Long-term proton pump inhibitor exposure showed no measurable increase in gastric non-cardia adenocarcinoma risk, according to a large, multinational, population-based case-control study in five Nordic countries.
Investigators analyzed data from the Nordic Gastric and Esophageal Tumor Study, which linked nationwide registries in Denmark, Finland, Iceland, Norway, and Sweden between 1994 and 2020. The study included 17,232 patients with gastric non-cardia adenocarcinoma and 172,297 matched controls selected from the general population, matched on age, sex, calendar year, and country. All of the participants had at least 5 years of prescription history to allow consistent exposure assessment.
Exposure was defined as long-term proton pump inhibitor use exceeding 1 year, calculated using cumulative defined daily doses. To reduce protopathic bias, dispensations within the 12 months preceding the index date were excluded. The primary outcome was gastric non-cardia adenocarcinoma; cardia tumors were excluded to minimize confounding by gastroesophageal reflux disease. Conditional logistic regression models adjusted for Helicobacter pylori eradication treatment, peptic ulcer disease, smoking-related and alcohol-related disorders, obesity or type 2 diabetes, and the use of metformin, non-steroidal anti-inflammatory drugs, and statins.
Long-term proton pump inhibitor use was observed in 10.2% of cases and 9.5% of controls. The elevated risk seen in unadjusted models was attenuated after adjustment and was no longer statistically significant. Analyses of long-term histamine-2 receptor antagonist use yielded similar null results. After adjustment for H pylori treatment, peptic ulcer disease, metabolic factors, and medication use, proton pump inhibitor use was comparable to nonuse in the risk of gastric adenocarcinoma.
Sensitivity analyses showed increased risk estimates when exposure within 6 months of diagnosis, short-term use, inclusion of cardia adenocarcinoma, or exclusion of H pylori–related covariates were incorporated into the models.
Limitations included the observational case-control design and the potential for residual confounding, including confounding by indication, despite extensive multivariable adjustment. Although prospectively collected nationwide registry data minimized recall and selection bias, certain variables weren't captured, including dietary exposures such as salt intake and detailed family history. In addition, rare conditions, including prior benign gastric surgery and Zollinger-Ellison syndrome were too uncommon to be meaningfully incorporated into the analysis.
“Every one of the various steps used to prevent biases was essential to prevent the reporting of a potentially false association,” noted lead study author Onyinyechi Duru, a doctoral student of Upper Gastrointestinal Surgery in the Department of Molecular Medicine and Surgery at the Karolinska Institutet and Karolinska University Hospital in Sweden, and colleagues.
The study authors reported funding from the Swedish Research Council, Nordic Cancer Union, and Swedish Cancer Society, with no relevant financial relationships or other conflicts of interest related to the study.
Source: The BMJ