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We read four manuscripts published in Gut about the relationship between proton pump inhibitors use and gastric cancer.1–4 Proton pump inhibitors are widely used for the management of peptic ulcer disease, gastroesophageal reflux disease and eradication of Helicobacter pylori infection.5 However, its safety for long-term use has raised pubic concern.6 In order to clarify the relationship between proton pump inhibitors use and gastric cancer, we used the 2000–2013 database of Taiwan National Health Insurance Program to conduct a population-based case–control study. The study design and data source were adapted from previous studies.7 8 Subjects aged 20–84 years with newly diagnosed gastric cancer were selected as the cases. Subjects without gastric cancer were randomly selected from the same database as the matched controls. The index date was defined as the date of each case being diagnosed with gastric cancer. Both cases with gastric cancer and matched controls were matched with sex, age (every five years) and the year of index date. In order to reduce the latency bias, subjects whose first-time prescriptions for proton pump inhibitors were noted ≤12 months before the index date were excluded from the study. Therefore, only those subjects whose first-time prescriptions for proton pump inhibitors were noted >12 months before the index date could be included. In addition, subjects with other cancers before the index date were excluded.
There were 649 cases with gastric cancer and 649 propensity score-matched controls without gastric cancer, with similar distributions of sex, age and comorbidities (table 1). The conditional logistic regression model was used to estimate the OR and 95% CI for gastric cancer associated with proton pump inhibitors use (table 2). The ORs of gastric cancer were 1.59 (95% CI 1.24 to 2.05) for subjects with cumulative duration of proton pump inhibitors use ≤6 months and 2.00 (95% CI 1.36 to 2.95) for subjects with cumulative duration of proton pump inhibitors use >6 months compared with never use.
Epidemiological studies demonstrated that proton pump inhibitors use was associated with increased risk of gastric cancer.9 10 Even after eradication therapy for Helicobacter pylori infection, the risk still existed.1 Moreover, some comments demonstrated that this kind of association could be confounded by the underlying indication for proton pump inhibitors therapy, immortal time bias, latency bias or low level of serum vitamin B12.3 4 9 10
To date, no definite evidence demonstrates that proton pump inhibitors can directly induce the development of gastric cancer. In our study, proton pump inhibitors use was associated with increased odds of gastric cancer. There seems to be a duration-dependent relationship about proton pump inhibitors use on the risk of gastric cancer. That is, the longer the use of proton pump inhibitors, the greater the risk of gastric cancer.
In view of the high accessibility of the Taiwan’s medical system, it does not need to take 12 months to diagnose gastric cancer from the onset of gastric cancer-related symptoms. In our study, subjects whose first-time prescriptions for proton pump inhibitors were noted ≤12 months before the index date were excluded. The latency bias could be reduced. Therefore, subjects included were those who needed proton pump inhibitors to treat their acid-related GI diseases rather than gastric cancer-related symptoms.
Because stringent inclusion and exclusion criteria were applied, the eligible subject number was small. It did not allow us to analyse the use duration of individual proton pump inhibitors on the risk of gastric cancer. We were only able to demonstrate the use duration of overall proton pump inhibitors on the risk of gastric cancer in table 2. Furthermore, it indicates a research direction about individual proton pump inhibitors on the risk of gastric cancer. Ours was a case–control study. The case group had a diagnosis of gastric cancer. The control group did not have a diagnosis of gastric cancer. Both groups retrospectively analysed the differences of proton pump inhibitors use. Misclassifications of proton pump inhibitors exposure is not likely in the case and the control groups. Thus, immortal time bias is less likely to happen. Due to the inherent limitation of the database used, there was no record on serum vitamin B12. We could not include vitamin B12 for analysis.
We conclude that after excluding immortal time bias and latency bias, proton pump inhibitors use is associated with increased odds of gastric cancer, which seems to be duration-dependent.
S-WL and H-CL contributed equally.
Contributors S-WL and H-CL contributed to the conception of the article, initiated the draft of the article, revised the article and contributed equally to the article. C-LL conducted the data analysis and revised the article. K-FL participated in the data interpretation and revised the article.
Funding This study was supported in part by the Ministry of Health and Welfare, Taiwan (MOHW107-TDU-B-212-123004).
Disclaimer This funding agency did not influence the study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None declared.
Patient consent Not required.
Ethics approval The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the Research Ethics Committee of China Medical University and Hospital in Taiwan (CMUH-104-REC2-115).
Provenance and peer review Not commissioned; externally peer reviewed.
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