© The Author 2006. Published by Oxford University Press.
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Cholesterol-Lowering Drugs and Colorectal Cancer Incidence in a Large United States Cohort
Affiliation of authors: Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA
Correspondence to: Eric J. Jacobs, PhD, Epidemiology and Surveillance Research, American Cancer Society, National Home Office, 1599 Clifton Road NE, Atlanta, GA 30329 (e-mail: Eric.Jacobs{at}cancer.org).
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ABSTRACT |
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3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, account for most cholesterol-lowering drug use in the United States. A recent large case-control study reported that use of statins for more than 5 years was associated with a 47% reduction in risk of colorectal cancer. No other large studies have examined this association. We examined the association between use of cholesterol-lowering drugs and colorectal cancer incidence among 132 136 men and women in the Cancer Prevention Study II Nutrition Cohort. We identified 815 incident cases of colorectal cancer among study participants during follow-up from the date of completion of a study questionnaire in 1997 through August 31, 2001. Current use of cholesterol-lowering drugs was not associated with colorectal cancer incidence (multivariable adjusted rate ratio [RR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.26). Current use of cholesterol-lowering drugs for 5 years or more was also not associated with colorectal cancer incidence (multivariable adjusted RR = 1.09, 95% CI = 0.83 to 1.43). Our results do not support the hypothesis that statin use strongly reduces risk of colorectal cancer. However, we cannot rule out a small reduction in risk or an effect associated with only specific types or doses of statins.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, were introduced in the United States in 1987, and by 1997, approximately 86% of users of cholesterol-lowering drugs were using statins (1). Several different statins inhibit colorectal carcinogenesis in rodent models (2–6). Results from studies of statin use and colorectal cancer are summarized in Table 1. The largest is the Molecular Epidemiology of Colorectal Cancer (MECC) study, a case-control study conducted in Israel (7) which included 1953 case patients diagnosed with colorectal cancer between 1998 and 2004 and 2015 control subjects. The MECC study found that statin use of more than 5 years was associated with a 47% reduction in risk of colorectal cancer (7). There was no apparent association between colorectal cancer and use of bezafibrate, the most commonly used nonstatin cholesterol-lowering drug, although the statistical power to investigate this association was limited (7). In contrast to results from the MECC study, none of the eight previous, small prospective studies found a statistically significant association between statin use and the risk of colorectal cancer, although none of these studies specifically examined long-duration use (8–15). Four of these studies were randomized trials (8–11), and four were observational analyses that used prospectively collected information from pharmacy databases (12–15).
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We examined the association between use of cholesterol-lowering drugs and colorectal cancer incidence in the Cancer Prevention Study II (CPS-II) Nutrition Cohort during the period from the date of completion of a study questionnaire in 1997 through August 31, 2001. We considered overall use of cholesterol-lowering drugs to be a reasonable surrogate measure for use of statins because during this period, most users of cholesterol-lowering drugs took statins. The CPS-II Nutrition Cohort includes adults in the United States and is described in detail elsewhere (16). The Emory University Institutional Review Board approved all aspects of the CPS-II Nutrition Cohort. Participants completed a questionnaire at enrollment in 1992 and were sent follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers in the fall of 1997, 1999, and 2001. For this analysis, follow-up began at completion of the 1997 questionnaire, because data from retail pharmacies in the United State indicate that approximately 86% of those on cholesterol-lowering drugs used statins in 1997, compared with 62% in 1992 (1). After exclusions for history of colorectal cancer, loss to follow-up, and incomplete information, 132 136 participants remained for analysis. Among these participants, we ascertained 815 incident cases of colorectal cancer from the date of completion of the 1997 questionnaire through August 31, 2001. Cases of colorectal cancer were identified by self-reports of cancer on the follow-up questionnaires (subsequently verified by obtaining medical records or by state cancer registries) (16) or through linkage with the National Death Index (17).
The 1997 questionnaire asked participants if they had taken any "cholesterol-lowering drugs" regularly during the past year and provided, as examples, the brand names for four statins commonly used at that time (lovastatin, pravastatin, simvastatin, and fluvastatin) (1), as well as the brand names for the fibrate drug gemfibrozil and the bile acid-binding resin cholestyramine. Information on past use of cholesterol-lowering drugs was available from the 1992 questionnaire, which included a similar question.
We used Cox proportional hazards modeling (18) to calculate rate ratios for colorectal cancer incidence. We categorized use of cholesterol-lowering drugs as never, former, or current, with a time-dependent variable initially defined by use reported in 1997 and updated by use reported in 1999. Current users were further categorized as having less than 5 years of drug use if they did not report use in 1992 or 5 years or more of drug use if they reported use in 1992. The proportional hazards assumption was verified by modeling interactions between cholesterol-lowering drug exposure and a linear time variable.
As expected, the great majority of people who used cholesterol-lowering drugs in 1997 reported being told by a physician that they had "elevated cholesterol," although elevated cholesterol was not uncommon among nonusers (Table 2). Users of cholesterol-lowering drugs were more likely than nonusers to report a history of heart attack, to use nonsteroidal anti-inflammatory drugs regularly, to eat less red meat, and to have had colorectal endoscopy.
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Current use of cholesterol-lowering drugs (rate ratio [RR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.26) and even current use of 5 years or more (RR = 1.09, 95% CI = 0.83 to 1.43) was not associated with colorectal cancer (Table 3). No association between use of cholesterol-lowering drugs and colorectal cancer was observed in subgroups defined by sex, use of nonsteroidal anti-inflammatory drugs, or history of colorectal endoscopy. Similarly, no association with use of cholesterol-lowering drugs was observed in analyses by stage of colorectal cancer at diagnosis or by anatomic subsite (proximal colon, distal colon, or rectum). Results were similar when the first 2 years of follow-up were excluded (RR for
5 years of use = 1.05, 95% CI = 0.67 to 1.64).
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Our null results are similar to those of previous small prospective studies (8–15) but differ from the 47% reduction in risk associated with long-duration statin use in the large MECC case-control study (7). Although our study population was from the United States and the MECC study population consisted predominantly of Israeli Jews, we know of no clear reason to expect a different association between statin use and colorectal cancer in these two populations. Variation in the types of statins used seems unlikely to fully account for the differing results. In the MECC study, pravastatin and simvastatin accounted for nearly all statin use, and each of these statins was associated with a similar reduction in risk, suggesting a general effect of statins, rather than of any one specific type. Moreover, pravastatin and simvastatin were the two most commonly prescribed statins in the United States in 1997 (1), the start of follow-up in our study. It is possible that selection bias or recall bias contributed to the reduction in risk observed in the MECC case-control study. Alternatively, because we examined use of all cholesterol-lowering drugs as a surrogate measure for statin use, misclassification of statin use could have obscured a modest reduction in risk in our study. However, such misclassification appears unlikely to have obscured a strong reduction in risk. On the basis of national data, the prevalence of statin use among all users of cholesterol-lowering drugs was approximately 62% in 1992 and 86% in 1997 (1). If we apply these prevalences to our results, we can estimate that 53% of participants reporting use of cholesterol-lowering drugs in both 1992 and 1997 were using statins in both years (0.62 x 0.86). If using statins for 5 years or more caused a 47% reduction in risk, we would have expected to observe a 25% reduction in risk (0.53 x 0.47), equivalent to a rate ratio of 0.75, which is not consistent with our observed risk estimate (RR = 1.09, 95% CI = 0.83 to 1.43).
Our results do not support the hypothesis that statins, as a class of drugs, strongly reduce risk of colorectal cancer. However, we cannot rule out a small reduction in risk or an effect associated with only specific types or doses of statins.
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Manuscript received June 10, 2005; revised October 13, 2005; accepted October 21, 2005.
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