A large population-based study published in The BMJ has found no significant association between long-term use of proton pump inhibitors (PPIs) and the risk of developing non-cardia gastric adenocarcinoma — the most common form of stomach cancer — across five Nordic countries.
PPIs are widely prescribed for acid-related conditions such as gastro-oesophageal reflux disease (GORD) and peptic ulcer disease. Despite their broad use, concerns have existed for decades that long-term suppression of gastric acid might increase gastric cancer risk through mechanisms such as changes in gastric flora or compensatory hypergastrinaemia.
CLINICAL SUMMARY
What was examined
A population-based case-control study across five Nordic countries assessing whether long-term proton pump inhibitor (PPI) use is associated with risk of non-cardia gastric adenocarcinoma.
Key findings
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Long-term PPI use (>1 year), excluding the 12 months before diagnosis, was not associated with an increased risk of non-cardia gastric adenocarcinoma after adjustment for confounders.
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No significant association was observed between long-term histamine-2 receptor antagonist (H2RA) use and gastric cancer risk.
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Apparent associations seen with short-term PPI use or inclusion of cardia cancers were consistent with bias related to early cancer symptoms prompting treatment.
Clinical implications
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The findings provide reassurance regarding gastric cancer risk when PPIs are used long-term for appropriate indications.
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Careful study design, including exclusion of recent exposure and adjustment for Helicobacter pylori–related factors, is critical when evaluating cancer risk with acid-suppressive therapy.
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Regular review of ongoing PPI needs remains important, given other recognised risks of long-term therapy.
Researchers conducted a population-based case-control study using national healthcare registries in Denmark, Finland, Iceland, Norway,y and Sweden. The analysis included 17 232 patients with confirmed non-cardia gastric adenocarcinoma and 172 297 matched controls from the general population.
Long-term PPI use was defined as cumulative use of more than one year, excluding the 12 months immediately before cancer diagnosis (to reduce bias from early symptoms being treated with PPIs). In addition, histamine-2-receptor antagonist (H2RA) use was examined as a comparator to assess specificity. The analysis adjusted for multiple potential confounders, including Helicobacter pylori eradication therapy, smoking-related diseases, alcohol-related conditions, obesity or type 2 diabetes, and use of other medications.
After full adjustment for confounding factors, the researchers observed no statistically significant association between long-term PPI use and gastric non-cardia adenocarcinoma risk (adjusted odds ratio ~1.01). Long-term H2RA use also showed no significant association with cancer risk. In addition, short-term PPI exposure and inclusion of cardia gastric cancers (which are linked to reflux) in analyses could produce misleading positive associations, highlighting the importance of rigorous methodological design.
These findings stand in contrast to some earlier studies and meta-analyses that suggested an elevated cancer risk with prolonged PPI use, likely due to methodological limitations such as protopathic bias, failure to exclude cardia cancers, and inadequate adjustment for H. pylori infection.
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Gastric cancer remains a major global health concern, but the non-cardia subtype — which was the focus of this study — is most strongly linked to H. pylori infection rather than acid suppressive therapy per se. By sequencing large, prospectively collected registry data and applying rigorous controls for known confounders, this study provides reassurance about the long-term cancer safety profile of PPIs when used appropriately.
The results suggest that concerns about a direct causal link between long-term PPI therapy and stomach cancer risk may be overstated, provided that clinicians continue to use PPIs judiciously and manage underlying risk factors such as H. pylori infection. Regular medication reviews remain important, both to ensure ongoing indication for therapy and to monitor for other known adverse effects of long-term PPI use (e.g., nutritional deficiencies, enteric infections).
Paper: Long term use of proton pump inhibitors and risk of stomach cancer: population-based case-control study in five Nordic countries. doi:10.1136/bmj-2025-086384. Access online here.
