase in the rate of cancer.

Finally, it is important to recognize that the premature publication of interim research findings of major clinical trials is an important and growing problem that should be avoided. Established methods for monitoring interim safety and efficacy data in trials have generally worked quite well to help ensure that patients are properly protected and the treatments are reliably evaluated.10,11 Interim results should be made public only if clear evidence of significant benefit or harm has emerged before the scheduled end of the trial. Premature release of statistically inappropriate study results often leads to the production of unnecessary anxiety among both physicians and patients and frequently leads to discontinuation of needed medications. I agree with the conclusions of Peto and colleagues that the need for premature disclosure of interim findings could be lessened in the future by the initiation of larger, more definitive outcome trials earlier in the life cycle of potentially important new drugs and devices.7,12


1. Baigent C, et al; Cholesterol Treatment Trialists' (CTT) collaborators. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet 2005;366:1267-1278. Errata: Lancet 2005;366:1358; 2008;371:2084.

2. Sacks FM, et al; Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.

3. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomized controlled trial. Lancet 2002;360:1623-1630.

4. Rossebo AS, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-1356.

5. Collins R, Armitage J. High-risk elderly patients PROSPER from cholesterol-lowering therapy. Lancet 2002;360:1618-1619.

6. Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity. I. Clinical trials. Lancet 2001;357:373-380.

7. Peto R, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-1366.

8. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003;63(Suppl 84):S207-S210.

9. Cannon CP, et al. Rationale and design of IMPROVE-IT (IMProved Reduction Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimibe/simva-statin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndrome. Am Heart J 2008;156:826-832.

10. Ellenberg SS, et al. Data Monitoring Committees in Clinical Trials: A Practical Perspective. Chichester, England: John Wiley; 2002.

11. DAMOCLES Study Group, NHS Health Technology Assessment Programme. A proposed charter for clinical trial data monitoring committees: Helping them to do their job well. Lancet 2005;365:711-722.

12. Califf RM, et al. Curbing the cardiovascular disease epidemic: Aligning industry, government, payers, and academics. Health Aff (Millwood) 2007;26:62-74.