Safety of Chronic Proton Pump Inhibitor Therapy: An Updated Systematic Review of Serious Adverse Events

Background: Proton Pump Inhibitors (PPIs) are widely prescribed for acid-related disorders and are generally considered safe for short-term therapy. However, growing evidence has raised concerns regarding Serious Adverse Events (SAEs) associated with long-term PPI use. This systematic review synthesizes current evidence on the spectrum of SAEs linked to prolonged PPI exposure. Methods: A comprehensive literature search was conducted in MEDLINE, Scopus, and the Cochrane Library from database inception to August 2025. Eligible studies included randomized controlled trials, cohort studies, case–control studies, and meta-analyses reporting effect estimates (HR, RR, or OR) with 95% confidence intervals. Due to substantial heterogeneity in study design, populations, exposure definitions, and outcome measures, findings were synthesized narratively in accordance with PRISMA guidelines. Risk of bias was assessed using validated tools appropriate for each study design. Results: A total of 99 studies met the inclusion criteria. Chronic PPI use was associated with increased risks of several renal outcomes, including acute kidney injury, chronic kidney disease, endstage renal disease, and nephrolithiasis. Elevated risks were also reported for infectious complications, particularly Clostridioides difficile infection, campylobacteriosis, and spontaneous bacterial peritonitis. Gastrointestinal and hepatobiliary outcomes included microscopic colitis, inflammatory bowel disease, cholelithiasis, fundic gland polyps, and gastrointestinal malignancies. Neurological associations were observed for dementia and Parkinson's disease. Cardiovascular outcomes linked to longterm PPI use included stroke, myocardial infarction, heart failure, atrial fibrillation, venous thromboembolism, and hypertension. Additional associations were reported for type 2 diabetes mellitus, bone fractures, rheumatoid arthritis, respiratory infections, and increased all-cause mortality. Most evidence was observational and subject to residual confounding. Discussion: The findings of this systematic review demonstrate that chronic PPI use is associated with a broad and concerning spectrum of serious adverse events across multiple organ systems. The evidence is predominantly derived from observational studies, which are subject to residual confounding, protopathic bias, and reverse causality. The dose-response relationships observed in several studies strengthen the biological plausibility of these associations, particularly for renal outcomes, C. difficile infection, and bone fractures. The clinical implications are substantial given the widespread and often inappropriate long-term use of PPIs. This review highlights the urgent need for more judicious prescribing practices, periodic reassessment of treatment indications, and further high-quality research, including large prospective cohorts and ethically feasible randomized trials, to establish causal relationships and identify populations at greatest risk. Conclusion: Long-term PPI use is associated with a broad range of potential serious adverse events across multiple organ systems. Although causality cannot be definitively established, the consistency of findings and biological plausibility support cautious prescribing, periodic reassessment of longterm therapy, and consideration of alternative treatment strategies when appropriate.