In this large population-based case control study to determine the risk of common cancers associated with use of statins, we confirmed that use of statins does not affect the overall risk of cancer. We did find some evidence of an increased risk of colorectal cancer in patients using statins for 4 or more years or with a high statin dose. We also found an increased risk of bladder cancer and lung cancer in patients prescribed statins for 4 or more years. Conversely, we found a reduced risk of haematological malignancies in statin users.
There are a large number of studies devoted to statins and cancer risk summarised in meta-analyses[6
] which did not show an adverse or protective effect of statins on the overall incidence of cancer. However, the categorisation of 'any cancer' is not a specific enough endpoint of study as it covers a range of diseases, each with a different aetiology and course of development.
Colorectal cancer, as one of the most common cancers, has been studied extensively but only eight epidemiological studies looked at the effect of long-term statin use (at least 4 years). Four of them[38
] had odds ratios greater than unity (from 1.00 to 1.15) and four of them[22
] reported odds ratios less than unity (from 0.71 to 0.83), but none of these findings reached statistically significant levels even at the 5% level. The effect of dose in our study might, however, be a replication of the effect of cumulative use because a high dose was more likely to be prescribed for patients who had been on statins for substantial period of time.
The other two most common cancers, breast and prostate, also account for a number of studies but there has been no definite outcome in associating any of these with use of statins and our null results are consistent with this. Studies for prostate cancer have been aggregated into a meta-analysis [45
], which did not find any significant association with overall risk of prostate cancer and another meta-analysis[46
] looking at breast cancer studies also failed to demonstrate a protective or adverse effect of statins.
For bladder cancer, results of a meta-analysis considering 5 studies showed an increased, but not significant, association between stain use and cancer risk[7
]. There have been very few studies investigating the long-term effect of statin use on bladder cancer. One study[39
] showed an increased risk for more than 5 years of statin use, which is consistent with our findings, but another very recent one found no significant association for current use of statins for more than 5 years [22
]. Both studies, however, were much smaller.
Our findings of a significant increase in unadjusted lung cancer risk for statin use and for long-term use were both significantly decreased by adjusting for cardiovascular disease, but after adjusting for all factors, long-term use still showed a significant association with increased lung cancer risk. There is no causal link between cardiovascular disease and lung cancer but there is a strong association of both conditions with smoking. The finding about possible increased risk from long-term use is consistent with the results of two other studies[22
], although their findings were not significant.
The decreased risk of haematological malignancies could be explained by reverse causality, as patients with such diagnoses are more likely to have lower lipid levels[47
] although we did restrict our statin exposure to prescriptions at least 12 months before diagnosis. The effect of statins on leukaemia has been studied in vitro
and there is evidence that statins might suppress the growth of promyelocitic[48
] and lymphocytic[49
] leukemic cells. However, no epidemiological studies have provided significant evidence of any statin effect on incidence of leukaemia.
Our study has several strengths. It is substantially larger and has greater statistical power than any previous study. This has allowed us to perform the analyses separately for different cancers within the same population. We had a substantial number of patients with at least 10 years of records, which also allowed us to examine long-term statin use. The study is based on computer-recorded prescribing and morbidity data collected prospectively. The study was not subject to response bias or recall bias as the exposure data were recorded before the date of diagnosis or pseudo-diagnosis. Any bias from misclassification is likely to be small because the level of accuracy and completeness of medical records in general practices has been shown to be high [50
Matching the controls on sex, age, practice and calendar year removed confounding by these factors. Any bias from misclassification of statin use is likely to be minimal as more than 99% of all general practitioners' repeat prescriptions are recorded on computer[51
]. We minimised the possibility of misleading data from the effects of undiagnosed cancer in new medical records by excluding prescriptions, diagnoses of co-morbidities and records of body mass index made within the 12 months prior to the date of the diagnosis or pseudo-diagnosis of cancer.
Our study has some limitations. Information on certain risk factors for cancer, such as level of physical activity, alcohol use, and diet, and information on cancer screening tests (mammography, prostate-specific antigen test and colonoscopy) were not reliably recorded on the database and not included in the analysis so there may be some residual confounding. Although we adjusted the risk of cancer for possible effects of smoking, obesity, deprivation, co-morbidities and the use of other medications, residual confounding may also result from misclassification of those variables. Values of body mass index or smoking status, were missing for about 22% of cases and 25% of controls, so we substituted missing values using multiple imputation. We did not include blood test results in the analysis, in particular high-density lipoproteins and total-serum cholesterol, because they were not consistently recorded on the data base and would be more likely to be recorded in statin users.
Although our data contain detailed information on drug prescriptions, this may not reflect actual use. However there is no reason to think that any non-adherence would systematically differ between cases and controls.
Another possible source of misclassification arises from a statin (simvastatin 10 mg) having become available over the counter in May 2004 in the UK, which would affect mostly younger people who are not entitled to free prescriptions[52
] and only a small part of the study period. However, among statin users 81.4% of cases and 82.4% of controls were aged 65 years or older and therefore entitled to free prescribed medications. Analyses repeated on this group of patients obtained similar results, which suggests that any misclassification of use of medication because of over-the-counter purchase is not an explanation for our findings.