Long term use of proton pump inhibitors and risk of stomach cancer: population based case-control study in five Nordic countries

Abstract Objective To help to clarify whether long term use of proton pump inhibitors is associated with an increased risk of gastric adenocarcinoma by designing a study that considered the existing literature’s methodological weaknesses. Design Population based case-control study using prospectively collected data from multiple complete nationwide registries in five Nordic nations. Setting All healthcare in five Nordic countries—Denmark, Finland, Iceland, Norway, and Sweden—between 1994 and 2020. Participants Case patients with gastric adenocarcinoma, each matched for age, sex, calendar year, and country with 10 control participants randomly identified from each country’s entire population. Exposure The exposure was long term (>1 year) proton pump inhibitor use, excluding the 12 months before the diagnosis date (cases) or inclusion date (controls). Long term (>1 year) use of histamine-2-receptor antagonists was analysed to assess the validity and specificity of the findings for proton pump inhibitor use Main outcomes measures The outcome was gastric non-cardia adenocarcinoma. Gastric cardia adenocarcinoma was excluded to avoid confounding by indication (that is, gastro-oesophageal reflux). As well as controlling for the matching variables, multivariable logistic regression provided odds ratios with 95% confidence intervals, adjusted for country, Helicobacter pylori treatment, peptic ulcer disease, smoking related diseases, alcohol related diseases, obesity or type 2 diabetes, and drug treatment with metformin, non-steroidal anti-inflammatory drugs, and statins. Results The study included 17 232 cases of gastric (non-cardia) adenocarcinoma and 172 297 controls. Long term proton pump inhibitor use occurred in 1766 (10.2%) cases and 16 312 (9.5%) controls. No association was found between long term proton pump inhibitor use and gastric adenocarcinoma (adjusted odds 1.01, 95% confidence interval 0.96 to 1.07). The risk was similar for histamine-2-receptor antagonist use (adjusted odds ratio 1.03, 0.86 to 1.23). Multiple sources of error that led to a false positive association were identified—inclusion of proton pump inhibitor use shortly before the gastric adenocarcinoma diagnosis, short term use of proton pump inhibitors, cardia adenocarcinoma, and lack of adjustment for Helicobacter pylori related variables. Conclusions Long term proton pump inhibitor use may not be associated with an increased risk of gastric adenocarcinoma.