Background: Proton-pump inhibitors (PPIs) have raised concerns regarding an increased risk of gastric cancer.

Aim: This study aims to evaluate the association between PPI use and the risk of gastric cancer.

Methods: A systematic search of Medline/PubMed, Embase, and Scopus databases was conducted to identify both randomized and non-randomized studies examining the link between PPIs and gastric cancer. Histamine-2 receptor antagonist (H2RA) users were chosen as controls to minimize confounding by indication and focus on patients requiring gastric acid suppression. Two authors independently extracted data and assessed bias risks. Maximally-adjusted relative risk (RR) estimates were extracted, and random- and fixed-effect models calculated summary estimates. Heterogeneity and small-study effects were examined, and GRADE was used to evaluate evidence certainty.

Results: Of 8375 records, 12 non-randomized studies (>6 million patients; 11,554 gastric cancers) and two randomized clinical trials (498 patients; 1 gastric cancer) met eligibility criteria. Randomized evidence provided very-low certainty evidence. Meta-analysis of six adequately adjusted non-randomized studies (2.5 million patients; 7372 gastric cancers) revealed no association between PPIs and gastric cancer (RR_random = 1.07, 0.97-1.19; RR_fixed = 1.05, 0.98-1.12), with low certainty of evidence. No convincing evidence of dose-response or increased risk with long-term use was found. Lack of or minimal adjustment for confounding was associated with larger effect sizes.

Conclusions: Non-randomized studies with adequate confounding control found no association between PPIs and gastric cancer. Previous published studies indicating an increased risk of gastric cancer associated with PPIs may suffer residual confounding.