Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

Highlights

• Angiotensin-converting enzyme inhibitors protect against colorectal cancer.

• This effect is limited to males and people under 65 years old.

• The stronger association is observed in proximal colon.

Abstract

The potential protective effect of renin–angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3912 population controls frequency matched (by age, sex and region) from the Spanish multicenter case-control study MCC-Spain. We found a significant protective effect of the angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65 years group (OR = 0.65 95%CI (0.48–0.89)) and to a lesser degree to men (OR = 0.81 95%CI (0.66–0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65 years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65 years old, which increases in proximal colon in the latter. If confirmed, these results may suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location.

Introduction

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide with approximately 450,000 new cases detected in Europe in 2012 (Arnold et al., 2015, Ferlay et al., 2013). In the last decades, the field of chemoprevention has experimented a rising interest, with the use of certain drugs to reduce the individual risk of cancer. Nowadays, the role of aspirin therapy in the reduction of colorectal cancer risk and precancerous adenomas (Flossmann and Rothwell, 2007, Cole et al., 2009) is well known and there is increasing evidence of the chemopreventive effect of many others drugs used for cardiovascular diseases such as statins (Bardou et al., 2010) and renin-angiotensin system (RAS) inhibitors (Mansouri et al., 2013). In addition, recent observational studies and one meta-analysis have shown a protective effect of RAS therapy against CRC (Azoulay et al., 2012, Kedika et al., 2011, Makar et al., 2014, Dai et al., 2015). Despite these encouraging findings, other studies have yielded conflicting results (Hallas et al., 2012, Sipahi et al., 2010, Yoon et al., 2011), calling for additional studies before recommending the clinical use of RAS inhibitors for CRC chemoprevention. The mechanism of action of the RAS-inhibitors combines both pro and antitumor effects, probably explain the controversial results obtained in observational studies. Moreover, the potential interaction with lifestyle factors (eg, diet) warrants more investigation (Song and Giovannucci, 2014). Finally, it is important to identify whether there is a differential effect regarding the tumor anatomic subsite, given that, to the best of our knowledge, no previous studies have analyzed these aspects.

Therefore, the purpose of this work is to evaluate the effects of angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) on overall colorectal cancer risk, and on its different anatomic locations, in a large population-based case-control study conducted in Spain, the MCC-Spain study.