Long-term PPI use may not increase stomach cancer risk

medwireNews: A large population-based study has found no significant association between long-term use of proton pump inhibitors (PPIs) and an increased risk for gastric adenocarcinoma.

The researchers point out in The BMJ that they “made extensive efforts to avoid and assess all the methodological limitations hampering the existing literature,” much of which has shown a positive association between PPI use and gastric cancer.

Moreover, the lack of an association in the current study “is supported by the absence of strong mechanistic evidence to suggest that proton pump inhibitor use leads to any development of precancerous or cancerous lesions of the gastric mucosa,” they write.

Jesper Lagergren (Karolinska Institutet, Stockholm, Sweden) and co-authors continue: “This finding should offer relief for patients needing long term proton pump inhibitor therapy and is valuable for clinical decision making in healthcare settings.”

They caution, however, that “long term proton pump inhibitor use might cause side effects and increase the risk of some other potentially serious conditions such as Clostridium difficile associated diarrhoea, osteoporosis, and vitamin or electrolyte malabsorption, highlighting the need to balance the benefits and disadvantages of such use.”

The case–control study, NordGETS, includes prospectively collected data from nationwide registries in Denmark, Finland, Iceland, Norway, and Sweden covering the period between 1994 and 2020.

In all, 17,232 patients with noncardia gastric adenocarcinoma were each matched to 10 individuals without a history of gastroesophageal cancer by age, sex, calendar year, and country at the index date (the diagnosis date for cases and the inclusion date for controls), giving a control population of 172,297.

Of note, long-term PPI use – defined as use of more than a year, excluding the 12-month period before the index date – occurred in a comparable 10.2% of people with gastric cancer and 9.5% of controls over the course of the study.

And after adjusting for a raft of confounders including the matching variables as well as Helicobacter pylori treatment, peptic ulcer disease, smoking- and alcohol-related diseases, obesity or type 2 diabetes, and treatment with metformin, nonsteroidal anti-inflammatory drugs, and statins, there was no significant difference in the risk for gastric cancer between long-term users of PPIs and nonusers (nonsignificant hazard ratio [HR]=1.01).

The team also assessed long-term use of histamine-2-receptor antagonists as a comparator exposure as they “are mainly used for the same indications as proton pump inhibitors and are not associated with gastric adenocarcinoma.” This lack of association was confirmed in the study, with no increased risk for gastric cancer among long-term users versus nonusers (nonsignificant HR=1.03).

In summary, Lagergren et al reiterate that “[c]onfounding was counteracted by exclusion of cardia adenocarcinoma, dismissal of proton pump inhibitor exposure 12 months before index date, assessment of long term (more than one year) exposure to proton pump inhibitor use, and adjustment for the main risk factors, including Helicobacter pylori infection related covariates.”

And they stress that “[e]very one of the various steps used to prevent biases was essential to prevent the reporting of a potentially false association.”

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BMJ 2026; 392: e086384