Long-Term Proton Pump Inhibitor Therapy: Is It Really Safe? A Narrative Review

Background: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications worldwide and remain the cornerstone of treatment for acid-related gastrointestinal disorders. Despite their effectiveness and good safety profile, concerns have arisen regarding overuse and potential long-term adverse effects. Aim: This review assessed the safety of long-term PPI therapy, summarized current evidence on adverse effects and addressed common misconceptions. Material and methods: A narrative review of PubMed/MEDLINE and Google Scholar literature (2020–2026) was conducted, including key earlier studies. Priority was given to systematic reviews, meta-analyses, randomized trials and guidelines from ACG, AGA, NICE, FDA, and EMA. Results: Long-term PPI use has been linked to vitamin B12 and iron deficiency, fractures, chronic kidney disease, Clostridioides difficile infection and possible cognitive impairment. However, most data are observational, and causality is unproven. Higher risk occurs in older adults, patients with comorbidities and those on prolonged high-dose therapy. Inappropriate prescribing and prolonged treatment without clear indications remain significant clinical concerns. Conclusions: PPIs are effective and generally safe when used appropriately. Potential risks should not limit their use when indicated. Therapy should be individualized, regularly reassessed and use the lowest effective dose for the shortest duration.