Elsevier

Annals of Epidemiology

Volume 22, Issue 1, January 2012, Pages 17-27
Annals of Epidemiology

Prospective Analysis of Association Between Use of Statins or Other Lipid-Lowering Agents and Colorectal Cancer Risk

This study was presented in part at the 2010 AACR Frontiers in Cancer Prevention, Philadelphia, PA.
https://doi.org/10.1016/j.annepidem.2011.10.006Get rights and content

Purpose

To determine whether 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) are associated with a decreased risk of colorectal cancer.

Methods

The population included 159,219 postmenopausal women enrolled in the Women’s Health Initiative in which 2000 pathologically confirmed cases of colorectal cancer were identified during an average of 10.7 (S.D. 2.9) years. Information on statins was collected at baseline and years 1, 3, 6, and 9. Self- and interviewer-administered questionnaires were used to collect information on other risk factors. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by the use of Cox proportional hazards regression to evaluate the relationship between statin use and risk. Statistical tests were two-sided.

Results

Statins were used by 12,030 (7.6%) women at baseline. The annualized colorectal cancer rate was 0.13% among users and 0.12% among nonusers. The multivariable adjusted HR for users versus nonusers was 0.99 (95% confidence interval [CI], 0.83–1.20, p = .95), and 0.79 (95% CI, 0.56–1.11) for users of ≥3 years. In the multivariable adjusted time-dependent model, the HR for lovastatin was 0.62 (95% CI, 0.39–0.99). There was no effect of tumor location, stage or grade.

Conclusions

There was a reduction in colorectal cancer risk associated with lovastatin and a nonsignificant association with longer duration of use.

Introduction

Colorectal cancer is the third-leading cause of cancer incidence and death among women in the United States, with an estimated 70,480 new cases and 24,790 deaths reported in 2010 (1). With the appropriate use of treatment, colorectal cancer is potentially curable, especially if discovered at an early stage; however, the clinical presentation can be insidious, and patients frequently present at an advanced stage (2). Although regular screening of asymptomatic patients by fecal occult blood testing, sigmoidoscopy, or colonoscopy is effective in decreasing the mortality associated with colorectal cancer, the majority of the population receives no screening or inadequate screening 3, 4, and rates of screening are much lower than for other common malignancies. The high death rate from colorectal cancer and inadequate acceptance of screening support the need to focus on chemoprevention as a way to more effectively impact colorectal cancer mortality.

A number of measures, including regular intake of aspirin or nonsteroidal anti-inflammatory drugs (5), calcium and vitamin D intake (6), and dietary changes including increased fiber (7) and whole grain intake (8), have been associated with lower colorectal cancer risk in observational studies; however, validation by randomized controlled trials have been disappointing 9, 10. Colorectal cancer involves the progression through well-defined morphological, cellular, and genetic events in the adenoma to carcinoma pathway (11). Statins are a logical candidate for chemoprevention in that they have pleiotropic effects in addition to cholesterol-lowering including, inhibition of rho GTPases 12, 13, 14, induction of apoptosis 12, 15, 16, 17, 18, decrease in markers of chronic inflammation (19), inhibition of cell proliferation 20, 21, 22, and decrease in formation and progression of aberrant crypt foci (23). In a population based case-control study, Poynter et al. (24) demonstrated a 47% reduction in colorectal cancer risk among users of statins for 5 or more years. The relationship between statins and reduction in colorectal cancer risk has been reviewed in four recently completed meta-analyses 25, 26, 27, 28. Overall, the authors of observational studies have shown a modest reduction in risk; however, these findings have not been demonstrated in randomized controlled trials.

The purpose of this study was to test whether statins and other lipid-lowering agents are associated with a lower risk of colorectal cancer among participants in the Women’s Health Initiative (WHI), which is the largest multicenter longitudinal study of postmenopausal women in the United States. In the WHI, detailed information on statin use and duration of use was collected at study entry, and additional follow-up information was collected at years 1, 3, 6, and 9. Cancer outcome data is available for an average (SD) of 10.7 (2.9) years of follow-up.

Section snippets

Study Population

The WHI includes an observational study (OS; n = 93,676) and three clinical trials (CTs; n = 68,132) of hormone therapy, dietary modification, and calcium/vitamin D supplementation in postmenopausal women of mixed race and ethnicity (29). Recruitment was conducted between October 1, 1993, and December 31, 1998, at 40 clinical centers in the United States. Eligibility criteria included women ages 50–79 years who were postmenopausal, planned to remain in area where they were recruited, and had an

Results

The WHI cohort consisted of 12,030 statin users (7.6%)at baseline. Table 1 shows characteristics of WHI participants by statin use. Although most of the absolute differences between statin users and nonusers were small, many were statistically significant because of the large sample size. Statin users were more likely to be older than nonusers (mean age, SD, 65.6 [6.5] and 63.0 [7.2] years, respectively) and to have a greater BMI (28.9 [5.5] and 27.9 [6.0] kg/m2). Statin use was associated with

Discussion

We hypothesized that statins are associated with a lower risk of colorectal cancer on the basis of in vitro and in vivo data suggesting that the mechanism of anticancer effects are through inhibition of small GTPases (Ras and Rho) 12, 13, 14 induction of apoptosis 12, 16, 17, 18, 25, and regression of aberrant crypt foci (23). The authors of previous epidemiologic studies have reported an association of statins with either a reduction in risk of cancer overall 40, 41, or specifically a

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    The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The study was also funded by the Cancer Center Support Grant NIH: NCI P30CA022453.

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