Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden

BMJ Open. 2017 Oct 30;7(10):e017739. doi: 10.1136/bmjopen-2017-017739.


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.

Keywords: chemoprevention; gastric cancer; ppi; proton pump inhibitors.

MeSH terms

  • Adenocarcinoma / etiology*
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aspirin / administration & dosage
  • Cohort Studies
  • Female
  • Gastroesophageal Reflux / drug therapy
  • Histamine H2 Antagonists / adverse effects
  • Histamine H2 Antagonists / therapeutic use
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Risk Factors
  • Stomach Neoplasms / epidemiology
  • Stomach Neoplasms / etiology*
  • Sweden / epidemiology
  • Time Factors


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors
  • Aspirin