Proton pump inhibitors and upper gastrointestinal cancer: a matched case-control study addressing confounding by indication

Objectives To assess the association between proton pump inhibitor (PPI) use and upper gastrointestinal (GI) cancer while addressing potential confounding by indication. Design Matched case-control study using multivariable conditional logistic regression. Setting Electronic health records from a national health provider. Participants Patients diagnosed with upper GI cancer (n=875), each matched with 10 cancer-free controls (n=8750) by age, sex, and ethnic group. Main outcome measures Adjusted odds ratios (aORs) for upper GI cancer associated with prior exposure to PPIs, H2 receptor antagonists, or antacids, with medication exposure modelled as multiple binary variables corresponding to distinct time windows before the index date. Additional models adjusted for GI-related diagnoses recorded prior to the index date (e.g., gastritis, gastroesophageal reflux disease, peptic ulcer disease).

PPI use in the five years before the index date was initially associated with increased odds of upper GI malignancy (e.g., esomeprazole aOR 3.90 [95% CI 3.14 to 4.84]; omeprazole aOR 2.60 [2.22 to 3.06]). However, when exposure was modelled as separate binary variables for each time window, the association was strongest for use within six months of diagnosis and was not observed—or reversed—for more remote exposures. After excluding the final year before diagnosis and adjusting for symptom-related diagnoses, no positive association remained. Remote PPI use was associated with reduced risk (e.g., omeprazole more than 3 years before the index date: aOR 0.62 [0.51 to 0.75]).

and Relevance The association between PPI use and upper GI malignancy appears to reflect confounding by indication, with PPIs prescribed in response to early symptoms associated with increased cancer risk. After accounting for timing of use and underlying GI diagnoses, no harmful association remained. These findings suggest that new-onset upper GI symptoms warrant investigation for malignancy, rather than attribution of risk to acid-suppressive therapy. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was internally funded by Leumit Health Services and was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Leumit Health Services Institutional Review Board (IRB) with a waiver of informed consent (approval number: LEU-0010-21). The waiver was justified on the basis that this large retrospective study used de-identified clinical data and posed no risk to participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Because this study is based on individual-level clinical data, data sharing is restricted. Access to the data may be granted to qualified researchers upon reasonable request, subject to approval by the Leumit Health Services Institutional Review Board (IRB).