The possibility of an association between statin therapy and an increased risk of cancer hit the headlines in 1996 with the publication of results from the Cholesterol and Recurrent Events (CARE) Trial.1 This study in patients with raised cholesterol levels who had previously suffered a myocardial infarction, investigated the use of 40 mg of pravastatin daily in preventing a fatal coronary event or a non-fatal myocardial infarction.
In the CARE trial there were 161 fatal or non-fatal primary cancers in the placebo group, compared to 172 in the pravastatin group. These cancers affected a range of different sites, but although there was only one case of breast cancer in the placebo group, there were 12 in the pravastatin group (p=0.002). This increased incidence of breast cancer was surprising as it had not been reported previously in other trials with this drug and had not been seen in animal testing.
Further concerns about the association between statin therapy and cancer incidence were raised by the PROSPER trial,2 which investigated the benefits of pravastatin in patients aged 70–82 years who were at increased risk of vascular disease. This trial found that a diagnosis of new cancer was 25% more frequent in the pravastatin group, but a meta-analysis of other statin trials carried out by the study group did not show any excessive cancer in patients treated with statins. The Heart Protection Study,3 which recruited a large number of women and elderly patients, showed no effect of simvastatin on the incidence of cancer. New primary cancers were diagnosed in 7.9% of those treated with simvastatin compared with 7.8% of those in the placebo group. The Cholesterol Treatment Trialists’ Collaborators looked at 5103 cancers in statin trials and found no evidence that reducing low density lipoprotein (LDL) cholesterol by 1 mmol/l with a statin increased the risk of developing cancer, or of an excess of cancer with duration of treatment.4 Although in statin trials there may be an inverse relationship, which is not statistically significant, between LDL cholesterol levels and cancer levels in patients on active treatment when compared with placebo, a recent analysis has concluded that statin therapy is not associated with an increased risk of cancer.5
The SEAS study
The SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study was a randomised, double-blind study, involving 1873 patients with mild-to-moderate asymptomatic aortic stenosis. In this trial, patients were randomised to receive 40 mg of simvastatin plus 10 mg of either ezetimibe or placebo.6 The rationale behind this trial was that aortic stenosis has a similar pathophysiology to vascular atherosclerosis; it was postulated that by lowering cholesterol levels, vascular outcomes would be improved. In the SEAS study the combination of simvastatin and ezetimibe reduced LDL cholesterol by an average of 61%, which would correspond to a reduction of about 2 mmol/l. However, this treatment had no impact on the progression of aortic stenosis and associated events, although benefit was seen in terms of ischaemic cardiovascular events, mainly through the reduced need for coronary artery bypass surgery.6
An unexpected finding in the trial, however, was an excess of cancers observed in the simvastatin plus ezetimibe group: 105 cases compared with 70 in the placebo group (p=0.01). These cancers were in a variety of sites. Also of note was that deaths from cancer were more frequent in the active treatment group (39 as opposed to 23 in the placebo group), but this was only of borderline statistical significance (p=0.05).6
It has been suggested that ezetimibe interferes with the gastrointestinal absorption not only of cholesterol, but possibly of other molecules that could conceivably affect the growth of cancer cells.7
Testing the hypothesis
In order to determine whether there was an increased risk of cancer resulting from treatment with simvastatin plus ezetimibe, cancer data from the SEAS study were compared by Richard Peto and colleagues from the Clinical Trials unit in Oxford with two large ongoing trials. These were the Study of Heart and Renal Protection (SHARP) study, and Improved Reduction of Outcomes Vytorin Efficacy International Trial (IMPROVE-IT).8
In the SEAS trial it was pointed out that if there was an excess of cancers due to this drug combination, then certain cancer types should dominate (based on previous epidemiological studies of cancer in humans and studies of chemical carcinogens in animals), but this was not found to be the case. The SEAS trial was also seen as a hypothesis-generating analysis, and examination of the two other trials was seen as hypotheses-testing analysis of cancer data. Among the patients in the active treatment groups in SHARP and IMPROVE-IT, there was an excess of death from cancer (although this was not significant)—97 versus 72 in the control group (p=0.07). No significant excess of death from any particular type of cancer was observed in the SHARP, IMPROVE-IT, or SEAS trials.8
When all three trials were considered together, there was a nominally significant excess of deaths from cancer among the patients assigned to receive ezetimibe compared with controls: 134 versus 92, respectively, with an uncorrected p-value of 0.007. This p-value does not provide unbiased evidence for the hypothesis generated by the SEAS trial, and all the other data do not provide credible evidence of any adverse effect on cancer by the addition of ezetimibe to statin therapy.8
Use of ezetimibe
In Technology Appraisal 132, NICE recommends the use of ezetimibe for lipid lowering if a patient is intolerant to statin therapy or if the use of statins is contraindicated.9 It also recommends the co-administration of ezetimibe with initial statin therapy if LDL cholesterol is not controlled after titration of a statin, or if titration is not indicated. This recommendation is based on the evidence that ezetimibe is an effective LDL cholesterol-lowering agent, and that the reduction of LDL cholesterol is associated with improved cardiovascular outcomes. This was despite the fact that clinical benefit has yet to be shown for the drug in major outcome trials.
Doubts on the efficacy of ezetimibe were raised with the release of the ENHANCE trial, which involved 720 patients with heterozygous familial hypercholesterolaemia treated with either simvastatin 80 mg plus ezetimibe 10 mg, or simvastatin 80 mg plus placebo over a 2-year period.10 This study measured change in carotid intima thickness (IMT) at the end of 2 years. Although there was a significant difference in LDL cholesterol lowering between the two treatment groups, 58% versus 41% for the ezetimibe/simvastatin and simvastatin groups, respectively, there was no difference between the two treatment groups in terms of carotid IMT measurements. It was noted however that the ENHANCE trial was an imaging study rather than a clinical outcome one, and that the use of surrogate markers such as carotid IMT does not give a clear indication whether a drug is clinically effective or not.
Previous statin trials have not shown any increased risk of cancer in patients treated with a statin, and, on the basis of the recent trials involving ezetimibe, we still do not have any credible evidence of any adverse effect on cancer. Looking at the SEAS, SHARP, and IMPROVE-IT trials together, there was no increase with time in the relative risk of cancer incidence and mortality. At present, primary care prescribing of statins and ezetimibe should continue unchanged in line with NICE guidance.
The SHARP and IMPROVE-IT trials are continuing and this will allow more reliable evidence to emerge about the effects of combined ezetimibe and statin therapy. This evidence will include not only data on the effect on cancer rates, but also, importantly, the effect on major cardiovascular outcomes, including myocardial infarction and stroke. With time we will then be in a position to judge whether the effect of lowering LDL cholesterol using this combination of drugs can produce better outcomes than those achieved by statin monotherapy.
- Sacks F, Pfeffer M, Moye L et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335 (14): 1001–1009.
- Shepherd J, Blauw G, Murphy M et al; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360 (9346): 1623–1630.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 (9326): 7–22.
- Baigent C, Keech A, Kearney P 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 randomised trials of statins. Lancet 2005; 366 (9493): 1267–1278.
- Alsheikh-Ali A, Trikalinos T, Kent D, Karas R. Statins, low-density lipoprotein cholesterol, and risk of cancer. J Am Coll Cardiol 2008; 52 (14): 1141–1147.
- Rossebø A, Pedersen T, Boman K et al; SEAS Investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359 (13): 1343–1356.
- Drazen J, D’Agostino R, Ware J et al. Ezetimibe and cancer—an uncertain association. N Engl J Med 2008; 359 (13): 1398–1399.
- Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008; 359 (13): 1357–1366.
- National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. Technology Appraisal 132. London: NICE, 2007.
- Kastelein J, Akdim F, Stroes E et al; ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358 (14): 1431–1443.G