Proton pump inhibitors (PPIs) use is associated with hypergastrinemia and gut microbiota alteration. Concern over the risk that these factors may increase chances of colorectal cancer (CRC) has risen. To investigate the association between PPIs use and CRC using a large population-based cohort and examine whether the PPIs may differ regarding the risk of CRC.

We conducted a nationwide cohort study using a database from Taiwan National Health Insurance followed up longitudinally from 1999 through 2011. Patients with PPIs use were compared with non-use controls at a 1:1 ratio, for age, sex, comorbidities, and medications. We performed Cox proportional-hazards regression analysis to estimate the association between PPIs use and the development of CRC.

Among the 45382 eligible PPIs users, 172 (0.4%) developed CRC during a median follow-up of 5.4 years. PPIs use was associated with a higher risk of CRC with an adjusted HR of 2.03 (95% CI 1.56–2.63, P<0.001). The risk increased with more frequent use of PPIs (HR 1.59, 95% CI 1.19–2.14; 2.59, 95% CI 1.84–3.65 and 4.33, 95% CI 2.75–6.80 for ≤30 cDDD per year, 30–90 cDDD per year, and ≥90 cDDD per year, respectively). There was also a statistically significant trend toward an increased risk with long-term PPIs use for more than one year. All PPIs, except pantoprazole and rabeprazole, were associated with an increased risk of CRC.

The present study suggests that PPIs use might increase the risk of CRC in a dose-dependent manner.