Proton pump inhibitors and risk of gastric cancer: population-based cohort study

Gut. 2022 Jan;71(1):16-24. doi: 10.1136/gutjnl-2021-325097. Epub 2021 Jul 5.


Objective: To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs).

Design: Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations.

Results: After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses.

Conclusion: The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low.

Keywords: acid-related diseases; epidemiology; gastric cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Female
  • Histamine H2 Antagonists / adverse effects
  • Humans
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Proton Pump Inhibitors / adverse effects*
  • Stomach Neoplasms / chemically induced*
  • Stomach Neoplasms / epidemiology
  • United Kingdom / epidemiology


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors

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