Compared with the use of histamine-2 receptor antagonists (H2RAs), the use of proton pump inhibitors (PPIs) is associated with an increased risk for gastric cancer, although the absolute risk remains low, according to a study published in Gut.

Previous observational studies suggest that PPI use is associated with an increased risk for gastric cancer. However, these studies were limited by important methodological shortcomings, which may have exaggerated their findings. Therefore, researchers set out to discern whether new users of PPIs are at an increased risk for gastric cancer compared with news users of H2RAs.

The investigators used the United Kingdom Clinical Practice Research Datalink (CPRD) to conduct this population-based cohort study. They identified 973,281 news users of PPIs and 193,306 new users of H2RAs from January 1, 1990 to April 30, 2018. Secondary analyses evaluated duration and dose-response associations.

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The PPI exposure group was followed for a median duration of 5.1 (quartile (Q) 1, 2.7; Q3, 8.4) years while the H2RA group was followed for 4.2 (Q1, 1.9; Q3, 8.3) years. This follow-up included a 1-year lag period.

The researchers observed that the use of PPIs was associated with a 45% increased risk for gastric cancer compared with the use of H2RAs (Hazard Ratio [HR], 1.45; 95% CI, 1.06 to 1.98). The number needed to harm was determined to be 2121 and 1191 patients for 5 and 10 years after treatment initiation, respectively. 

In secondary analyses, the HRs increased with cumulative duration of use, cumulative omeprazole equivalents, and time since treatment initiation. These study results remained consistent across several sensitivity analyses.

This study had several limitations. The investigators did not stratify based on gastric cancer type (cardia vs noncardia), as this information is not consistently recorded in the CPRD. Additionally, some secondary analyses may be underpowered. Finally, due to the observational nature of the study, residual confounding is possible.

The study authors concluded, “In summary, the results of this large real-world study suggest that patients newly treated with PPIs may be at an increased risk of gastric cancer compared with patients newly treated with H2RAs, although the absolute risk remains low.”

They added, “While PPIs have established clinical benefits when used according to evidence-based guidelines, this study highlights the need for physicians to regularly reassess the necessity of ongoing treatment. This is especially important in patients who are prescribed PPIs in the long term and for patients without an evidence-based indication for use.”

Disclosure: Some study authors declared affiliations with the industry. Please see the original reference for a full list of authors’ disclosures.

Disclosure: This research was supported by the Canadian Institutes of Health Research (FDN-143328).


Abrahami D, McDonald EG, Schnitzer ME, Barkun AN, Suissa S, Azoulay L. Proton pump inhibitors and risk of gastric cancer: population-based cohort study. Gut. Published online July 2, 2021. doi:10.1136/gutnj-2021-325097