Statins and Colorectal Cancer

Paul Lochhead; Andrew T. Chan


Clin Gastroenterol Hepatol. 2013;11(2):109-118. 

In This Article

Statins and Colorectal Cancer Risk in Randomized Trials

As a result of numerous large RCTs of lipid-lowering and major vascular events, a wealth of clinical data on statin use has accrued. Most statin RCTs have reported data on overall cancer incidence, and some studies have reported site-specific incidence (Table 1).[17,53–60] Thus, cardiovascular RCTs represent a valuable resource for assessing differences in cancer incidence between groups in which statin use has been randomly assigned. Several tabular meta-analyses of RCT data, performed using differing inclusion criteria and methodologies,[19,20,22,61] concur that statin use over follow-up periods of around 4 to 6 years is not associated with an increase in overall cancer incidence. Although this obviously is reassuring, aggregate cancer risk does not address the possibility of differential effects of statin use on the risks of specific cancer types. In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial,[62] for example, the observed reduction in cardiovascular risk largely was offset by an excess of gastrointestinal malignancies in those assigned to statin, compared with placebo. Although meta-analyses of colorectal cancer risk in cardiovascular RCTs face the limitation of a reduced number of studies with available site-specific cancer data, these meta-analyses have consistently failed to show an association between statins and colorectal cancer.[20,22,61] Thus, the increased number of gastrointestinal cancers observed in the PROSPER trial may have arisen by chance. Most recently, the Cholesterol Treatment Trialists' Collaboration published a meta-analysis of individual data from 175,000 participants in 27 statin RCTs, 5 of which were trials of more LDL-lowering vs standard LDL-lowering.[63] Over a median follow-up period of 4.8 years, the number of incident colorectal cancers was not significantly different between those assigned to statin (or more statin) compared with controls (or less statin). Furthermore, there were no associations between overall cancer risk and duration of therapy, participant age, type of statin, or baseline LDL level.[63]

One major criticism of cancer risk estimates from meta-analyses of statin RCTs is insufficient duration of follow-up. The longest average follow-up period in the cited meta-analyses was 5.9 years,[61] with some meta-analyses including individual RCTs with only 2 years of follow-up or less.[19,20,22] Individually, a small number of studies have accumulated longer post-trial follow-up. The West of Scotland Coronary Prevention Study, which randomized participants to pravastatin or placebo for 5 years, found no difference in colorectal cancer incidence between groups 10 years after the completion of the trial.[58] Similarly, over cumulative follow-up periods of 10 years for the Scandinavian Simvastatin Survival Study,[56] and 11 years for the Heart Protection Study,[64] no intergroup differences were observed for colorectal or gastrointestinal cancer incidence, respectively. The adenoma-carcinoma sequence is postulated to take at least 10 years, and the initiation of colorectal neoplasia from normal mucosa may take even longer. Unless the effects of statins are restricted to advanced stages of colorectal neoplasia, it is likely that the majority of RCTs have insufficient follow-up to fully assess the potential beneficial or adverse effects of statins on colorectal carcinogenesis. In addition, as secondary end points, data on cancer incidence and mortality are not collected systemically in cardiovascular RCTs, and thus may be subject to ascertainment bias. Given that many cardiovascular trials have been conducted in high-risk populations, competing risks also becomes an important potential source of bias. Individuals randomized to placebo may die from major vascular events before they have had time to develop cancer.