Proton Pump Inhibitors and Gastric Cancer: A Large-Scale Propensity Score-Matched Analysis

Background/Aims: We aimed to elucidate whether proton pump inhibitor (PPI) users are at increased risk of gastric cancer compared with non-PPI users or histamine-2 receptor antagonist (H2RA) users. Methods: A population-based cohort study was conducted using data from the UK Biobank from 1990 to 2016. We compared the incidence of gastric cancer after a minimum of 1-year drug exposure between PPI users and non-PPI or H2RA users using Cox proportional hazards models. Secondary analyses assessed the duration and dose-response associations. Sensitivity analyses incorporating various matching ratios, extended lag periods, and propensity score stratification were performed. Results: After large-scale propensity score matching, we included 42,732 new PPI users, 42,732 non-PPI users, and 4,762 new H2RA users. During a median follow-up of 6.7 years, PPI users had a 2.32-fold higher risk of gastric cancer than non-PPI users (hazard ratio [HR], 2.324; 95% confidence interval [CI], 1.646 to 3.282), with numbers needed to harm of 488 and 442 at 2 and 4 years, respectively. Compared with H2RA users, PPI users also had a significantly higher incidence of gastric cancer (HR, 5.343; 95% CI, 1.557 to 18.335). The risk of gastric cancer tended to increase with a longer cumulative duration of PPI use and higher cumulative doses of PPIs. Moreover, these results remained robust after adjustments for various lag periods, matching ratios, and propensity score stratification. Conclusions: PPI use was associated with a higher incidence of gastric cancer, albeit with a low absolute risk. Therefore, long-term PPI use should be considered cautiously, even in regions with a low risk of gastric cancer.