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Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden
  1. Nele Brusselaers1,
  2. Karl Wahlin2,
  3. Lars Engstrand3,
  4. Jesper Lagergren2,4
  1. 1Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Molecular Medicine and Surgery, Upper Gastrointestinal Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  3. 3Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
  4. 4Division of Cancer Studies, King’s College London, London, UK
  1. Correspondence to Dr Nele Brusselaers; nele.brusselaers{at}


Objective Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs. Concerns have been raised about a potentially increased risk of gastric cancer following long-term use. Our aim is to assess the risk of gastric cancer associated with PPI use, taking into account underlying indications.

Design This is a population-based cohort study. Standardised incidence ratios (SIRs) and 95% CIs were calculated to compare the risk of gastric cancer among long-term PPI users with the corresponding background population, while taking confounding by indication into account.

Setting Population-based study in Sweden (2005–2012).

Participants This study included virtually all adults residing in Sweden exposed to maintenance therapy with PPIs.

Exposure/Intervention Maintenance use of PPIs, defined as at least 180 days during the study period. Maintenance use of histamine 2 receptor antagonist was evaluated for comparison reasons.

Outcome measures Gastric cancer (cardia and non-cardia), and subgroup analysis for gastric adenocarcinoma, as defined by the Swedish Cancer Registry.

Results Among 797 067 individuals on maintenance PPI therapy, the SIR of gastric cancer was over threefold increased (SIR=3.38, 95% CI 3.23 to 3.53). Increased SIRs were found in both sexes and all age groups, but were especially increased among PPI users younger than 40 years (SIR=22.76, 95% CI 15.94 to 31.52). Increased SIRs were found for each indication studied, including those without an association with gastric cancer, for example, gastro-oesophageal reflux (SIR=3.04, 95% CI 2.80 to 3.31), and those with a supposedly decreased risk, for example, aspirin users (SIR=1.93, 95% CI 1.70 to 2.18). The association was similar for cardia and non-cardia gastric cancer. Analyses restricted to adenocarcinoma showed similar results to those for all gastric cancers. Long-term users of histamine 2 receptor antagonists, which have the same indications as PPIs, were not at any increased risk.

Conclusions Long-term PPI use might be an independent risk factor for gastric cancer. This challenges broad maintenance PPI therapy, particularly if the indication is weak.

  • proton pump inhibitors
  • chemoprevention
  • gastric cancer
  • ppi

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  • Contributors NB had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NB conducted and is responsible for the data analysis. Everyone who contributed significantly to the work is listed as coauthor. Study concept and design: all authors. Acquisition of data: NB and JL. Data collection and preparation for analyses: NB and JL. Analysis and interpretation of data: all authors. Drafting of the manuscript: NB. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: NB and KW. Obtained funding: JL and NB.

  • Funding The work was supported by the Swedish Research Council (839-2008-7496), Swedish Cancer Society (CAN 2015/460), the Karolinska Institutet Distinguished Professor Award to JL (D-02418/2010) and SFO Epidemiology (Young Scholar Grant to NB).

  • Competing interests None declared.

  • Ethics approval The study was approved by the Regional Ethical Review Board in Stockholm (2014/1291-31/4).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We are willing to share data upon request after ethical approval has been approved by the relevant committee and the governmental agencies that maintain the data.

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