Abstract
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.