[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-455289-105":59,"doc-detail-455289-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","context-matters-causality-and-global-epidemiology-of-proton-pump-inhibitor-safety-perspective","Context matters - Causality and global epidemiology of proton pump inhibitor safety - Perspective","","Proton pump inhibitors (PPIs) are widely used for acid-related disorders, but long-term overuse has raised safety concerns, including potential links to upper gastrointestinal cancer. A PLOS Medicine perspective discusses an Israel-based pharmacoepidemiological study designed to reduce confounding by indication and reverse causation. By analyzing matched cases and controls and time windows before diagnosis, it finds markedly increased cancer risk shortly before detection that declines after longer intervals. The results suggest earlier associations reflect methodological bias rather than true PPI carcinogenicity.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/context-matters-causality-and-global-epidemiology-of-proton-pump-inhibitor-safety-perspective/455289/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/context-matters-causality-and-global-epidemiology-of-proton-pump-inhibitor-safety-perspective/455289.png","ImageObject",300,407,{"name":92,"@type":93},"PakDamar76","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is causality between long-term PPI use and upper GI cancer difficult to establish?","Question",{"text":112,"@type":113},"Observational data can be distorted by confounding by indication and reverse causation (protopathic bias). Patients receiving PPIs may already have GI conditions that predispose them to cancer, and PPIs may start in response to early, undiagnosed cancer symptoms.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What approach did the study use to address confounding and reverse causation?",{"text":117,"@type":113},"The study used a large national database in Israel, matched 875 cases to 8,750 controls, adjusted for underlying indications for PPI prescription, and stratified exposure by time windows prior to diagnosis.",{"name":119,"@type":110,"acceptedAnswer":120},"What pattern of cancer risk was observed relative to PPI use timing?",{"text":121,"@type":113},"The risk was markedly elevated within one year before diagnosis, particularly in exposure windows occurring 0–0.1 years and 0.1–0.5 years before diagnosis. The risk diminished with increasing time since last use, and no excess risk appeared when use occurred more than one year before diagnosis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455289,1791090336,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":19,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":52,"preview_page_count":4},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","OPEN ACCESS  \nCitation: Okabayashi S, Kaplan GG (2026)  \nContext matters: Causality and global epidemiology of proton pump inhibitor safety. PLoS Med 23(1): e1004862. [https://doi](https://doi). org/10.1371/journal.pmed.1004862  \nPublished: January 7, 2026  \nCopyright: © 2026 Okabayashi, Kaplan. This is an open access article distributed under the terms of the Creative Commons Attribution  License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nFunding: The authors received no specific funding for this work.  \nCompeting interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:  \nG.G. K. has received honoraria for speaking or consultancy from AbbVie, Janssen, Pfizer, Amgen, and Takeda. He has received research support from Ferring, Janssen, AbbVie, GlaxoSmithKline, Merck, and Shire. He has been a consultant for Gilead. He shares ownership of a patent: Treatment of Inflammatory  \nPERSPECTIVE  \nContext matters: Causality and global  \nepidemiology of proton pump inhibitor safety Shinji Okabayashi, Gilaad G. Kaplan*  \nDivision of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada  \n* ggkaplan@ucalgary.ca  \nProton pump inhibitors revolutionized acid-related disorder therapy, yet widespread overuse has raised concerns about long-term safety. A recent study in PLOS Medicine presents new evidence assessing whether links between their prolonged use and upper gastrointestinal cancer are causal.  \nSince their introduction into clinical practice in the 1980s, proton pump inhibitors (PPIs) have transformed the management of acid-related disorders [ 1] . Their potent suppression of gastric acid secretion has made them indispensable for the treatment of gastroesophageal reflux disease and peptic ulcer disease, prevention of nonsteroidal anti-inflammatory drug–induced ulcers, and as a component of eradication therapies for Helicobacter pylori, the most common chronic bacterial stomach infection. The widespread use of PPIs has dramatically improved patients’ quality of life and reduced serious complications such as bleeding ulcers. Yet, this very success has led to a paradox: the habitual, long-term use of PPIs far beyond clearly defined clinical indications. For years, growing evidence has highlighted concerns over the widespread overuse of PPIs [2] and their potential adverse effects [3 ,4], such as kidney disease, bone fractures, infection, and upper gastrointestinal (GI) cancer, which have resulted in enduring controversies [4 ,5] .  \nIn this context, a recent pharmacoepidemiological study in PLOS Medicine [6] provides timely and rigorous evidence that revisits this long-standing debate. The authors sought to overcome the inherent limitations of observational research by employing a rigorous study design and multiple complementary analytical approaches to reassess the association between long-term PPI use and upper GI cancer. Research into the effect of long-term PPI use on upper GI cancer has been hindered primarily due to confounding by indication and time-related biases, particularly reverse causation. Confounding by indication refers to a situation in  \nwhich patients receiving PPIs for GI symptoms often have preexisting GI conditions, including H. pylori infection, that predispose them to the subsequent development of  \nPLOS Medicine | [https://doi.org/10.1371/journal.pmed.1004862](https://doi.org/10.1371/journal.pmed.1004862) January 7, 2026 1 / 4  \nDisorders, Autoimmune Disease, and PBC.  \nUTI Limited Partnership, assignee. Patent WO2019046959A1 . PCT/CA2018/051098, 7 Sept. , 2018. S.O. received speaking fees for invited lectures from Mitsubishi Tanabe Pharma and Mochida Pharmaceutical, and consulting fees from EA Pharma.  \nupper GI cancer. As a result, the observed association may be distorted, making it seem as though PPI use itself ","cbCaikMI32pqjKvv","https://ap.wps.com/l/cbCaikMI32pqjKvv","pdf",712929,"English","# Perspective\n## Context and rationale for reassessing PPI safety\n## Methodological challenges: confounding and reverse causation\n## Study design and key findings from the national database\n## Implications and consistency with meta-analyses","[{\"question\":\"Why is causality between long-term PPI use and upper GI cancer difficult to establish?\",\"answer\":\"Observational data can be distorted by confounding by indication and reverse causation (protopathic bias). Patients receiving PPIs may already have GI conditions that predispose them to cancer, and PPIs may start in response to early, undiagnosed cancer symptoms.\"},{\"question\":\"What approach did the study use to address confounding and reverse causation?\",\"answer\":\"The study used a large national database in Israel, matched 875 cases to 8,750 controls, adjusted for underlying indications for PPI prescription, and stratified exposure by time windows prior to diagnosis.\"},{\"question\":\"What pattern of cancer risk was observed relative to PPI use timing?\",\"answer\":\"The risk was markedly elevated within one year before diagnosis, particularly in exposure windows occurring 0–0.1 years and 0.1–0.5 years before diagnosis. The risk diminished with increasing time since last use, and no excess risk appeared when use occurred more than one year before diagnosis.\"}]","Context matters - Causality and global epidemiology of proton pump inhibitor safety - Perspective | PDF",1790742544]