Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases

doi:10.1016/j.cgh.2016.02.017

Clinical Gastroenterology and Hepatology

Volume 14, Issue 7, July 2016, Pages 973-979

https://doi.org/10.1016/j.cgh.2016.02.017 Get rights and content

Background & Aims

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Chemopreventive strategies have produced weak or inconsistent results. Statins have been associated inversely with sporadic CRC. We examined their role as chemopreventive agents in patients with IBD.

Methods

We collected data from 11,001 patients with IBD receiving care at hospitals in the Greater Boston metropolitan area from 1998 through 2010. Diagnoses of CRC were determined using validated International Classification of Diseases, 9th revision, Clinical Modification codes. Statin use before diagnosis was assessed through analysis of electronic prescriptions. We performed multivariate logistic regression analyses, adjusting for potential confounders including primary sclerosing cholangitis, smoking, increased levels of inflammation markers, and CRC screening practices to identify an independent association between statin use and CRC. We performed sensitivity analyses using propensity score adjustment and variation in the definition of statin use.

Results

In our cohort, 1376 of the patients (12.5%) received 1 or more prescriptions for a statin. Patients using statins were more likely to be older, male, white, smokers, and have greater comorbidity than nonusers. Over a follow-up period of 9 years, 2% of statin users developed CRC compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24–0.53). On multivariate analysis, statin use remained independently and inversely associated with CRC (odds ratio, 0.42; 95% confidence interval, 0.28–0.62). Our findings were robust on a variety of sensitivity and subgroup analyses.

Conclusions

Statin use was associated inversely with the risk of CRC in a large IBD cohort. Prospective studies on the role of statins as chemopreventive agents are warranted.

Section snippets

Study Population

The population for this study consisted of a cohort of patients with CD or UC receiving care at 1 of 2 referral hospitals serving the Greater Boston metropolitan area. The development of this cohort has been described previously.27, 28, 29, 30 We identified all eligible patients with at least 1 International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) code for CD (555.x) or UC (556.x). By using a combination of ICD-9-CM codes for disease complications and

Results

Our study consisted of 11,001 patients with IBD among whom 1376 (12.5%) received 1 or more prescriptions for a statin (Table 1). Statin users were likely to be older, male, and white compared with nonusers. They were also more likely to have UC (62% vs 49%), although being less likely to require immunomodulator or anti-TNF biologic therapy use when compared with nonusers. Statin use also was associated with lower rates of surgery (8% vs 13%) and hospitalization (28% vs 31%) (P < .05 for both).

Discussion

Colorectal cancer is an important cause of morbidity and mortality in patients with inflammatory bowel diseases.1, 2, 3, 4, 5, 6 The efficacy of chemopreventives in reducing this risk has been weak and inconsistent, limited by the quality of data, much of which are from small cohorts or inadequately adjust for confounding disease-related factors.5, 6, 34 In this study, we used a large cohort of IBD patients with a long follow-up period to show a strong and robust inverse association between use

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Statin use and risk of colorectal cancer in patients with inflammatory bowel disease
2023, eClinicalMedicine
Statin use has been linked to a reduced risk of advanced colorectal adenomas, but its association with colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) - a high risk population for CRC - remains inconclusive.
From a nationwide IBD cohort in Sweden, we identified 5273 statin users and 5273 non-statin users (1:1 propensity score matching) from July 2006 to December 2018. Statin use was defined as the first filled prescription for ≥30 cumulative defined daily doses and followed until December 2019. Primary outcome was incident CRC. Secondary outcomes were CRC-related mortality and all-cause mortality. Cox regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).
During a median follow-up of 5.6 years, 70 statin users (incidence rate (IR): 21.2 per 10,000 person-years) versus 90 non-statin users (IR: 29.2) were diagnosed with incident CRC (rate difference (RD), −8.0 (95% CIs: −15.8 to −0.2 per 10,000 person-years); aHR = 0.76 (95% CIs: 0.61 to 0.96)). The benefit for incident CRC was duration-dependent in a nested case-control design: as compared to short-term use (30 days to <1 year), the adjusted odd ratios were 0.59 (0.25 to 1.43) for 1 to <2 years of use, 0.46 (0.21 to 0.98) for 2 to <5 years of use, and 0.38 (0.16 to 0.86) for ≥5 years of use (P _{for tread} = 0.016). Compared with non-statin users, statin users also had a decreased risk for CRC-related mortality (IR: 6.0 vs. 11.9; RD, −5.9 (−10.5 to −1.2); aHR, 0.56 (0.37 to 0.83)) and all-cause mortality (IR: 156.4 vs. 231.4; RD, −75.0 (−96.6 to −53.4); aHR, 0.63 (0.57 to 0.69)).
Statin use was associated with a lower risk of incident CRC, CRC-related mortality, and all-cause mortality. The benefit for incident CRC was duration-dependent, with a significantly lower risk after ≥2 years of statin use.
This research was supported by Forte (i.e., the Swedish Research Council for Health, Working Life and Welfare).
Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management
2022, Gastroenterology
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC), despite decreases in CRC incidence in recent years. Chronic inflammation is the driver of neoplastic progression, resulting in dysplastic precursor lesions that may arise in multiple areas of the colon through a process of field cancerization. Colitis-associated CRC shares many molecular similarities with sporadic CRC, and preclinical investigations have demonstrated a potential role for the microbiome in concert with the host immune system in the development of colitis-associated colorectal cancer (CAC). Some unique molecular differences occur in CAC, but their role in the pathogenesis and behavior of inflammation-associated cancers remains to be elucidated. Nonconventional types of dysplasia have been increasingly recognized, but their natural history is not well defined, and they have not been incorporated into surveillance algorithms. The concept of cumulative inflammatory burden highlights the importance of considering histologic inflammation over time as an important risk factor for CAC. Dysplasia is arguably the most important risk factor for developing CAC, and advances have been made in the endoscopic detection and removal of precancerous lesions, thereby deferring or avoiding surgical resection. Some of the agents used to treat IBD are chemopreventive. It is hoped that by gaining better control of the underlying inflammation with newer medications and better endoscopic detection and management, a more sophisticated appreciation of clinicopathologic risk factors, and growing awareness of the genetic, immunologic, and environmental causes of colitis- associated neoplasia, that colitis-associated colorectal neoplasia will become even more predictable and manageable in the coming years.
Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis
2021, Gastroenterology
Citation Excerpt :
Our pooled univariable analysis of 4 studies did not show a protective effect (OR, 0.71; 95% CI, 0.14-3.67). One cohort study did not report a protective effect of anti-TNF-α in a multivariable model (OR, 1.01; 95% CI, 0.62-1.65).32 One case-control study showed a protective effect of anti-TNF-α in a multivariable hazard model (HR, 0.22; 95% CI, 0.10-0.50) (Supplementary File 33A–E).33
Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). We performed a systematic review and meta-analysis to identify all prognostic factors for advanced colorectal neoplasia (aCRN, high-grade dysplasia, or CRC) in patients with IBD.
A systematic literature search was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Risk of bias was assessed using the Quality in Prognostic Studies tool. Random-effects models were created separately for odds and hazard ratios, different study designs, and univariable or multivariable data. The evidence for all prognostic factors was categorized as “weak”, “moderate”, or “strong”, based on estimate of effect sizes, heterogeneity, and risk of bias.
A total of 164 studies were included, allowing pooled analysis of 31 potential prognostic factors. In the univariable analysis, the evidence for extensive disease was classified as strong while evidence for low-grade dysplasia, strictures, primary sclerosing cholangitis, post-inflammatory polyps, family history of CRC, and ulcerative colitis versus Crohn’s disease was considered moderate. Evidence for any dysplasia, colon segment resection, aneuploidy, male sex, and age was classified as weak. In addition, histologic inflammation was identified as a risk factor in multivariable analysis (weak evidence). The evidence for the protective factors colonoscopic surveillance, 5-Aminosalicylic Acid, thiopurines, and smoking was moderate in univariable analysis. Multivariable analysis provided weak evidence for statin use.
In this systematic review and meta-analysis, we identified 13 risk factors and 5 protective factors for aCRN in IBD patients, based on univariable and/or multivariable pooled analyses. These findings might lay the groundwork for an improved CRC risk stratification-based surveillance in IBD.
Preventing Colitis-Associated Colon Cancer With Antioxidants: A Systematic Review
2021, Cellular and Molecular Gastroenterology and Hepatology
Citation Excerpt :
Other synthetic compounds such as GL-V9, a flavonoid derivative with strong antioxidant and anti-inflammatory activities, protect against tumorigenesis in a CAC model through NLRP3 inflammasome degradation.100 Statins were found to reduce CAC in IBD patients in one study101 but not in another study.102 Among natural antioxidants, vitC reduces oxidative DNA damage by neutralizing mutagenic ROS and RNI3,103 and protects from inflammation-associated tumorigenesis in different animal models of CAC.3
Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers.
Associations Between Drug Exposure and Outcomes in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Disease
2020, Clinical Gastroenterology and Hepatology
Statins and inflammatory bowel disease: Where do we stand?
2020, European Journal of Internal Medicine
Citation Excerpt :
Other clinical studies reported a beneficial effect of statins in patients with multiple sclerosis and systemic lupus erythematosus [61,62]. Experimental evidence shows anti-inflammatory and immunomodulatory effects of statin use, suggesting a possible role of this class of drugs in IBD and autoimmune disorders [14,63–74]. The inhibition of the mevalonate pathway causes the reduction of farnesylpyrophosphates and geranylgeranylpyrophosphates permitting the attachment of different GTPases to the cell membrane [64].
Inflammatory bowel disease is a chronic autoimmune disorder of the western world that is rapidly expanding in newly industrialized countries. Novel strategies are urgently needed to prevent and improve the treatment of this costly and disabling disease. Statins are the most commonly prescribed drugs worldwide. Besides their lipid-lowering effects, statins may exert complex immunomodulatory properties and multiple pleiotropic effects including the inhibition of T-cell activation, antigen-presenting function and leukocyte infiltration of target organs which might render statins as beneficial agents for inflammatory and autoimmune conditions. In this review, we summarize the experimental findings on the topic, and critically appraise the epidemiological evidence regarding the value of statins as a potential strategy for preventing and treating inflammatory bowel disease.
Several experimental studies have shown that statins reduce inflammation in animal models of colitis; however, clinical studies investigating their disease-modifying and preventive potential in IBD have demonstrated some limitations and conflicting results. The available epidemiological evidence is not yet sufficient to support the use of statin for preventing or treating inflammatory bowel disease. Additional high-quality research is warranted.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by National Institutes of Health (U54-LM008748 to I.K.); the American Gastroenterological Association and the US National Institutes of Health (K23 DK097142 to A.N.A.); National Institutes of Health grant K08 AR060257 and the Harold and Duval Bowen Fund (K.P.L.); and supported by grants from the National Institutes of Health (K24 AR052403, P60 AR047782, and R01 AR049880 to E.W.K.).

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Original articleAlimentary tractStatin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Population

Results

Discussion

Gastroenterol Clin North Am

J Crohns Colitis

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

J Crohns Colitis

J Chronic Dis

J Am Med Inform Assoc

Best Pract Res Clin Gastroenterol

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Colorectal cancer in patients with inflammatory bowel disease: can we predict risk?

World J Gastroenterol

Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002)

Gut

Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk?

World J Gastroenterol

AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease

Gastroenterology

Review article: colorectal carcinoma and inflammatory bowel disease

Aliment Pharmacol Ther

Original article
Alimentary tract
Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases