Proton pump inhibitors, commonly known as PPIs, are among the most widely prescribed medications worldwide. They are used primarily to treat conditions such as gastro-oesophageal reflux disease (GERD), peptic ulcers, and Zollinger-Ellison syndrome by reducing stomach acid production. Since their introduction in the 1980s, PPIs have been considered highly effective and generally safe. However, there has been longstanding concern regarding their potential link to gastric cancer, especially when used for extended periods.
A new population-based study across five Nordic countries provides robust evidence addressing this concern. Published in BMJ 2026; 392 (doi: 10.1136/bmj-2025-086384), this research examined whether long-term PPI use is associated with an increased risk of gastric adenocarcinoma. The findings suggest that long-term use of PPIs may not be linked to stomach cancer, offering important insights for patients and healthcare providers alike.
Gastric cancer ranks as the fifth most common malignancy globally, with adenocarcinoma accounting for more than 95 percent of cases. Other gastric tumors, such as neuroendocrine tumors, lymphomas, and gastrointestinal stromal tumors, have distinct causes and treatment strategies.
The primary risk factor for non-cardia gastric adenocarcinoma, which affects the lower part of the stomach, is infection with Helicobacter pylori. For cardia gastric adenocarcinoma, which occurs near the junction of the stomach and esophagus, gastro-oesophageal reflux disease is the dominant risk factor. Other contributing factors include smoking, obesity, excessive alcohol consumption, and certain dietary habits, including high salt intake.
PPIs, by reducing stomach acid, can lead to compensatory overproduction of the hormone gastrin. This hypergastrinaemia may stimulate the proliferation of gastric cells, potentially leading to polyps, some of which have been speculated to have malignant potential. This proposed mechanism has fueled concerns that long-term PPI use could increase the risk of gastric cancer.
Earlier studies and meta-analyses suggested that PPI users might have a higher risk of gastric cancer. Reported risk estimates ranged from 1.67 to 2.88 times higher compared with non-users. However, most of these studies had significant methodological limitations:
Given these issues, the relationship between long-term PPI use and gastric cancer remained uncertain.
To overcome the weaknesses of previous research, a multinational, population-based case-control study called NordGETS was conducted across Denmark, Finland, Iceland, Norway, and Sweden. The study used prospectively collected registry data from 1994 to 2020, covering nearly all patients with gastric cancer in these countries.
Data were obtained from high-quality national registries, including:
The unique personal identity numbers in Nordic countries allowed precise data linkage across registries, ensuring complete and accurate information.
The study conducted additional analyses to examine potential sources of bias:
These analyses confirmed that careful methodological design is crucial to avoid false-positive conclusions.
This study provides strong evidence that long-term PPI therapy may not increase the risk of non-cardia gastric adenocarcinoma. Patients with GERD or other chronic acid-related conditions can be reassured about the cancer risk of sustained PPI use when used for legitimate indications.
Although PPIs appear safe regarding gastric cancer risk, long-term use still carries other potential side effects, including:
Healthcare providers should regularly reassess the necessity of continued PPI therapy and weigh benefits against potential risks.
The study highlights how methodological flaws in prior research can produce misleading conclusions. Accurate assessment of long-term medication safety requires:
Without these precautions, studies may report spurious associations that do not reflect real-world risk.
Earlier systematic reviews reported pooled risk estimates between 1.67 and 2.88, suggesting a positive association. This study demonstrates that much of that perceived risk was likely due to:
By addressing these methodological issues, this research provides a clearer, more reliable estimate, showing no increased risk of non-cardia gastric adenocarcinoma with long-term PPI use.
Animal studies have suggested that long-term acid suppression could lead to hypergastrinaemia and hyperproliferation of gastric mucosa. However, in humans, these changes do not appear to result in precancerous or cancerous lesions. Fundic gland polyps, often observed with chronic PPI use, have not been shown to transform malignantly.
This mechanistic evidence further supports the epidemiological finding that long-term PPI therapy is not a significant risk factor for non-cardia gastric cancer.
Overall, this research supports a balanced, evidence-based approach to PPI use.
The Nordic multicountry study published in BMJ 2026 provides compelling evidence that long-term PPI therapy does not increase the risk of gastric non-cardia adenocarcinoma. By using a rigorous, population-based approach, adjusting for critical confounders, and addressing methodological pitfalls of previous studies, the research offers clear guidance for clinicians and patients. While PPIs should always be used appropriately, concerns regarding stomach cancer risk with long-term use may be substantially reduced.
This blog is based on open-access research published under CC BY-NC license. It is intended for informational purposes only and should not be considered medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any medication.
