Decades of registry data suggest reassurance for clinicians and patients relying on chronic acid suppression.
Long-term use of proton pump inhibitors does not appear to increase the risk of developing stomach cancer, according to a large population-based study.
The research drew on more than two decades of health data from five Nordic countries, with results published in the BMJ.
The findings are likely to reassure both clinicians and patients who depend on prolonged proton pump inhibitor (PPI) therapy for conditions such as gastro-oesophageal reflux disease and peptic ulcer disease.
Concerns about a potential link between PPIs and gastric cancer have circulated since the 1980s, fuelled by more recent studies suggesting up to a twofold increased risk.
However, much of that earlier evidence has been limited by methodological weaknesses, including confounding by indication and reverse causation, the researchers wrote.
To address these uncertainties, researchers conducted a large case-control study using national healthcare registries from Denmark, Finland, Iceland, Norway and Sweden between 1994 and 2020.
They identified 17,232 patients diagnosed with stomach cancer and matched each case with 10 controls by age, sex, calendar year and country, yielding a comparison group of 172,297 individuals drawn from the general population.
Long-term use of PPIs, defined as more than one year of treatment, was assessed while deliberately excluding drug exposure in the 12 months before diagnosis or study entry.
This approach was intended to reduce the risk of falsely attributing drug use to cancer development when early, undiagnosed disease may already have influenced prescribing. Use of histamine-2 receptor antagonists, another acid-suppressing drug class, was also examined.
The analysis accounted for a wide range of potential confounders, including age, sex, prior treatment for Helicobacter pylori, history of peptic ulcer disease, smoking- and alcohol-related conditions, obesity or type 2 diabetes and drug treatment with metformin, non-steroidal anti-inflammatory drugs and statins.
No association was found between long term proton pump inhibitor use and gastric adenocarcinoma (adjusted odds 1.01, 95% confidence interval 0.96 to 1.07).
The risk was similar for histamine-2-receptor antagonist use (adjusted odds ratio 1.03, 0.86 to 1.23).
“Multiple sources of error that led to a false positive association were identified – inclusion of proton pump inhibitor use shortly before the gastric adenocarcinoma diagnosis, short term use of proton pump inhibitors, cardia adenocarcinoma and lack of adjustment for Helicobacter pylori related variables,” the researchers wrote.
They noted that many studies that had assessed proton pump inhibitor use and risk of gastric cancer have reported an increased risk.
As an observational study, the research could not establish causality, and the authors acknowledged that residual confounding from unmeasured factors such as diet or family history could not be completely excluded.
However, they emphasised that the scale of the study and the long duration and quality of the registry data allowed them to mitigate many of the biases that had affected previous investigations.
“The finding of no association may offer relief for patients who need long term proton pump inhibitor therapy in the treatment of gastro-oesophageal reflux disease or for other clear indications,” the researchers wrote.
“This knowledge is also of value for clinical decision making in healthcare settings.
Related
“However, 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 and to regularly reassess the need for continued proton pump inhibitor treatment.”
In an associated editorial published in the BMJ, experts acknowledged PPIs were among the most used drugs worldwide and were “certainly overused”.
“Overall, the findings from Duru and colleagues are reassuring in dispelling concerns about an association between proton pump inhibitors and gastric cancer,” they wrote.
“This concern is one of the many purported risks of proton pump inhibitors. Several of these other potential risks, such as fractures and community acquired pneumonia, are also uncertain and have been challenged or refuted.
“Regarding cancer outcomes specifically, the study by Duru and colleagues illustrates the importance of considering lag time in ascertainment of exposure to avoid reverse causation. This aligns with previous similar work on proton pump inhibitors showing an association between their use and pancreatic cancer only when lag times are not considered.”
Recognising the conflicting and uncertain evidence base on PPI-related harms, current recommendations suggested that concern about adverse effects alone (whether gastric cancer, dementia risk, pneumonia, or others) “should not be a reason to avoid prescribing or taking proton pump inhibitors, nor to stop them, and indications may exist that justify long term (more than eight weeks) use”.
“Rather, reducing overuse of proton pump inhibitors should be based on lack of indication for long term use or lack of indication for one in the first place,” the authors wrote.
“At the same time, well conducted observational studies on harms remain crucial for providing an accurate picture of the safety of proton pump inhibitors and ensuring that they are not indiscriminately avoided or stopped when necessary and beneficial.”
