In this case–control study, statin use was associated with a significantly reduced incidence of CRC. These findings remained after adjustment for potential confounding factors. There was a significant duration- and dose–response relationship with greater statin exposure offering more protection against CRC. The use of simvastatin was significantly protective but although exactly the same pattern was seen with the other statins, the numbers were too small to reach conventional statistical significance. These data support a causal relationship between statin exposure and reduced risk of colorectal neoplasia. These results are consistent with previous studies and a meta-analysis suggesting a protective effect [8–12], and the protective effective against CRC seen in the original randomized trials of statin use in cardiovascular disease [18, 28], although the strength of the apparently protective effect is rather greater in our study than several other positive studies. Not all case–control and cohort studies have shown consistent results and no association with reduced risk has been reported [20, 22–25]. There may be several reasons for the inconsistencies between studies, including different populations with different underlying CRC risk, different control groups, and inadequate length of follow up in cohort studies or insufficient statin exposure to detect a protective effect (some studies including all patients with statin exposure of only 3 months).
There is biological plausibility to our data: we detected both time- and dose-dependent effects against CRC development and experimental studies are supportive of CRC-protective effects of statins. In addition to in vitro cell line studies, statins have been shown to reduce polyp formation in Min−/− mouse models  and pre-neoplastic and neoplastic lesions in animal models [30, 31]. A single study has shown that statin use was associated with a reduced rate of post-polypectomy adenomatous polyp formation , although another study with shorter follow up failed to detect any protective effect of statins against polyp recurrence .
More recent studies have suggested that biological differences may underlie some of the variability in the apparent effects of statins. Upregulation of HMG-CoA has been reported in CRCs but one study has shown this to be more marked in left sided cancers . Similarly HMG-CoA genotype seems to influence the protective effect of statins: a higher activity allele was associated with a protective effect, whereas a significant protective effects was not associated with a lower activity allele . The polyp-cancer sequence is estimated to take 10–15 years and it is not clear, where along this sequence the effect of statins may be most noticeable . Experimental studies have shown that statins may become less effective in cell lines as more genetic and hence functional changes downstream of the putative cellular effect of statins accumulate [34, 35]. If, for example, the effect of stains is more prominent at stages of polyp-development or progression, then the average age of initiation of statin therapy in any population is likely to contribute to differing effects of statins on CRC incidence between studies.
The main specific strengths of our study are the comprehensive drug history available and the fact that all patients underwent diagnostic colonoscopy. Many previous studies have used prescribing records and although these studies have many advantages, they may misreport actual drug exposure as not all prescribed medication is actually consumed. In addition in the United Kingdom aspirin, ibuprofen, diclofenac and simvastatin are available to purchase without prescription, thus we feel our records of drug exposure are both accurate and comprehensive. Asymptomatic colon cancer is not uncommon and our use of a control group, who all underwent colonoscopy will have minimized bias due to misdiagnosis which is a problem in uninvestigated cohorts. There are data from the USA showing that patients with co-morbidity undergo more frequent screening colonoscopies . We only included cases and controls having their first ever diagnostic colonoscopy, so removing any potential bias from repeated colonoscopy or previous polyp removal. A potential disadvantage of our design studying symptomatic patients attending for diagnostic colonoscopy is that the control group may exhibit more health-seeking behavior and be more health conscious and hence introduce bias. However all had genuine symptoms for which colonoscopy would be indicated and as all were provided under the United Kingdom National Health Service, no direct financial or insurance incentives will have influenced decisions regarding colonoscopy. An ideal study would examine statin use in cases and controls from asymptomatic patients invited for colonoscopic colon cancer screening, rather than symptomatic patients; however this would not be possible as the United Kingdom national screening programme is based on initial faecal occult blood screening, followed by colonoscopy only in those testing positive. Interestingly the association of reduced CRC incidence in statin uses was also seen in the sub-group of patients that presented via the national screening program with positive faecal occult bloods, although the overall number of cases in this group was too small to draw definite conclusions (statin use: controls 14/26, 53%, cases 3/13, 23% OR 0.37 (0.06 – 1.17)).
The issue of bias inherent to the control group affecting the results must always be considered in case–control and cohort studies, in particular the possibility that statin users are generally more health-conscious and this explains their lower CRC risk. As with previous studies in this field, we cannot exclude this completely but we feel this is an unlikely explanation of the findings. It is possible that statin-users may have had more specific dietetic input and this lead to a positive change in diet which influenced cancer risk. The majority of statin prescribing was by the patients’ primary care physician for the primary prevention of vascular disease and as such was not governed by any specific protocol and both patient and clinician perception are likely to have influence the use of statins. The control group is comparable to a standard low-moderate CRC risk cohort undergoing diagnostic colonoscopy for any indication in the UK and comparable to the age-matched population as a whole. In terms of smoking, alcohol intake, BMI and type 2 diabetes as markers of health-related behaviors, the control group did not appear to be especially healthier than the cases and the effect of statins persisted after correction for all known confounding variables. The risk of colonic neoplasia is probably increased in both diabetes mellitus and established coronary artery disease [6, 37], and this would have been expected to reduce any effects of statins observed in our study. Chronic statin use is associated with a very low incidence of gastrointestinal side effects and so it seems unlikely that statins are over-represented in the control group because they were responsible for symptoms initiating the referral for colonoscopy . It could be argued that because of the proclivity for aspirin to cause gastrointestinal bleeding and anaemia, this could have led to over-representation of aspirin in the control group and indeed there was a slightly higher number of controls in which anaemia was the presenting condition. Whilst this is possible, our study showed a protective effect of aspirin entirely consistent with other studies that used different control groups , and the effect of statins persisted after correction for aspirin use. We also showed an apparent protective effect of metformin against CRC, again consistent with previous studies, suggesting our results have external validity .
This study did have limitations, some of which were inherent with the case control study design. Despite this study being sufficiently powered to produce statistically significant results, this was a relatively small cohort compared to some similar case control studies. Data collection was cross referenced using patient interviews and clinical notes but recall bias may have caused inaccuracy and difficulty in determining the extent of exposure to medications, although as most subjects were interviewed in the same situation pre-colonoscopy, this is unlikely to unduly influence cases or controls. Data were collected for many potential confounding factors that had been identified from the literature but other uncontrolled confounders could have affected the results. We did not attempt to address the issues regarding diet and cancer risk and further studies in the area would benefit from including this. Although we utilized both pre- and post-cancer diagnosis interviews to establish statin exposure, we do not feel this introduced any bias of recall. All drugs exposures were accurately cross-referenced to medical records (including pre-colonoscopy medical notes), statins are characteristically long-term therapies and once started are very rarely stopped and although patients were informed we were interested in risk factors for their diseases, they were unaware of which particular factors. Our results show no difference in statin use between those interviewed pre- and post-colonoscopy. However the issue of residual confounding by other unrecognized factors must still be considered. Similarly, although adequately powered for our pre-designed end-point, the relatively small size of our study may have contributed to the relatively large protective association that we have described.
Investigating the effect of statins and aspirin produced interesting findings. The use of statins or aspirin produced a significant protective effect, although statin use was considerably more prevalent in this population. There was a suggestion that the combination of aspirin and statin was associated with a lower incidence of CRC, and in vitro cell line and mouse models studies would support a beneficial interaction between statins and cyclo-oxygenase inhibitors [14, 40, 42, 43, 43].