Association between proton pump inhibitor use and upper gastrointestinal cancer: A matched case-control study accounting for reverse causation and confounding by indication

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 adjustment for symptom-related diagnoses, PPI use was associated with increased odds of cancer (e.g., esomeprazole aOR 4.01, 95% CI 3.20, 5.03, p<0.001; omeprazole aOR 2.38, 95% CI 1.99, 2.85, p<0.001). When exposure was modeled by time window, associations diminished for exposures >1 year before diagnosis. After excluding the final year before diagnosis and adjusting for symptom-related diagnoses, we did not detect a harmful association between PPI use and upper GI cancer. Remote use (>3 years) was instead associated with lower odds (e.g., omeprazole aOR 0.62, 95% CI 0.51, 0.75, p<0.001), with similar patterns in a gastric-only subgroup (701 cases, 7,010 controls). Key limitations include potential residual confounding, lack of direct dietary and family-history data, and incomplete capture of over-the-counter PPI use. Conclusions Apparent harmful associations between PPI use and upper GI cancer were concentrated in the months immediately preceding diagnosis and disappeared after adjusting for diagnostic context and excluding the final year before diagnosis. In these adjusted analyses, we found no evidence of increased odds with long-term PPI use, and remote use (>3 years before diagnosis) was associated with reduced cancer odds for omeprazole and lansoprazole. These findings underscore the importance of investigating new-onset upper GI symptoms rather than attributing malignancy risk to acid-suppressive therapy.