Proton Pump Inhibitor Use and Risk of Gastric Cancer: Current Evidence from Epidemiological Studies and Critical Appraisal

SIMPLE SUMMARY: Proton pump inhibitors (PPIs) are prescribed for reducing the amount of stomach acid. PPIs increase the systemic level of gastrin, a trophic hormone, which is reported to be linked with carcinogenesis. Previous epidemiological studies have shown that the use of PPIs increase the risk of gastric cancer, questioning the safety of PPI therapy for reducing gastric acid suppression. The findings of this study show that PPI use is associated with the risk of gastric cancer (RR 1.80, 95% CI, 1.46–2.22, p < 0.001) compared with non-users. The evidence from this study suggests that clinicians should maintain heightened vigilance regarding the adverse effect of PPI therapy and weigh the long-term outcomes. ABSTRACT: Proton pump inhibitors (PPIs) are used for maintaining or improving gastric problems. Evidence from observational studies indicates that PPI therapy is associated with an increased risk of gastric cancer. However, the evidence for PPIs increasing the risk of gastric cancer is still being debated. Therefore, we aimed to investigate whether long-term PPI use is associated with an increased risk of gastric cancer. We systematically searched the relevant literature in electronic databases, including PubMed, EMBASE, Scopus, and Web of Science. The search and collection of eligible studies was between 1 January 2000 and 1 July 2021. Two independent authors were responsible for the study selection process, and they considered only observational studies that compared the risk of gastric cancer with PPI treatment. We extracted relevant information from selected studies, and assessed the quality using the Newcastle−Ottawa scale (NOS). Finally, we calculated overall risk ratios (RRs) with 95% confidence intervals (CIs) of gastric cancer in the group receiving PPI therapy and the control group. Thirteen observational studies, comprising 10,557 gastric cancer participants, were included. Compared with patients who did not take PPIs, the pooled RR for developing gastric cancer in patients receiving PPIs was 1.80 (95% CI, 1.46–2.22, p < 0.001). The overall risk of gastric cancer also increased in patients with gastroesophageal reflux disease (GERD), H. pylori treatment, and various adjusted factors. The findings were also consistent across several sensitivity analyses. PPI use is associated with an increased risk of gastric cancer in patients compared with those with no PPI treatment. The findings of this updated study could be used in making clinical decisions between physicians and patients about the initiation and continuation of PPI therapy, especially in patients at high risk of gastric cancer. Additionally, large randomized controlled trials are needed to determine whether PPIs are associated with a higher risk of gastric cancer.