Proton pump inhibitors and the risk of gastric cancer: a systematic review, evidence synthesis and life course epidemiology perspective

Abstract

Objectives Since proton pump inhibitors (PPI) have been introduced, many concerns were raised regarding potential gastric carcinogenicity. We aim to summarise and weigh the epidemiological evidence and address possible causality. Design Systematic literature review, evidence synthesis and life-course assessment. Data sources PubMed, Web of Science and Cochrane database (from inception up to October 2024), and back- and forward citation tracking (Web of Science). Eligibility criteria Original studies and quantitative evidence syntheses assessing the association between PPIs and gastric cancer in humans, without language restrictions. Data extraction and synthesis Study design, definitions (and participant numbers) of PPI use and gastric cancer, study characteristics (setting, period, follow-up, lag-time), age and sex distribution presented in tables and evidence mapping. Results We identified 33 original studies, 21 meta-analyses, three umbrella meta-analyses, one individual patient data meta-analysis and a Markov model (2006-2023). PPIs were consistently associated with an increased gastric cancer risk with 20/21 meta-analyses reporting pooled relative risks between 1.3 and 2.9. Available trials were underpowered. Reverse causation/protopathic bias, residual confounding (by indication) and lag time seem the largest methodological challenges, as well as disentangling the effects of Helicobacter pylori and its' eradication. Insufficient data are available on age and sex-specific risks, with no studies specifically addressing PPIs in young populations. We hypothesise a sensitive-period exposure model, in which PPI use during pregnancy and early life may be particularly damaging regarding long-term cancer risk. An exploration of Swedish cancer incidence data suggests potential cohort effects as overall gastric cancer risk decreased over time (1970-2022). The risk has increased in young (<40 years) men since the early 2000s, ∼10 years after the introduction of Helicobacter pylori eradication and PPIs. Conclusion Although for older individuals with valid indications, the gastric cancer risk related to PPI use may be limited, we do argue for a more rational and evidence-supported use of PPIs in young populations.