{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T03:08:31Z","timestamp":1773198511036,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-00561352"],"award-info":[{"award-number":["RS-2025-00561352"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00217123"],"award-info":[{"award-number":["RS-2023-00217123"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Hydrochlorothiazide and chlorthalidone are widely used thiazide diuretics, and pharmacovigilance reports have suggested a possible link between their use and glaucoma. Therefore, this study aims to evaluate whether the use of hydrochlorothiazide or chlorthalidone is associated with an increased risk of glaucoma in a nationwide population-based claims cohort to clarify the true risk and guide clinical practice. Pharmacovigilance disproportionality analyses of the Food and Drug Administration Adverse Event Reporting System (FAERS) reports were conducted to identify candidates for glaucoma-related diuretics. In the nationwide Korean Health Insurance Review and Assessment (HIRA) cohort of new users of hydrochlorothiazide or chlorthalidone, incidence of overall and subtype-specific glaucoma was assessed, and pre- and post-exposure incidence rate ratios (IRRs) were calculated. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) for clinical risk factors. Hydrochlorothiazide and chlorthalidone demonstrated positive disproportionality signals for glaucoma (ROR, 3.34; 95% confidence interval [CI], 2.85\u20133.91 and 11.37; 95% CI, 7.67\u201316.86, respectively). In the HIRA cohort of new users of hydrochlorothiazide (n = 250,296) or chlorthalidone (n = 10,005) from January 2019 to December 2020, the cumulative incidence of glaucoma\/ocular hypertension rose gradually for both drugs, reaching approximately 2%\u20133% by study end. Pre- versus post-exposure IRRs for overall glaucomatous conditions were 1.02 (95% CI 0.98\u20131.06) for hydrochlorothiazide and 1.03 (95% CI 0.84\u20131.26) for chlorthalidone; IRRs for ocular hypertension were 1.02 (95% CI 0.97\u20131.07) and 1.09 (95% CI 0.87\u20131.37), respectively. Multivariate analyses found no significant association between the drugs and overall glaucomatous conditions (adjusted HR 1.01; 95% CI 0.86\u20131.19). In dose-stratified analyses, hydrochlorothiazide showed a modest increase in glaucoma risk in the highest cumulative exposure group (for overall glaucomatous conditions, HR 1.21; 95% CI 1.12\u20131.31; log-rank\n                    <jats:italic>P<\/jats:italic>\n                    &amp;lt; 0.01), whereas chlorthalidone showed no consistent dose\u2013response trends. Although the FAERS pharmacovigilance suggested a potential glaucoma risk with hydrochlorothiazide and chlorthalidone, population-based validation found no significant association. Pharmacovigilance signals should be confirmed with population-based data to identify true drug\u2013glaucoma associations.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1768133","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:43:45Z","timestamp":1773125025000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrochlorothiazide and chlorthalidone use and glaucoma risk: pharmacovigilance analysis and nationwide cohort study"],"prefix":"10.3389","volume":"17","author":[{"given":"Jooyoung","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Hanyang University Guri Hospital","place":["Guri, Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pre-Medicine, College of Medicine, and Biostatistics Laboratory, Medical Research Collaborating Center, Hanyang University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ko Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jee-Eun","family":"Chung","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University","place":["Ansan, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Joon","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Hanyang University Seoul Hospital, Hanyang University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.2147\/OPTH.S27695","article-title":"Topiramate and the vision: a systematic review","volume":"6","author":"Abtahi","year":"2012","journal-title":"Clin. Ophthalmol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.ogla.2024.04.006","article-title":"Blind spots in therapy: unveiling drug-induced angle-closure glaucoma through a national analysis","volume":"7","author":"Aftab","year":"2024","journal-title":"Ophthalmol. Glaucoma"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e108226","DOI":"10.1371\/journal.pone.0108226","article-title":"Systemic hypertension as a risk factor for open-angle glaucoma: a meta-analysis of population-based studies","volume":"9","author":"Bae","year":"2014","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1016\/j.clinthera.2018.07.012","article-title":"Pharmacovigilance: an overview","volume":"40","author":"Beninger","year":"2018","journal-title":"Clin. Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e748","DOI":"10.1097\/IJG.0000000000000430","article-title":"Presumed furosemide-associated bilateral angle-closure glaucoma","volume":"25","author":"Boundaoui","year":"2016","journal-title":"J. Glaucoma"},{"key":"B6","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.cgh.2017.11.025","article-title":"Advantages and limitations of the federal adverse events reporting system in assessing adverse event reporting for eluxadoline","volume":"16","author":"Chedid","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2014-206690","article-title":"Bilateral acute angle closure glaucoma associated with hydrochlorothiazide-induced hyponatraemia","volume":"2014","author":"Chen","year":"2014","journal-title":"BMJ Case Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1167\/iovs.62.6.27","article-title":"Association between chronic renal disease and the risk of glaucoma development: a 12-year nationwide cohort study","volume":"62","author":"Cho","year":"2021","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e12357","DOI":"10.1097\/MD.0000000000012357","article-title":"Patterns of care for glaucoma patients in Korea from 2002 to 2013 using the national health insurance service claims data","volume":"97","author":"Choi","year":"2018","journal-title":"Med. Baltim."},{"key":"B10","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.ophtha.2020.07.051","article-title":"Association of antihypertensive medication with retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness","volume":"128","author":"Chong","year":"2021","journal-title":"Ophthalmology"},{"key":"B11","first-page":"134","article-title":"Hygroton-induced myopia","volume":"110","author":"D'Alena","year":"1969","journal-title":"Calif. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3713818","DOI":"10.1155\/2016\/3713818","article-title":"Bilateral, simultaneous, acute angle closure glaucoma in Pseudophakia induced by chlorthalidone","volume":"2016","author":"Durai","year":"2016","journal-title":"Case Rep. Ophthalmol. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ophtha.2006.05.075","article-title":"Predictive factors for open-angle glaucoma among patients with ocular hypertension in the european glaucoma prevention study","volume":"114","author":"European Glaucoma Prevention Study","year":"2007","journal-title":"Ophthalmology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/clpt.2014.17","article-title":"Exploring the FDA adverse event reporting system to generate hypotheses for monitoring of disease characteristics","volume":"95","author":"Fang","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"B15","unstructured":"FDA adverse event reporting system (FAERS) public dashboard\n          \n          \n          2023"},{"key":"B16","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s40264-024-01423-7","article-title":"The REporting of A disproportionality analysis for DrUg safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV): explanation and elaboration","volume":"47","author":"Fusaroli","year":"2024","journal-title":"Drug Saf."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1001\/archopht.1995.01100100019012","article-title":"Bilateral acute angle-closure glaucoma associated with drug sensitivity to hydrochlorothiazide","volume":"113","author":"Geanon","year":"1995","journal-title":"Arch. Ophthalmol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0331444","DOI":"10.1371\/journal.pone.0331444","article-title":"A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for Definity","volume":"20","author":"Jiang","year":"2025","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e2014008","DOI":"10.4178\/epih\/e2014008","article-title":"A guide for the utilization of health insurance review and assessment service national patient samples","volume":"36","author":"Kim","year":"2014","journal-title":"Epidemiol. Health"},{"key":"B20","doi-asserted-by":"publisher","first-page":"718","DOI":"10.3346\/jkms.2017.32.5.718","article-title":"Towards actualizing the value potential of Korea health insurance review and assessment (HIRA) data as a resource for health research: strengths, limitations, applications, and strategies for optimal use of HIRA data","volume":"32","author":"Kim","year":"2017","journal-title":"J. Korean Med. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e2314816","DOI":"10.1001\/jamanetworkopen.2023.14816","article-title":"Practice patterns of screening for hydroxychloroquine retinopathy in South Korea","volume":"6","author":"Kim","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"B22","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.oret.2023.10.005","article-title":"Nationwide usage of pentosan polysulfate and practice patterns of pentosan polysulfate maculopathy screening in South Korea","volume":"8","author":"Kim","year":"2024","journal-title":"Ophthalmol. Retina"},{"key":"B23","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1001\/jamaophthalmol.2025.3612","article-title":"Systemic drugs associated with maculopathy","volume":"143","author":"Kim","year":"","journal-title":"JAMA Ophthalmol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"40757","DOI":"10.1038\/s41598-025-24620-5","article-title":"Nationwide health claims analysis of phenothiazine-associated retinopathy risk in chlorpromazine and perphenazine users","volume":"15","author":"Kim","year":"","journal-title":"Sci. Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"11270","DOI":"10.1038\/s41598-024-62041-y","article-title":"Screening practices and risk assessment for maculopathy in pentosan polysulfate users across different exposure levels","volume":"14","author":"Kwon","year":"2024","journal-title":"Sci. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1167\/iovs.65.14.4","article-title":"Change in systemic medication and its influence on intraocular pressure - results from the gutenberg health study","volume":"65","author":"Laspas","year":"2024","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/j.1442-9071.2006.01365.x","article-title":"Bilateral angle closure glaucoma induced by sulphonamide-derived medications","volume":"35","author":"Lee","year":"2007","journal-title":"Clin. Exp. Ophthalmol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"16224","DOI":"10.1038\/s41598-023-43420-3","article-title":"Effect of antihypertensive medications on the risk of open-angle glaucoma","volume":"13","author":"Lee","year":"","journal-title":"Sci. Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ajo.2023.03.032","article-title":"Increased risks of open-angle glaucoma in untreated hypertension","volume":"252","author":"Lee","year":"","journal-title":"Am. J. Ophthalmol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"20420986221125006","DOI":"10.1177\/20420986221125006","article-title":"Pharmacovigilance: reporting requirements throughout a product's lifecycle","volume":"13","author":"Lucas","year":"2022","journal-title":"Ther. Adv. Drug Saf."},{"key":"B31","doi-asserted-by":"publisher","first-page":"386","DOI":"10.4103\/0301-4738.33830","article-title":"Drug-induced acute myopia following chlorthalidone treatment","volume":"55","author":"Mahesh","year":"2007","journal-title":"Indian J. Ophthalmol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1016\/j.ophtha.2007.03.047","article-title":"Systemic antihypertensive medication and incident open-angle glaucoma","volume":"114","author":"Muskens","year":"2007","journal-title":"Ophthalmology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1001\/jamaophthalmol.2022.3723","article-title":"Association of drugs with acute angle closure","volume":"140","author":"Na","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3524","DOI":"10.1167\/iovs.09-4821","article-title":"Hypotensive medication, statins, and the risk of glaucoma","volume":"51","author":"Owen","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1486128","DOI":"10.1155\/2018\/1486128","article-title":"Bilateral angle narrowing and acute myopia induced by indapamide: a case report","volume":"2018","author":"Pedrosa","year":"2018","journal-title":"Case Rep. Ophthalmol. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"S526","DOI":"10.4103\/IJO.IJO_3035_24","article-title":"Secondary angle closure induced by hydrochlorothiazide in a patient on oral steroids and immunosuppressants: a case report","volume":"73","author":"Premkumar","year":"2025","journal-title":"Indian J. Ophthalmol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1080\/09286586.2023.2264387","article-title":"Use of diuretics and risk of acute angle closure: a case-control study","volume":"31","author":"Qiao","year":"2024","journal-title":"Ophthalmic Epidemiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/eye.2011.128","article-title":"Non-steroidal drug-induced glaucoma","volume":"25","author":"Razeghinejad","year":"2011","journal-title":"Eye (Lond)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"214","DOI":"10.3341\/kjo.2011.25.3.214","article-title":"Acute-onset bilateral myopia and ciliochoroidal effusion induced by hydrochlorothiazide","volume":"25","author":"Roh","year":"2011","journal-title":"Korean J. Ophthalmol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","article-title":"Data mining of the public version of the FDA adverse event reporting system","volume":"10","author":"Sakaeda","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1097\/IJG.0000000000000037","article-title":"Uveal effusion as a mechanism of bilateral angle-closure glaucoma induced by chlorthalidone","volume":"24","author":"Singer","year":"2015","journal-title":"J. Glaucoma"},{"key":"B42","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s40264-013-0075-1","article-title":"Choosing thresholds for statistical signal detection with the proportional reporting ratio","volume":"36","author":"Slattery","year":"2013","journal-title":"Drug Saf."},{"key":"B43","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/s0002-9394(14)72174-9","article-title":"Choroidal effusion as a mechanism for transient myopia induced by hydrochlorothiazide and triamterene","volume":"120","author":"Soylev","year":"1995","journal-title":"Am. J. Ophthalmol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/1471-2415-13-58","article-title":"Indapamide-induced transient myopia with supraciliary effusion: case report","volume":"13","author":"Vegh","year":"2013","journal-title":"BMC Ophthalmol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.ophtha.2023.05.001","article-title":"Association of systemic medication use with glaucoma and intraocular pressure: the European eye epidemiology consortium","volume":"130","author":"Vergroesen","year":"2023","journal-title":"Ophthalmology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"370","author":"von Elm","year":"2007","journal-title":"Lancet"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1062160","DOI":"10.3389\/fmed.2023.1062160","article-title":"Low-dose topiramate and hydrochlorothiazide-associated early acute myopia and angle narrowing: a case report","volume":"10","author":"Wu","year":"2023","journal-title":"Front. Med. (Lausanne)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1111\/ceo.14454","article-title":"Drug-associated glaucoma: a real-world study based on the food and drug administration adverse event reporting system database","volume":"53","author":"Wu","year":"2025","journal-title":"Clin. Exp. Ophthalmol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e102972","DOI":"10.1371\/journal.pone.0102972","article-title":"Diabetes mellitus as a risk factor for open-angle glaucoma: a systematic review and meta-analysis","volume":"9","author":"Zhou","year":"2014","journal-title":"PLoS One"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1768133\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:43:47Z","timestamp":1773125027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1768133\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":49,"alternative-id":["10.3389\/fphar.2026.1768133"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1768133","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]},"article-number":"1768133"}}