Jenny N. Poynter, M.P.H., Stephen B. Gruber, M.D., Ph.D., M.P.H., Peter D.R. Higgins, M.D., Ph.D., Ronit Almog, M.D., M.P.H., Joseph D. Bonner, M.S., Hedy S. Rennert, M.P.H., Marcelo Low, M.P.H., Joel K. Greenson, M.D., and Gad Rennert, M.D., Ph.D.
Background Statins are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase and effective lipid-lowering agents. Statinsinhibit the growth of colon-cancer cell lines, and secondaryanalyses of some, but not all, clinical trials suggest thatthey reduce the risk of colorectal cancer.
Methods The Molecular Epidemiology of Colorectal Cancer studyis a population-based case–control study of patients whoreceived a diagnosis of colorectal cancer in northern Israelbetween 1998 and 2004 and controls matched according to age,sex, clinic, and ethnic group. We used a structured interviewto determine the use of statins in the two groups and verifiedself-reported statin use by examining prescription records ina subgroup of patients for whom prescription records were available.
Results In analyses including 1953 patients with colorectalcancer and 2015 controls, the use of statins for at least fiveyears (vs. the nonuse of statins) was associated with a significantlyreduced relative risk of colorectal cancer (odds ratio, 0.50;95 percent confidence interval, 0.40 to 0.63). This associationremained significant after adjustment for the use or nonuseof aspirin or other nonsteroidal antiinflammatory drugs; thepresence or absence of physical activity, hypercholesterolemia,and a family history of colorectal cancer; ethnic group; andlevel of vegetable consumption (odds ratio, 0.53; 95 percentconfidence interval, 0.38 to 0.74). The use of fibric-acid derivativeswas not associated with a significantly reduced risk of colorectalcancer (odds ratio, 1.08; 95 percent confidence interval, 0.59to 2.01). Self-reported statin use was confirmed for 276 ofthe 286 participants (96.5 percent) who reported using statinsand whose records were available.
Conclusions The use of statins was associated with a 47 percentrelative reduction in the risk of colorectal cancer after adjustmentfor other known risk factors. Because the absolute risk reductionis likely low, further investigation of the overall benefitsof statins in preventing colorectal cancer is warranted.
Colorectal cancer is the third most commonly diagnosed cancerin the United States, with approximately 145,000 new cases and56,300 deaths projected for 2005.1 An intensive search to identifychemopreventive agents as a means to reduce the complicationsand deaths due to colorectal cancer has revealed aspirin andother nonsteroidal antiinflammatory drugs (NSAIDs) as attractivecandidates,2,3,4,5,6 although concern about toxicity may limitbroad application of these agents.
The rate-limiting enzyme in mevalonate synthesis is 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase.7,8 The statins are a class ofagents designed to inhibit HMG-CoA reductase, and they are effectivein the management of hypercholesterolemia. Owing to the involvementof HMG-CoA reductase in cholesterol synthesis and growth control,statins may have chemopreventive activity against cancer.9 Invitro data support a potential role for the use of statins incolorectal cancer. HMG-CoA reductase is overexpressed in colorectal-cancercells,10 and statins have been shown to induce apoptosis incancer cell lines in vitro.11,12
Several randomized clinical trials designed to assess the safetyof statins and cardiovascular outcomes among patients receivingthem have also assessed the incidence of cancer. The resultswere not consistent: in some trials, more cases of cancer occurredamong patients treated with statins than among those who didnot receive these agents, and in other trials, fewer cases occurred.13,14,15,16,17,18,19,20,21Since all these studies were designed to assess end points relatedto cardiovascular disease, the small numbers of cancers observedlimit their statistical power to detect associations betweenstatin use and the risk of cancer. To clarify this association,we evaluated data gathered in a population-based, epidemiologic,case–control study.
Methods
Participants
The Molecular Epidemiology of Colorectal Cancer study is a population-basedcase–control study of incident colorectal cancer in northernIsrael. Patients were eligible for participation if they hadreceived a diagnosis of colorectal cancer between May 31, 1998,and March 31, 2004, and lived in a geographically defined areaof northern Israel. Controls were identified from the same sourcepopulation with the use of the Clalit Health Services (CHS)database. CHS is the largest health care provider in Israeland covers approximately 70 percent of the older population(persons at least 60 years of age). Health care coverage inIsrael is mandated and is provided by four groups akin to healthmaintenance organizations. Thus, all study participants (patientsand controls) had similar health insurance and similar accessto health services. Controls were individually matched to patientsaccording to the year of birth, sex, primary clinic location,and ethnic group (Jewish vs. non-Jewish). Potential controlswere excluded if they had a history of colorectal cancer. Participantsprovided written informed consent at the time of enrollment.
Participants were interviewed to obtain demographic informationand information about their personal and family history of cancer,reproductive history, medical history, medication use, and healthhabits; they also completed a dietary questionnaire. Diagnosesof colorectal cancer were confirmed by means of a standardizedpathological review by one pathologist. The institutional reviewboards at the Carmel Medical Center, Haifa, and the Universityof Michigan, Ann Arbor, approved all procedures.
Exposure Data
Participants were asked to recall each medication they had usedfor at least five years, and statin use was determined on thebasis of this list. The use of aspirin and other NSAIDs wasalso assessed; information gathered included dose, durationof use, and indication for use. For analyses of aspirin or otherNSAIDs, exposure was defined as five or more years of totaluse, and no exposure was defined as less than five years ofuse or no use.
A complete, three-generation pedigree and information on thefamily history of cancer were also recorded for each participant.The report of colon or rectal cancer in at least one first-degreerelative was considered to represent a family history of colorectalcancer. Assessment of physical activity was based on a validatedinstrument22 used to evaluate three dimensions of physical activity:sports, leisure, and occupational activities. Sports activitywas the dimension considered in these analyses since it is thedimension most strongly associated with colorectal cancer inthis analysis.
Ethnic group was determined by assessing participants' religiousaffiliation, self-described ethnic group, and the country ofbirth of their parents and grandparents. Ashkenazi Jewish heritagewas determined as previously described.23
Comprehensive dietary histories were obtained with the use ofa validated food-frequency questionnaire modified for the Israelidiet. Vegetable consumption was categorized into three groupson the basis of the number of servings consumed per day in thecontrol group (fewer than 5.2, 5.2 to 7.5, and more than 7.5servings per day). The lowest category of consumption was usedas the reference category. Red-meat consumption was also categorizedinto three groups on the basis of the number of servings consumedper day in the control group. A participant's history of medicalconditions was elicited by asking whether he or she had everreceived a diagnosis of any of 15 medical conditions, includinghypercholesterolemia, ischemic heart disease, and inflammatorybowel disease.
Validation of Statin Use
Participants' reports of statin use were matched against CHSprescription records to verify use. Prescription records wereavailable for 1998 through 2004 and included the number of prescriptionsfilled per year. The prescription file was started in 1998,so any prescriptions filled before 1998 could not be validatedby this means. Prescription records for statins during the yearbefore diagnosis were reviewed for all patients who were invitedto participate in the study; for controls, prescription recordsduring the year before enrollment in the study were reviewed.In this way, potential differences between participating andnonparticipating patients and controls in terms of statin usewere evaluated.
Statistical Analysis
Statistical analyses were performed with the use of SAS software(version 8.2), and all reported P values are two-sided. A contingencytable was used to assess crude associations between statin useand the risk of colorectal cancer. Stratified analyses and unconditionallogistic regression were used to assess the association betweenstatin use and the risk of colorectal cancer, to adjust forconfounding, and to identify any potential effect modification.To account for the study design, matched analyses were performedwith the use of both contingency-table methods and conditionallogistic regression.
Results
Of the 3181 potentially eligible patients in whom colorectalcancer was ascertained during the study period, 618 (19.4 percent)could not be located or approached, including 275 (8.6 percent)who had died. Thus, 2563 patients were approached and invitedto participate. Forty-two were subsequently excluded as toosick to participate or unable to communicate in Hebrew, Russian,Arabic, or English. Of the 2521 remaining eligible patients,335 declined to participate (13.3 percent). Therefore, 2186eligible patients agreed to participate, and 2146 completedthe in-person interview, which corresponds to a response rateof 67.5 percent of all eligible patients. In addition, 2162matched controls provided consent and were interviewed, representing52.1 percent of the eligible controls who were invited to participate.Findings reported here are based on data from the 1953 patientsand 2015 controls, corresponding to 1651 matched pairs, forwhom data were available at the time of a planned analysis inJuly 2004. For ease of presentation, results are given firstfor the unmatched analysis and then for the matched analysis.
Ashkenazi Jews were overrepresented among the patients, a findingcorresponding to the known increased risk of colorectal canceramong Ashkenazi as compared with non-Ashkenazi Jews.24 Hypercholesterolemiawas reported in 20.9 percent of the patients and 26.2 percentof the controls (Table 1).
Table 1. Demographic Characteristics of the Study Population.
The use of statins for at least five years was reported moreoften by controls than by patients (11.6 percent vs. 6.1 percent)and was associated with a significant reduction in the riskof colorectal cancer (odds ratio, 0.50; 95 percent confidenceinterval, 0.40 to 0.63) (Table 2). After adjustment for potentialconfounders (including age; sex; the use or nonuse of aspirinor other NSAIDs; ethnic group; the presence or absence of sportsparticipation, hypercholesterolemia, and a history of colorectalcancer in a first-degree relative; and level of vegetable consumption),the association between statins and the reduced risk of colorectalcancer remained significant. The level of education and levelof red-meat consumption were also evaluated as potential confoundersbut were not included in the final model, since they did notmeasurably influence the odds ratio. Matched analyses of 1651pairs revealed that the crude and adjusted odd ratios for statinuse were similar in magnitude to those found in the unmatchedanalysis and remained significant (Table 3). When the analysiswas limited to the 1520 patients who were members of CHS, theassociation was unchanged (odds ratio, 0.50; 95 percent confidenceinterval, 0.39 to 0.64). The frequency of statin use increasedwith increasing year of detection among both patients (P fortrend = 0.08) and controls (P for trend = 0.02). After controllingfor the year of detection, we found that the association betweenstatin use and the reduced risk of colorectal cancer remainedvirtually unchanged (odds ratio, 0.51; 95 percent confidenceinterval, 0.40 to 0.64).
Table 3. Effect of Statins on the Risk of Colorectal Cancer, Colon Cancer, and Rectal Cancer in Matched Pairs.
Simvastatin and pravastatin were the two most commonly usedstatins in this population, accounting for 55.6 percent and41.5 percent of use, respectively. In unadjusted analyses, thestrength of the association between statin use (vs. no statinuse) and a reduced risk of colorectal cancer was similar forsimvastatin (odds ratio, 0.49; 95 percent confidence interval,0.36 to 0.67) and pravastatin (odds ratio, 0.44; 95 percentconfidence interval, 0.31 to 0.63).
To assess whether the association was due to a general effectof cholesterol lowering or to a specific effect of statins,we also evaluated the association between other cholesterol-loweringdrugs and the risk of colorectal cancer. Twenty-one patientsand 20 controls used the fibric-acid derivative bezafibrate.There was no significant association between bezafibrate useand the risk of colorectal cancer (odds ratio, 1.08; 95 percentconfidence interval, 0.59 to 2.01). It is worthwhile to notethat only 1 percent of the study population reported using bezafibrate,so it is unlikely that we would be able to identify small effectsassociated with the use of fibric-acid derivatives. No otherclass of cholesterol-lowering agent or specific drug was reportedas being commonly used.
After adjustment for the use of aspirin or other NSAIDs forat least five years as well as other risk factors for colorectalcancer, statin use was still associated with a significant reductionin the risk of colorectal cancer (odds ratio, 0.55; 95 percentconfidence interval, 0.40 to 0.74) (Table 4). Because of reportsof a synergistic effect in vitro between NSAIDs and statins,we evaluated whether the use of aspirin or other NSAIDs modifiedthe protective effect of statins. We could find no evidenceof an effect modification on a multiplicative scale (P=0.36).
Table 4. Crude and Adjusted Associations between the Use of Statins and Aspirin or Other NSAIDs and the Risk of Colorectal Cancer.
A stratified analysis was performed to determine whether statinsappeared equally protective among patients with and those withouta family history of colorectal cancer. The protective associationremained significant among patients with a family history ofcolorectal cancer (odds ratio, 0.41; 95 percent confidence interval,0.19 to 0.93), and we noted no interaction between family historyand statin use (P for interaction = 0.67).
We analyzed the data separately for cancers of the colon andthe rectum and observed a significant inverse association forboth (Table 3). Statin users were almost as likely as nonusersto have colorectal cancer diagnosed at an early stage of disease(stage I or II) as compared with a later stage (stage III orIV) (odds ratio, 0.90; 95 percent confidence interval, 0.54to 1.50; P=0.69). Colorectal cancer was somewhat less likelyto be poorly differentiated among statin users (6.4 percent)than among nonusers (8.6 percent), although this differencewas not significant (P=0.48).
To evaluate the possibility of confounding by indication, weinvestigated statin use and the risk of colorectal cancer amongpatients who reported a previous diagnosis of hypercholesterolemiaor ischemic heart disease, and the protective effect of statinswas similar in these patients (Table 5). Because of our interestin the antiinflammatory properties of statins, we also examinedthe relationship between statin use and the risk of colorectalcancer among 55 patients with inflammatory bowel disease, andwe observed a protective effect of statins in this subgroup(P=0.006 for the comparison between users and nonusers of statins)(Table 5).
Table 5. Association between Statin Use and the Risk of Colorectal Cancer among Participants with Hypercholesterolemia, Ischemic Heart Disease, or Inflammatory Bowel Disease.
We validated regular statin use on the basis of prescriptionrecords from the CHS database for the 286 self-reported statinusers who were members of CHS. When we classified regular usersof statins as persons who filled a prescription for statinsthree or more times per year, self-reports were validated for276 of 286 participants (96.5 percent). Self-reported use couldnot be confirmed on the basis of prescription records for sixpatients and four controls.
We also used data from prescription records to evaluate differencesin statin use among patients and controls who declined to participatein the study. The use of statins during the year before diagnosis(for patients) and the year before enrollment (for controls)was compared. No significant difference in the rate of statinuse was observed between patients who were interviewed and thosewho declined to participate (5.2 percent vs. 6.0 percent, P=0.51).The findings were similar among participating controls and thosewho declined to participate (6.3 percent and 5.7 percent, respectively;P=0.39).
Discussion
Our data indicate that there is a strong inverse associationbetween the risk of colorectal cancer and the long-term useof statins. This association is consistent with preclinicaldata suggesting that it is biologically plausible that statinsmay have a role in colorectal cancer, as well as with evidencefrom secondary analyses of some, but not all, randomized, controlledtrials. These data are also consistent with the results of asmall, nested case–control study from Quebec, Canada,that reported a significant reduction in the occurrence of allcancers among statin users as compared with persons who didnot use statins (but who did take bile acid–binding resinsto lower cholesterol) and a nonsignificant protective effectof statin use among 56 patients with colon cancer (odds ratio,0.83; 95 percent confidence interval, 0.37 to 1.89).25 A nestedcase–control study from the Netherlands also showed asignificant reduction in the incidence of all cancers amongstatin users as compared with nonusers, which increased withincreasing duration of use, and a nonsignificant reduction inrisk among 292 patients with colon cancer (odds ratio, 0.87;95 percent confidence interval, 0.48 to 1.57) and 148 patientswith rectal cancer (odds ratio, 0.48; 95 percent confidenceinterval, 0.16 to 1.48).26 In contrast, an analysis of datafrom the General Practice Research Database found a marginallyincreased risk of cancers of the colon and rectum among personswho had used statins for longer than 60 months as compared withthose who had not used statins.27 All these previous observationalstudies are limited by the small numbers of cases of colorectalcancer.
In vitro data suggest that statins may have a synergistic effectwith NSAIDs.28,29 However, our results do not provide evidenceof an interaction between statins and aspirin or other NSAIDs(P for interaction = 0.36). Rodent models may not perfectlyrepresent human disease, and it is worth noting that the endpoint in the rat azoxymethane model is polyp formation ratherthan the development of colorectal cancer.
Statins have been shown to be associated with an acceptableadverse-effect profile in patients with hypercholesterolemia,30with a discontinuation rate of approximately 3 percent owingto such effects.31 If statins were to be considered for chemopreventivestudies in subjects without elevated cholesterol levels, thesafety of such an application would need to be evaluated inthis population.
We evaluated the potential absolute reduction in the risk ofcolorectal cancer after treatment with statins by estimatingthe number of cancers that could be prevented by statin usein both the Israeli population and a high-risk population. In2002, the age-adjusted incidence of colorectal cancer was 42per 100,000 Jewish men,32 and the rate was similar among Jewishwomen. Using the matched, adjusted odds ratio of 0.53 as anapproximation for the relative risk in order to calculate theabsolute reduction in risk,33 we determined that statin therapycould prevent 20.8 cases per 100,000 Jewish men. In the average-riskIsraeli population, 4814 persons would need to be treated withstatins to prevent one case of colorectal cancer. In a high-riskpopulation, such as those with a family history of colorectalcancer, approximately half as many would need to be treatedin order to prevent one case.
Our study has several limitations. Exposure data were collectedretrospectively and are therefore sensitive to recall bias.However, since participants are not likely to expect that theuse of statins is related to the risk of colorectal cancer,any resulting misclassification is most likely nondifferentialand would tend to attenuate true associations. Furthermore,we were able to validate self-reported statin use through aprescription database. The participation rate was lower amongcontrols than among patients, suggesting the possibility ofselection bias. Selection bias seems unlikely, however, sincethe rate of statin use was similar among those who participatedand those who declined. It is also possible that some controlshad undiagnosed colorectal cancer, and this type of misclassificationwould be likely to attenuate any observed association. Assessmentof potential confounders was also self-reported; measurementerror for these variables could limit our ability to controladequately for confounding. We had very limited informationon the dose and duration of use of statins and therefore couldnot analyze the data for evidence of a dose response.
We found that the use of statins is associated with a 47 percentrelative reduction in the risk of colorectal cancer after adjustmentfor other known risk factors and is specific to this class oflipid-lowering agents. Our finding suggests that statins deservefurther investigation in chemoprevention and therapeutic clinicaltrials.
Supported by a grant (1R01CA81488) from the National CancerInstitute; by gifts from the Ravitz Foundation and the WeinsteinFoundation; and by a grant (T32 HG000040, to Ms. Poynter) fromthe National Institutes of Health.
Dr. Greenson reports having served as an expert witness forParke-Davis (now Pfizer) with respect to a class of medicationsnot discussed in this article. Mr. Bonner reports having beenemployed by Parke-Davis (now Pfizer) and owning stock in Pfizer.
Source Information
From the Departments of Epidemiology (J.N.P., S.B.G.), Internal Medicine (S.B.G., P.D.R.H., J.D.B.), Human Genetics (S.B.G.), and Pathology (J.K.G.), University of Michigan, Ann Arbor; and the Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology and Clalit Health Services National Cancer Control Center — both in Haifa, Israel (R.A., H.S.R., M.L., G.R.).
Address reprint requests to Dr. Gruber at the Division of Molecular Medicine and Genetics, University of Michigan, 4301 MSRB III, Ann Arbor, MI 48109-0638, or at sgruber{at}umich.edu.
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Statins and the Risk of Colorectal Cancer
Setoguchi S., Avorn J., Schneeweiss S., Maisonneuve P., Eng. , Lowenfels A. B., Welch H. G., Poynter J. N., Gruber S. B., Rennert G.
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