Do long-term proton pump inhibitors (PPIs) increase the risk for gastric neuroendocrine tumors? A major Nordic study suggests a possible dose-dependent association. The findings — and their implications — were the subject of active debate at United European Gastroenterology Week (UEGW) 2025, one of Europe’s largest gastroenterology conferences.

Benefit-Risk Balance of PPIs

PPIs have been prescribed worldwide for decades and are among the most commonly used drugs globally. But their prolonged use has raised persistent questions: Could medications meant to protect the gastric mucosa actually promote the emergence of rare but serious gastric tumors?

A large Nordic analysis spanning 24 years and involving more than 19,000 patients reported an 83% increased risk for gastric neuroendocrine neoplasms (NENs) among heavy long-term PPI users, with the highest risk seen in patients younger than 65. The results, published as part of the Nordic Gastric and Esophageal Tumor Study (NordGETS), challenge the routine, long-term use of PPIs and call for a more careful assessment of chronic prescribing practices.

Long-Term PPI Use and Hypergastrinemia

Patients with chronic atrophic gastritis or Helicobacter pylori-related pangastritis already have a higher risk for noncardia gastric cancer. Severe chronic atrophic gastritis (such as in Biermer disease or pernicious anemia) also predisposes to gastric NENs due to chronic hypergastrinemia caused by hypochlorhydria.

Long-term PPI therapy induces secondary hypergastrinemia by suppressing gastric acid, prompting concerns about a potential role in gastric carcinogenesis. Several observational studies have reported increased gastric cancer risk among chronic PPI users. However, until now, the link between prolonged PPI exposure and gastric NENs had not been assessed on a population level.

Nordic Registries Offer a Rare Look

The NordGETS analysis included population-based registries from five Nordic countries — Denmark, Finland, Iceland, Norway, and Sweden — to evaluate gastric NEN risk among long-term PPI users.

This matched case-control study included all adults diagnosed with gastric or esophageal tumors between 1996 and 2020. Incident gastric NENs were identified in national cancer registries. PPI exposure was categorized into tertiles using defined daily doses (DDD) from prescription records. Multivariable logistic regression was used to calculate adjusted odds ratios (ORs) and 95% CIs, adjusting for chronic atrophic gastritis, duodenal or pancreatic NENs, and H pylori infection.

The study included 1790 patients with gastric NENs and 17,897 matched controls. After a median follow-up of 11.8 years, findings showed a significant dose-dependent increase in gastric NEN risk. Patients in the highest tertile of exposure (> 385 lifetime DDD) had a 1.83-fold higher risk (adjusted OR, 1.83; 95% CI, 1.56-2.15) than nonusers.

The association remained significant after excluding individuals with chronic atrophic gastritis, other NENs, or H pylori infection. Risk was also higher in individuals younger than 65 than in those aged 65 or older.

How Should Clinicians Interpret These Results?

The findings suggest that long-term PPI use is associated with increased gastric NEN risk independent of known risk factors such as atrophic gastritis and H pylori. The dose-response gradient strengthens the possibility of a causal relationship, though underlying mechanisms remain unclear and further research is needed to identify the most vulnerable subgroups. The higher risk in younger patients may reflect greater susceptibility or simply longer cumulative exposure to PPI-induced hypergastrinemia.

However, Eivind Ness-Jensen, PhD, of the Norwegian University of Science and Technology in Trondheim, Norway, first author and presenter at UEGW 2025, urged clinicians to interpret the results with caution: “The incidence of gastric NENs is very low, and the absolute risk of developing such tumors remains low, even among PPI users. These results should not call into question the use of PPIs in patients with an appropriate indication.”

He also emphasized that the data support a more thoughtful assessment of prolonged PPI therapy, particularly in younger patients and those with risk factors for gastric NENs.

The study benefits from exceptional statistical power — nearly 20,000 participants — and a robust multinational, population-based design that minimizes selection bias. However, some limitations remain, including the absence of serum gastrin measurements and the inability to account for additional unrecorded risk factors. And as an observational study, it cannot establish causation, only statistical association.

This story was translated from Medscape’s French edition.