Response to the letter regarding article, “The impact of renin-angiotensin system inhibitors on colorectal neoplasm development”

First, we agree that subgroup analyses based on drug class, as well as evaluations of doseresponse or duration-response relationships, would provide further insights into the specific effects of renin-angiotensin system (RAS) inhibitors on colorectal neoplasm risk.In our cohort, only 3 participants (2.2%) of the follow-up cohort were prescribed angiotensinconverting enzyme (ACE) inhibitors, and each received a different agent (captopril, ramipril, and perindopril).This was consistent with national prescription trends in Korea, as reported in the Fact Sheet published by the Korean Society of Hypertension (https://drive.google. com/file/d/1bCuaVFuQpq6R4XoNyG_OcJIRlpj8fIMd/view).Therefore, we were unable to perform subgroup analyses according to drug class.However, in the preclinical model, we demonstrated the chemopreventive effect of ACE inhibitors (enalapril) on the development of colorectal tumors.Furthermore, recent data have shown that both ACE inhibitors and angiotensin receptor blocker (ARB) exert anti-tumorigenic effects by blocking angiotensin receptors on the colonic epithelial cell membrane, as shown in Fig. 4 of the original article.Based on these findings, we evaluated the preventive effect of RAS inhibitors as a combined class.In addition, we defined RAS inhibitor exposure as 1 year of continuous use to minimize misclassification and ensure a biologically relevant exposure window.Although medication use was verified through self-reported questionnaires ("Have you been prescribed and taken any of the following medications in the past year?")and trained nurse interviews, detailed information on exact dosage and total duration was unfortunately not available due to the retrospective design and lack of written informed consent.Nevertheless, in the azoxymethane-dextran sulfate sodium and xenograft models, tumor number and volume were comparable between low-and high-dose enalapril groups.As stated in our original paper, further studies with larger sample sizes are required to determine the optimal dosage and duration for a clinically meaningful chemopreventive effect.