The impact of renin-angiotensin system inhibitors on colorectal neoplasm development

Background: Renin-angiotensin system (RAS) inhibitors have shown potential chemopreventive effects against colorectal cancer (CRC).However, little is known about the impact of RAS inhibitors on the risk of colorectal precancerous lesions.Methods: Preclinically, we established mouse models of colitis-associated colon cancer and xenografts: vehicle, 1 mg/kg, 5 mg/kg enalapril groups.Body weight, colon length, and colorectal tumor size were evaluated on the euthanization day.Clinically, we retrospectively recruited 8,388 asymptomatic adults undergoing their first-ever colonoscopy for health check-ups (index cohort).From the index cohort, we selected individuals undergoing follow-up colonoscopy (follow-up cohort).The study outcome was incidental and recurrent colorectal neoplasms, including CRC.We evaluated the prevalence and risk of colorectal neoplasms associated with RAS inhibitor use of ≥ 1 year.Results: In the experimental study, enalapril administration significantly attenuated weight loss and colon shortening, reduced tumor numbers in colitis-associated colon cancer models, and decreased tumor volume in the xenografts.In the index cohort, while the initial analysis showed a positive association with the RAS inhibitor use (unadjusted odds ratio [OR], 1.22), this shifted toward an inverse trend after adjusting for confounders (adjusted OR, 0.91).During follow-up (median, 41.0 months), incidental and recurrent colorectal neoplasms were less common in the RAS inhibitor group (32.6%) than in the other anti-hypertensives group (39.1%) (P < 0.001), despite similar intervals between the index and follow-up endoscopies.In the follow-up cohort, hypertension itself was a risk factor for colorectal neoplasm development (adjusted hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.00-2.53;P = 0.049), whereas RAS inhibitor use was significantly associated with a 27% lower risk (adjusted HR, 0.73; 95% CI, 0.59-0.95;P = 0.035).Conclusions: Long-term, regular use of RAS inhibitors independently reduces the risk of colorectal neoplasms, irrespective of dosage or drug type.Given their potential chemopreventive effects on colorectal neoplasms, RAS inhibitors may serve as a preventive strategy starting from the precancerous stage.