Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: A Korean nationwide prospective cohort study

Abstract

Purpose: Despite plausible mechanisms, the clinical significance of long-term proton pump inhibitor (PPI) use to colorectal cancer (CRC) remains unknown. The purpose of this study was to investigate the association between PPI use and CRC development.

Methods: We conducted a population-based prospective cohort study using the Korean nationwide claims database merged with national health examination data. The study cohort included a total of 451,284 participants who were tracked to identify cases of CRC since 2007. We assessed and standardized PPI use before the index date using the Defined Daily Dose system. We calculated the hazard ratios and their 95% confidence intervals to assess the association between PPI use and CRC occurrence using Cox proportional hazard regression models with adjustment for potential confounders. We performed subgroup analyses of the effect of PPI exposure on CRC development stratified by the CRC risk.

Results: There were 5,304 cases of CRC during the study period of 2,908,152 person-years. PPI use was not associated with CRC risk overall. The incidence of CRC was higher among individuals who were elderly, male, more obese, and drank alcohol more frequently and among those who had more comorbidities. Further subgroup analyses revealed that the hazard effect of PPI use increased linearly in a dose-dependent manner with the number of CRC risk factors for which the risk level was considered low.

Conclusion: Within the low-risk population, PPI use was associated with an increased risk of CRC, although the association did not weigh the effects of conventional risk factors.

Fig 1. Study design and recruitment of participants.

DDD, defined daily dose; CRC, Colorectal cancer; PPI, proton pump inhibitor; NHIC, National Health Insurance Corporation. *Using the claims database of the NHIC including aspirin, statin, and metformin. ^†From national health examinations including smoking status, drinking habit, and physical activity. ^‡Patients with any cancer diagnosis by ICD-10 “C” code, with past medical history of cancer according to health-check survey data, who died before the index date, or had missing non-survey health check-up variables were excluded from study.