{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T07:03:16Z","timestamp":1779951796746,"version":"3.53.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The relationship between antidiabetic drugs and thromboembolic events remains unclear. The FDA Adverse Event Reporting System (FAERS) data was used to systematically assess safety signals and polypharmacy-related drug\u2013drug interactions of antidiabetic medications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>By analyzing FAERS reports from 2004 to 2025 that included antidiabetic drugs, the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Information Component (IC), and the Empirical Bayes Geometric Mean (EBGM) were used to assess disproportionality. Factors such as the main suspected drug, event seriousness, age, sex, US origin, and the recent reporting period were examined in sensitivity analyses. Drug\u2013drug interactions (DDIs) were evaluated using the \u03a9 shrinkage measure and adjusted for false discovery rate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We analyzed 81,280,515 FAERS reports from 2004\u20132025, of which 498,750 (0.61%) involved at least one of 30 antidiabetic drugs, revealing strong arterial thromboembolic signals for rosiglitazone (IC = 4.68), gliclazide (IC = 1.55), linagliptin (IC = 1.56), dapagliflozin (IC = 1.25), and several DPP-4 inhibitors. Only insulin degludec (IC = 0.73, IC025 = 0.61) and insulin aspart (IC = 0.28, IC025 = 0.21) showed nominal venous thromboembolic signals. For GLP-1 agonists, no thromboembolic signals were detected. These observations were confirmed by sensitivity analyses across all subgroups. Moreover, 257 significant drug\u2013drug interactions were identified, particularly between insulin analogues and simvastatin, acetaminophen, or gabapentin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DPP-4 inhibitors, SGLT2 inhibitors, and certain insulins showed positive arterial thromboembolic signals. No positive thromboembolic signals were detected for GLP-1 agonists, consistent with their favorable cardiovascular safety profile observed in randomized controlled trials. Numerous significant drug\u2013drug interactions were also detected, particularly for insulin analogues with other drugs. Further research is necessary to understand the clinical importance of these interactions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1826021","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:20:55Z","timestamp":1779949255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative thromboembolic risk and polypharmacy-related drug\u2013drug interaction signals among antidiabetic medications: a large-scale FAERS pharmacovigilance study"],"prefix":"10.3389","volume":"17","author":[{"given":"Duaa","family":"Bafail","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany","family":"Ghazal","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Faculty of Biotechnology, University of Sadat City","place":["El Sadat City, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S111","DOI":"10.2337\/dc21-S009","article-title":"9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes 2021","volume":"44","year":"2021","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/pds.1742","article-title":"Quantitative signal detection using spontaneous ADR reporting","volume":"18","author":"Bate","year":"2009","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B3","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s002280050466","article-title":"A Bayesian neural network method for adverse drug reaction signal generation","volume":"54","author":"Bate","year":"1998","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1056\/NEJMoa2004967","article-title":"Cardiovascular outcomes with ertugliflozin in type 2 diabetes","volume":"383","author":"Cannon","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1001\/jamainternmed.2018.3034","article-title":"Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes","volume":"178","author":"Chang","year":"2018","journal-title":"JAMA Intern Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD","volume":"41","author":"Cosentino","year":"2019","journal-title":"Eur. Heart J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","article-title":"Type 2 diabetes mellitus","volume":"1","author":"DeFronzo","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cmet.2016.06.009","article-title":"The cardiovascular biology of glucagon-like peptide-1","volume":"24","author":"Drucker","year":"2016","journal-title":"Cell. Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1080\/00031305.1999.10474456","article-title":"Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system","volume":"53","author":"DuMouchel","year":"1999","journal-title":"Am. Stat."},{"key":"B11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1145\/502512.502526","article-title":"Empirical bayes screening for multi-item associations","volume-title":"Proceedings of the seventh ACM SIGKDD international conference on knowledge discovery and data mining","author":"DuMouchel","year":"2001"},{"key":"B12","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1007\/s00125-017-4301-8","article-title":"SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA adverse event reporting system","volume":"60","author":"Fadini","year":"2017","journal-title":"Diabetologia"},{"key":"B14","unstructured":"What is a serious adverse event?\n          \n          \n          2003"},{"key":"B15","unstructured":"Quarterly data extract files\n          \n          \n          2014"},{"key":"B16","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/0021-9681(65)90028-7","article-title":"The design and logic of a monitor of drug use","volume":"18","author":"Finney","year":"1965","journal-title":"J. Chronic Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0140-6736(19)31149-3","article-title":"Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial","volume":"394","author":"Gerstein","year":"2019","journal-title":"Lancet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.2337\/dc09-2054","article-title":"Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals","volume":"33","author":"Gogitidze","year":"2010","journal-title":"Diabetes Care"},{"key":"B19","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1001\/jama.2010.920","article-title":"Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone","volume":"304","author":"Graham","year":"2010","journal-title":"JAMA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1056\/NEJMoa1501352","article-title":"Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes","volume":"373","author":"Green","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"755","DOI":"10.2165\/00002018-200528090-00001","article-title":"Drug-induced thrombosis: an update","volume":"28","author":"Hauben","year":"2005","journal-title":"Drug Saf."},{"key":"B22","doi-asserted-by":"publisher","first-page":"385","DOI":"10.2165\/00002018-200629050-00003","article-title":"Under-reporting of adverse drug reactions: a systematic review","volume":"29","author":"Hazell","year":"2006","journal-title":"Drug Saf."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1016\/S0140-6736(09)60953-3","article-title":"Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial","volume":"373","author":"Home","year":"2009","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1001\/jama.298.22.2634","article-title":"Thiazolidinediones and cardiovascular outcomes in older patients with diabetes","volume":"298","author":"Lipscombe","year":"2007","journal-title":"JAMA"},{"key":"B25","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"Liraglutide and cardiovascular outcomes in type 2 diabetes","volume":"375","author":"Marso","year":"","journal-title":"N. Engl. J. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","article-title":"Semaglutide and cardiovascular outcomes in patients with type 2 diabetes","volume":"375","author":"Marso","year":"","journal-title":"N. Engl. J. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.numecd.2014.01.017","article-title":"Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials","volume":"24","author":"Monami","year":"2014","journal-title":"Nutr. Metab. Cardiovasc Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1056\/NEJMoa072761","article-title":"Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes","volume":"356","author":"Nissen","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1001\/archinternmed.2010.207","article-title":"Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality","volume":"170","author":"Nissen","year":"2010","journal-title":"Arch. Intern Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3740","DOI":"10.1002\/sim.2473","article-title":"Extending the methods used to screen the WHO drug safety database towards analysis of complex associations and improved accuracy for rare events","volume":"25","author":"Nor\u00e9n","year":"2006","journal-title":"Stat. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3057","DOI":"10.1002\/sim.3247","article-title":"A statistical methodology for drug-drug interaction surveillance","volume":"27","author":"Nor\u00e9n","year":"2008","journal-title":"Stat. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1177\/0962280211403604","article-title":"Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery","volume":"22","author":"Nor\u00e9n","year":"2013","journal-title":"Stat. Methods Med. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1080\/14740338.2021.1902502","article-title":"Thromboembolic events with insulin degludec: a disproportionality analysis of the FDA adverse event reporting system","volume":"20","author":"Raschi","year":"2021","journal-title":"Expert Opin. Drug Saf."},{"key":"B35","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1001\/jama.2018.18269","article-title":"Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial","volume":"321","author":"Rosenstock","year":"","journal-title":"JAMA"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1001\/jama.2019.13772","article-title":"Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial","volume":"322","author":"Rosenstock","year":"","journal-title":"JAMA"},{"key":"B37","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B38","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/S0140-6736(09)61965-6","article-title":"Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials","volume":"375","author":"Sattar","year":"2010","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1161\/CIRCRESAHA.117.311588","article-title":"Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors","volume":"122","author":"Scheen","year":"2018","journal-title":"Circ. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1056\/NEJMoa1307684","article-title":"Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus","volume":"369","author":"Scirica","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1001\/jama.298.10.1189","article-title":"Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis","volume":"298","author":"Singh","year":"2007","journal-title":"JAMA"},{"key":"B42","doi-asserted-by":"publisher","first-page":"691","DOI":"10.2165\/11536390-000000000-00000","article-title":"The development and evaluation of a triage algorithm for adverse drug reaction signals","volume":"33","author":"Strandell","year":"2010","journal-title":"Drug Saf."},{"key":"B43","doi-asserted-by":"publisher","first-page":"381","DOI":"10.2165\/00002018-200225060-00001","article-title":"Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA\u2019s spontaneous reports database","volume":"25","author":"Szarfman","year":"2002","journal-title":"Drug Saf."},{"key":"B44","doi-asserted-by":"publisher","first-page":"k4365","DOI":"10.1136\/bmj.k4365","article-title":"Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study","volume":"363","author":"Ueda","year":"2018","journal-title":"BMJ"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/pds.668","article-title":"A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions","volume":"11","author":"van Puijenbroek","year":"2002","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1056\/NEJMoa1305889","article-title":"Alogliptin after acute coronary syndrome in patients with type 2 diabetes","volume":"369","author":"White","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.2337\/dc10-0013","article-title":"Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes","volume":"33","author":"Wright","year":"2010","journal-title":"Diabetes Care"},{"key":"B49","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1111\/1755-5922.12075","article-title":"Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants","volume":"32","author":"Wu","year":"2014","journal-title":"Cardiovasc Ther."},{"key":"B50","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S2213-8587(16)00052-8","article-title":"Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis","volume":"4","author":"Wu","year":"2016","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(18)32590-X","article-title":"SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials","volume":"393","author":"Zelniker","year":"2019","journal-title":"Lancet"},{"key":"B52","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1826021\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:20:57Z","timestamp":1779949257000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1826021\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":52,"alternative-id":["10.3389\/fphar.2026.1826021"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1826021","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1826021"}}