“Cholesterol pill warning” is the headline in the Daily Mail . Scientists have raised fears of a cancer link to cholesterol lowering drugs used by thousands, the newspaper says. The Daily Telegraph says that the risk of cancer is increased by 50% and the Daily Mirror reports, “a leading specialist said he would not take the drug called Inegy”.
Inegy contains a combination of simvastatin (a statin) and a newer cholesterol-lowering drug called ezetimibe, and was studied in a trial of 1,873 people who had aortic stenosis, a narrowing of the main valve from the heart. The drug combination has been shown to lower the average levels of “bad” LDL cholesterol, however, after four years, there was no difference in the number of aortic valve replacements performed in trial participants.
An unexpected finding was that 105 cancers occurred in the Inegy group compared with 70 in the untreated group. In order to investigate this result further, other researchers looked at another two ongoing trials of ezetimibe. When the results from all trials were combined, they did not find an increased incidence of cancer. However, the doubts raised about this combination will require further analysis to ensure the safety of the drug.
Where did the story come from?
The main study, known as the Simvastain and Ezetimibe in Aortic study (SEAS), was carried out by Dr Anne Rossebø and colleagues from the Aker University Hospital in Oslo, Norway. The study was supported by Merck and Schering Plough Pharmaceuticals, manufacturers of the drug Inegy. An analysis to assess the risk of cancer from three ezetimibe trials was conducted by Professor Richard Peto and colleagues from the Clinical Trial Service Unit (CTSU) in Oxford, UK and this was conducted independently of the funders of the original studies. An editorial was also published by five authors with the first named author Dr Jeffrey Drazen. All three publications appeared in the same issue of the peer-reviewed medical journal The New England Journal of Medicine .
What kind of scientific study was this?
The main SEAS study was a randomised, double-blind trial. The researchers randomised 1,873 patients with mild-to moderate, asymptomatic aortic stenosis into an active group, who received 40mg of simvastatin and 10mg of ezetimibe, and an inactive group, who were given a placebo daily. Patients were followed for an average of 52.2 months and the researchers looked for major cardiovascular events that occurred in that time. These included death from cardiovascular causes; aortic-valve replacement; non-fatal heart attack, hospitalisation for unstable angina, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention (such as stenting) and a particular type of stroke caused by arterial blockage called “non-haemorrhagic stroke”.
Due to the finding from the SEAS study, that cancer occurred more frequently in the simvastatin– ezetimibe group (further information below), another group of researchers from Oxford set out to perform a secondary analysis of the data. They used the data from SEAS trial as well as data from two other randomised clinical trials currently in progress to investigate whether adding ezetimibe to statin therapy in order to produce a larger drop in LDL “bad” cholesterol, might increase the incidence of cancer.
The two large ongoing trials the researchers included were the Study of Heart and Renal Protection (SHARP) trial that had enrolled 9,264 patients and followed them for an average of 2.7 years, and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) currently with 11,353 patients followed for an average of one year. The SHARP trial is examining the effects of the combined simvastatin-ezetimibe pill (20mg;10mg) compared with placebo in people with chronic kidney disease, and the IMPROVE-IT trial is comparing the simvastatin-ezetimibe pill (40mg;10mg) with 40mg simvastatin alone in people with acute coronary syndrome (classic heart attack and other heart attack-related conditions).
What were the results of the study?
In the SEAS trial, the combined endpoint of major cardiovascular events occurred in 333 patients (35.3%) in the active (simvastatin-ezetimibe) group and in 355 patients (38.2%) in the placebo group. The difference was not statistically significant (HR = 0.96; 95% CI, 0.83 to 1.12; P = 0.59). Aortic-valve replacement was performed in about the same number of patients in both groups, 267 patients (28.3%) in the active group versus 278 patients (29.9%) in the placebo group. The researchers report that significantly fewer patients had ischaemic cardiovascular events (such as heart attack) in the active group (148 patients) than in the placebo group (187 patients), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting.
Cancer occurred more frequently in the simvastatin-ezetimibe group (105 patients) versus the placebo group (70 patients) and this was statistically significant (P = 0.01). Some people already had cancer at the start of the trial and new cancer cases occurred during treatment in 101 patients from the active-treatment group versus 65 in the control group. Cancers were of several different types.
The results of the secondary analysis from the Oxford research group looking at cancer data in ongoing trials conclude that when SHARP and IMPROVE-IT events are combined, there was no overall excess of cancer (313 in active-treatment groups versus 326 of controls). This provides a risk ratio of 0.96 (95% CI, 0.82 to 1.12; P = 0.61), which is not statistically significant; they also say that there was no significant excess at any particular site.
Among all patients assigned to ezetimibe across the three trials, there were more deaths from cancer, 97 patients, versus 72 patients in the control group, though this was not a statistically significant difference. There were fewer cases of patients living with cancer in the treated group than in the control group (216 patients versus 254). The researchers report that there was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up, meaning that for the people who were followed up for longer, the rates of cancer did not increase.
What interpretations did the researchers draw from these results?
The researchers of the first study concluded that: “Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic valve events and ischaemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischaemic cardiovascular events but not events related to aortic-valve stenosis.”
The Oxford researchers who carried out the secondary analysis concluded that the “available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer”. They suggest that “follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably”.
What does the NHS Knowledge Service make of this study?
An editorial in the same journal makes several points regarding interpretation of the data and concludes that “physicians and patients are unfortunately left for now with uncertainty about the efficacy and safety of the drug”.
Particular points noted in the editorial and by the original authors are that:
- Although the randomised clinical trial is considered to be the most reliable tool to assess how well new drugs work and how safe they are, occasionally unanticipated findings occur. If these cannot be explained by any known mechanisms, uncertainty is raised concerning whether these could be due to chance or alternatively if this is a true adverse effect of the drug.
- Single studies are not ideal for ruling out the possibility of a chance effect, especially those with a low probability of occurrence in less than 5% of studies, and the authors rightly call for more studies to assess the rates of cancer with intensive cholesterol lowering regimens.
- The Oxford researchers have tried to supply this sort of information and have not been able to confirm the increased cancer in the SEAS trial, further raising doubt that the increase risk of cancer in the SEAS trial is a true effect.
- As none of the three trials were designed to address cancer risk as their main aim, they are inherently less reliable than studies that have this as a primary outcome.
- The trials all aimed to investigate intensive lipid lowering regimes, and these will not be the same for all patients taking the combination drug.
- These results do not apply to people taking statins alone, e.g. the commonly used drug simvastatin.
The Oxford group mention that the opposite direction of risks suggested by the data further make the hypothesis that ezetimibe causes cancer implausible. The risk of death from cancer was increased, while the chance of developing cancer that has not yet caused death was reduced.
Concerned patients should certainly discuss the results and their options fully with their medical advisors before taking any action based on these studies.