March 2026
Study finds long-term PPI use is not linked to stomach cancer
By Sasha Ellery BM BCh
Long-term proton pump inhibitor (PPI) therapy does not increase the risk of noncardia gastric adenocarcinoma when key biases seen in earlier studies are minimised, according to a large Nordic registry analysis published in the BMJ.
Researchers compared data on 17,232 individuals with gastric (noncardia) adenocarcinoma with 172,297 matched population controls across five Nordic countries. Crucially, they excluded people who had had PPI exposure in the 12 months immediately before diagnosis (for cases) or the study inclusion date (for controls) to reduce protopathic bias – where PPIs were prescribed for early, nonspecific symptoms of an as-yet undiagnosed cancer. Long-term PPI use occurred in 1766 (10.2%) cases and 16,312 (9.5%) controls.
After adjusting for multiple confounders, including Helicobacter pylori eradication therapy, peptic ulcer disease and other comorbidities, more than one year of cumulative PPI use was linked to no meaningful change in the risk of noncardia gastric adenocarcinoma (adjusted odds ratio, 1.01).
Speaking to Medicine Today, Professor Peter Katelaris, Head of the Gastroenterology Department at Concord Hospital, Sydney, said, ‘Because PPIs are so commonly used in comorbid people, they are frequently associated with a wide range of adverse outcomes, which makes some GPs nervous about prescribing this class of drug.’
He explained that the potential link between PPI use and gastric cancer had been suggested for a long time and had mostly been studied in heterogeneous, poorly controlled retrospective studies that showed an association with no evidence of causality.
A key supporting finding in the study was that the results were similar when the researchers looked at histamine-2-receptor antagonists (a different acid-suppressing drug class used for overlapping indications), which also showed no association with noncardia gastric adenocarcinoma. This suggested that the null result was not specific to one drug class and supported the validity of the findings for PPI use.
‘This well-controlled study showed that there was no evidence that the association of PPIs with gastric cancer was causal,’ said Professor Katelaris. He noted that observational data raised hypotheses but did not prove them. ‘It’s the best we have, however, and the result is reassuring.’
The researchers concluded that the null finding should reassure patients who need long-term PPIs for reflux disease or other clear indications. They added that PPIs may have potential harms (e.g. possible Clostridioides difficile infection, osteoporosis, vitamin or electrolyte malabsorption), so a risk–benefit analysis was required and the need for ongoing therapy should be regularly reassessed.
‘The mantra for PPIs is that they are an appropriate class of drug, when they are used properly,’ said Professor Katelaris. ‘Use them when there is a clear indication and a clear response, do not use them when there is not and use the lowest dose for the shortest time necessary. But do not avoid prescribing them appropriately to someone who needs them, out of the erroneous fear that they cause stomach cancer.’