Antihypertension and Colorectal Cancer Prevention: Getting Two Birds With One Stone?

Abstract

risk factors for CRC, long-term use of aspirin and nonsteroidal anti-inflammatory drugs can substantially reduce CRC risk. Given the complex lifestyle and medication pattern, it is difficult to determine the direction of aggregate confounding. Although the investigators considered several potential confounders, according to the criterion of “including only factors leading to change of at least 10% in the association,” only the average number of physician contacts after the incident diagnosis of hypertension was adjusted in addition to the matching factors (ie, sex, age, calendar period and duration of follow-up after diagnosis of hypertension before the index date). Although physician visits might reflect disease severity to a certain extent, many factors can influence patients’ contacts with doctors, and thus adjustment for this single composite factor may not address the complicated confounding pattern in this study. On the other hand, adjustment for physician visits could induce selection bias because both drug use and subclinical symptoms or important risk factors (eg, family history) for CRC can lead to more frequent physician visits (10). This is more notable when a statistically significant association with 3 or more years of ACEI/ARB therapy emerges only after such adjustment (crude relative risk [RR] = 0.92, 95% confidence interval [CI] = 0.79 to 1.08; adjusted RR = 0.84, 95% CI = 0.72 to 0.98), whereas statistically significant associations with some other agents disappear after the adjustment (for ≥5 years of diuretics use: crude RR = 0.80, 95% CI = 0.65 to 0.98; adjusted RR = 0.85, 95% CI = 0.70 to 1.05; for ≥5 years of beta-blocker use: crude RR = 0.80, 95% CI = 0.67 to 0.95; adjusted RR = 0.85, 95% CI = 0.71 to 1.01). Again, aggregation of small biases can induce a spuriously moderate association. Given the findings by Makar et al. (9), an obvious question arises: What is the mechanism if ACEI/ARB therapy really reduces CRC risk among hypertension patients? Accumulating data indicate that the renin-angiotensin system (RAS), the target of ACEI and ARB action, is frequently dysregulated in malignancy. Abnormalities in the RAS signaling influence proliferation and apoptosis of cancer cells and promote angiogenesis and formation of cancer inflammatory microenvironment (11). Some experimental data suggest an anticarcinogenic role of RAS inhibitors in colorectal tumors, although the exact mechanisms remain largely unclear. Recent in vivo evidence demonstrates that ACEI or ARB administration substantially reduces the total number of colonic premalignant lesions and decreases oxidative stress and expression of inflammatory cytokines in metabolically disordered mice, suggesting that suppression of inflammation might mediate the effect