Long-term use of proton pump inhibitors (PPIs) was not associated with an increased risk for gastric non-cardia adenocarcinoma in a large population-based study spanning five Nordic countries.

After accounting for multiple sources of bias that have affected earlier research, the apparent association seen in some prior studies disappeared, leading the investigators to conclude that long-term PPI use may not be associated with an increased risk for gastric adenocarcinoma.

The findings “may offer relief for patients who need long-term proton pump inhibitor therapy in the treatment of gastroesophageal reflux disease or for other clear indications,” wrote Jesper Lagergren, MD, PhD, with Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, and colleagues.

Daniela Jodorkovsky, MD, who wasn’t involved in the study but reviewed it for Medscape Medical News, agreed.

“Because this study was very rigorous in its methodology and had a huge number of patients, the lack of association is very reassuring. I think this puts an end to the worry about risk of gastric cancer and PPI use in the general population,” said Jodorkovsky, director of the Mount Sinai Center for GI Physiology and Motility, Mount Sinai West and Morningside, and associate professor of medicine, Icahn School of Medicine at Mount Sinai in New York City.

The study was published online in the BMJ.

Unfounded Concerns?

Gastric cancer is the fifth most common malignancy worldwide. Concerns about long-term PPI use and gastric cancer have persisted since these agents were introduced in the 1980s. The biological hypothesis has centered on PPI-induced hypergastrinemia, which can stimulate gastric mucosal cell proliferation and lead to gastric polyps with malignant potential.

Observational studies and meta-analyses published in recent years have suggested an increased risk for gastric cancer among PPI users, with pooled estimates approaching a twofold increase.

However, the literature is “hampered by several methodological limitations, making this possible association uncertain,” the authors noted.

Key limitations include low statistical power, short and incomplete follow-up, inclusion of PPI exposure shortly before gastric cancer was diagnosed (protopathic bias), differences in classification of cases, and inadequate adjustment for Helicobacter pylori-related factors.

To address these concerns, Lagergren and colleagues did a multinational population-based case-control study using prospectively collected registry data from Denmark, Finland, Iceland, Norway, and Sweden. “Extensive efforts” were made to avoid and assess all the methodological limitations hampering the existing literature, they said.

Long-term PPI exposure was defined as more than 1 year of use, excluding the 12 months before the diagnosis date to avoid confounding from symptoms of undiagnosed gastric cancer or the inclusion date for control individuals. Long-term use (> 1 year) of histamine-2 receptor antagonists (H2RAs) was also analyzed to gauge the validity and specificity of the findings for PPI use.

The final analysis included 17,232 gastric non-cardia adenocarcinoma cases and 172,297 matched control individuals, with long-term PPI use in 10.2% of cases and 9.5% of control individuals. Follow-up lasted up to 26 years.

In crude analyses, long-term PPI use appeared to be associated with an increased risk for gastric non-cardia adenocarcinoma (odds ratio [OR], 1.16), but this association was eliminated after multivariable adjustment (OR, 1.01), especially for H pylori-related variables.

A similar null association was observed for long-term H2RA use (adjusted OR, 1.03).

Judicious Prescribing

Additional analyses demonstrated how methodological choices could produce misleading positive associations, the authors noted.

For example, when the exclusion window before diagnosis was shortened from 12 months to 6 months, an increased risk for gastric non-cardia adenocarcinoma emerged (OR, 1.11).

In addition, long-term PPI users had an increased risk for gastric adenocarcinoma when analyses included cardia adenocarcinoma (OR, 1.13), with a similar association for long-term H2RA use (OR, 1.14).

Omitting H pylori-related covariates and peptic ulcer from the multivariable model similarly reintroduced positive associations with long-term PPI use and gastric non-cardia adenocarcinoma (OR, 1.11) and long-term H2RA use (OR, 1.10).

The authors emphasized that “every one of the various steps used to prevent biases was essential to prevent the reporting of a potentially false association.”

While the findings provide reassurance regarding gastric cancer risk for patients who require prolonged acid-suppressive therapy, the authors cautioned that long-term PPI use may cause side effects and increase the risk of some other “potentially serious” conditions, such as Clostridium difficile-associated diarrhea, osteoporosis, and nutrient malabsorption — underscoring the need to “balance the benefits and disadvantages” of long-term PPI use and to regularly reassess ongoing indications for therapy.

Jodorkovsky said it’s important to note that the study was done in Nordic countries, which may have a different ethnic and racial mix than other countries.

She also noted that the rate of H pylori in the study population is lower than rates in the US and Asia. “Therefore, the results are reassuring on a population level but may not be generalizable to specific patient populations with high rates of H pylori or patients with other risk factors for gastric cancer, such as family history,” Jodorkovsky told Medscape Medical News.

The study had no commercial funding. Lagergren and Jodorkovsky reported having no relevant disclosures.