Association between proton pump inhibitor use and upper gastrointestinal cancer: A matched case-control study accounting for reverse causation and confounding by indication
Abstract
BACKGROUND: Proton pump inhibitors (PPIs) are widely used for acid-related disorders, but observational studies have raised concerns about a possible association between long-term PPI use and upper gastrointestinal (GI) cancers. These associations may reflect confounding by indication and reverse causation. We aimed to evaluate the association between PPI use and upper GI cancer while explicitly addressing these biases.
METHODS AND FINDINGS: We conducted a matched case-control study using electronic health records from a national health organization in Israel. Cases were 875 adults (age 63.0 ± 11.9 years, 62.5% male) with incident upper GI cancer (esophageal, gastric, or duodenal) diagnosed between 2003 and 2024; each case was matched to 10 cancer-free controls (n = 8,750). Matching was performed on age, sex, ethnic sector (general, Jewish ultra-orthodox, and Arab), socioeconomic status, and year of enrollment. PPI exposure was ascertained from pharmacy records and modeled in discrete pre-diagnosis windows (0-6 months, 6-12 months, 1-3 years, and 3-10 years). Multivariable conditional logistic regression estimated adjusted odds ratios (aORs) and confidence intervals (CIs), with covariates including age, smoking, body mass index, socioeconomic status, healthcare utilization, pregnancy history (in women), alcohol use, Helicobacter pylori diagnosis, and upper GI symptom-related diagnoses (e.g., gastroesophageal reflux, gastritis, peptic ulcer disease). In models without…
How strong is the evidence?
Evidence Hub reads this as a case-control, done in people. Its evidence level is 4 of 5 (Low · observational). Observational designs can show an association but not prove cause. Reported size: 8,750 participants or records.
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