{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T11:11:35Z","timestamp":1793531495055,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"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. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to evaluate the real-world safety profile of combination therapy with a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) and metformin relative to monotherapy, utilizing the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We extracted adverse event (AE) reports from the FAERS database from the first quarter (Q1) of 2013 to the fourth quarter (Q4) of 2025 in which the combined regimen (ertugliflozin, dapagliflozin, empagliflozin, or canagliflozin plus metformin) was designated as the primary suspect. Disproportionality analyses were performed using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms. Additionally, we examined the time-to-onset distribution and the clinical outcomes of the documented AEs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 23,407 combination-therapy reports were included. At the System Organ Class (SOC) level, ROR-based signal detection identified pronounced disproportionalities in metabolism and nutrition disorders (ROR\u00a0=\u00a09.00), renal and urinary disorders (ROR\u00a0=\u00a03.91), reproductive system and breast disorders (ROR\u00a0=\u00a02.59), and infections and infestations (ROR\u00a0=\u00a02.49). At the Preferred Term (PT) level, the five most frequently reported events cross-validated by all four algorithms were diabetic ketoacidosis (n = 3,522), weight decreased (n = 1,294), blood glucose increased (n = 1,226), acute kidney injury (n = 1,153), and euglycaemic diabetic ketoacidosis (euDKA, n = 1,114). Notably, euDKA demonstrated the highest signal intensity (ROR\u00a0=\u00a0335.43), with the point estimate for the combination group being numerically higher than that observed for SGLT-2i monotherapy (ROR\u00a0=\u00a0185.24). Regarding documented outcomes, hospitalisation or prolonged hospitalisation constituted the most prevalent serious outcome (33.7%), followed by life-threatening events (7.6%) and death (2.7%). In the sub-cohort with definitive time-to-onset data, 39.56% of AEs occurred within the first 30 days following treatment initiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This pharmacovigilance analysis of the FAERS database detected significant disproportionality signals for SGLT-2i\/metformin combination therapy, particularly within metabolic\/nutritional, renal\/urinary, and infectious disease categories. The euDKA signal appeared prominent in descriptive comparisons. The predominance of hospitalisation-related events, coupled with the substantial concentration of AEs within the initial 30-day window, highlights the early treatment phase as a potentially critical monitoring period. These exploratory findings warrant rigorous validation through prospective cohort studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1917352","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:18Z","timestamp":1788496038000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Adverse event reporting signals for SGLT-2 inhibitor\u2013metformin combination therapy: a disproportionality analysis of the FAERS database"],"prefix":"10.3389","volume":"17","author":[{"given":"Wei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The Lu\u2019an Hospital Affiliated to Anhui Medical University (The Lu\u2019an People\u2019s Hospital)","place":["Lu\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimiao","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Lu\u2019an Hospital Affiliated to Anhui Medical University (The Lu\u2019an People\u2019s Hospital)","place":["Lu\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Lu\u2019an Hospital Affiliated to Anhui Medical University (The Lu\u2019an People\u2019s Hospital)","place":["Lu\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Facai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Lu\u2019an Hospital Affiliated to Anhui Medical University (The Lu\u2019an People\u2019s Hospital)","place":["Lu\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021","volume":"402","year":"2023","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s13020-025-01222-x","article-title":"Therapeutic potential of traditional Chinese medicine and mechanisms for the treatment of type 2 diabetes mellitus","volume":"20","author":"Wang","year":"2025","journal-title":"Chin Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10050706","article-title":"Diabetes and thrombosis: a central role for vascular oxidative stress","volume":"10","author":"Vaidya","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s11892-022-01453-4","article-title":"Recent developments in biomarkers for diagnosis and screening of type 2 diabetes mellitus","volume":"22","author":"Ortiz-Mart\u00ednez","year":"2022","journal-title":"Curr Diabetes Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112138","article-title":"Function of selected natural antidiabetic compounds with potential against cancer via modulation of the PI3K\/AKT\/mTOR cascade","volume":"144","author":"Nurcahyanti","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B6","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/bs.ircmb.2021.02.004","article-title":"Sexual hormones and diabetes: the impact of estradiol in pancreatic \u03b2 cell","volume":"359","author":"Merino","year":"2021","journal-title":"Int Rev Cell Mol Biol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.ncrna.2023.02.001","article-title":"Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications","volume":"8","author":"Sufianov","year":"2023","journal-title":"Non-coding RNA Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/dom.70197","article-title":"Triple oral therapy with metformin, DPP-4 inhibitor, and SGLT2 inhibitor for adults with type 2 diabetes: consensus recommendations of a Chinese expert panel (version 2025)","author":"Yu","year":"2025","journal-title":"Diabetes Obes Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2024.0660","article-title":"Initial pharmacological strategies in people with early type 2 diabetes mellitus: a systematic review and network meta-analysis","volume":"49","author":"Choi","year":"2025","journal-title":"Diabetes Metab J"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.7326\/M23-2788","article-title":"Newer pharmacologic treatments in adults with type 2 diabetes: a clinical guideline from the American College of Physicians","volume":"177","author":"Qaseem","year":"2024","journal-title":"Ann Intern Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-025-01616-z","article-title":"SGLT-2 inhibitors and GLP-1 receptor agonists as combination therapy in type 2 diabetes","volume":"26","author":"Liakos","year":"2026","journal-title":"Curr Diabetes Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15918","article-title":"Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: a retrospective cohort study using the TriNetX US collaborative networks","volume":"26","author":"Pai","year":"2024","journal-title":"Diabetes Obes Metab"},{"key":"B13","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s12933-025-02643-6","article-title":"The impact of metformin on kidney disease progression and mortality in diabetic patients using SGLT2 inhibitors: a real-world cohort study","volume":"24","author":"Agur","year":"2025","journal-title":"Cardiovasc Diabetol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1288362","article-title":"Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS)","volume":"15","author":"Bao","year":"2024","journal-title":"Front Pharmacol"},{"key":"B15","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":"B16","doi-asserted-by":"publisher","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":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","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's spontaneous reports database","volume":"25","author":"Szarfman","year":"2002","journal-title":"Drug Saf"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1320458","article-title":"A real-world pharmacovigilance study of mepolizumab in the FDA adverse event reporting system (FAERS) database","volume":"14","author":"Zou","year":"2023","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1200254","article-title":"A real-world pharmacovigilance analysis of FDA adverse event reporting system database for upadacitinib","volume":"14","author":"Wu","year":"2023","journal-title":"Front Pharmacol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/pds.964","article-title":"Comparison of data mining methodologies using Japanese spontaneous reports","volume":"13","author":"Kubota","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2023.0128","article-title":"Two-year therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and empagliflozin in drug-na\u00efve type 2 diabetes mellitus patients","volume":"48","author":"Park","year":"2024","journal-title":"Diabetes Metab J"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00867","article-title":"Sodium-glucose cotransporter inhibitors as antidiabetic drugs: current development and future perspectives","volume":"65","author":"Maccari","year":"2022","journal-title":"J Med Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/ehjcvp\/pvae045","article-title":"Comparative cardiovascular and renal effectiveness of empagliflozin and dapagliflozin: Scandinavian cohort study","volume":"10","author":"Engstr\u00f6m","year":"2024","journal-title":"Eur Heart J Cardiovasc Pharmacother"},{"key":"B25","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1186\/s12933-024-02491-w","article-title":"SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling","volume":"23","author":"G\u00f6pel","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-2043","article-title":"The SGLT2 inhibitor dapagliflozin increases the oxidation of ingested fatty acids to ketones in type 2 diabetes","volume":"45","author":"Herring","year":"2022","journal-title":"Diabetes Care"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.130962","article-title":"Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db\/db mice","volume":"265","author":"Harada","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108330","article-title":"Sodium-glucose co-transporter 2 inhibitors in patients with chronic kidney disease","volume":"242","author":"Solomon","year":"2023","journal-title":"Pharmacol Ther"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108503","article-title":"A systematic review on renal effects of SGLT2 inhibitors in rodent models of diabetic nephropathy","volume":"249","author":"Ashfaq","year":"2023","journal-title":"Pharmacol Ther"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02074-8","article-title":"Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials","volume":"400","year":"2022","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.50050","article-title":"Sodium-glucose cotransport protein 2 inhibitors in patients with type 2 diabetes and acute kidney disease","volume":"7","author":"Pan","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-0946","article-title":"A systematic review and meta-analysis on the safety and efficacy of sodium-glucose cotransporter 2 inhibitor use in hospitalized patients","volume":"47","author":"Gao","year":"2024","journal-title":"Diabetes Care"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-024-01539-1","article-title":"Metformin: past, present, and future","volume":"24","author":"Chaudhary","year":"2024","journal-title":"Curr Diabetes Rep"},{"key":"B34","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/s41421-023-00595-3","article-title":"Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis","volume":"9","author":"Cai","year":"2023","journal-title":"Cell Discov"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14474","article-title":"Comparative effectiveness and safety of sodium-glucose cotransporter-2 inhibitors versus metformin in patients with type 2 diabetes: an observational study using data from routine care","volume":"23","author":"Fralick","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.7326\/M21-4012","article-title":"Cardiovascular outcomes in patients initiating first-line treatment of type 2 diabetes with sodium-glucose cotransporter-2 inhibitors versus metformin: a cohort study","volume":"175","author":"Shin","year":"2022","journal-title":"Ann Intern Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-024-01537-3","article-title":"Diabetes, SGLT-2 inhibitors, and urinary tract infection: a review","volume":"24","author":"Pishdad","year":"2024","journal-title":"Curr Diabetes Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/obr.70100","article-title":"Efficacy of weight-lowering agents on fat distribution: a systematic review and network meta-analysis of randomized controlled trials","volume":"27","author":"Qiao","year":"2026","journal-title":"Obes Rev"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/obr.13336","article-title":"Sodium-glucose co-transporter 2 inhibitors on weight change and cardiometabolic profiles in individuals with overweight or obesity and without diabetes: a meta-analysis","volume":"22","author":"Wong","year":"2021","journal-title":"Obes Rev"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/antiox15050553","article-title":"Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes: from metabolic mechanisms to international guidelines","volume":"15","author":"V\u00e1rkonyi","year":"2026","journal-title":"Antioxidants (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1186\/s12933-024-02539-x","article-title":"SGLT2 inhibition and adipose tissue metabolism: current outlook and perspectives","volume":"23","author":"Morciano","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14508","article-title":"Effects of 1-year treatment with canagliflozin on body composition and total body water in patients with type 2 diabetes","volume":"23","author":"Matsuba","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0146-4","article-title":"Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss","volume":"1","author":"Day","year":"2019","journal-title":"Nat Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113882","article-title":"Distinctive effects of SGLT2 inhibitors on angiogenesis in zebrafish embryos","volume":"156","author":"Huttunen","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14928","article-title":"A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese adults with type 2 diabetes mellitus","volume":"25","author":"Ono","year":"2023","journal-title":"Diabetes Obes Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.3515","article-title":"Comparative efficacy and safety of antihyperglycemic drug classes for patients with type 2 diabetes following failure with metformin monotherapy: a systematic review and network meta-analysis of randomized controlled trials","volume":"38","author":"Zheng","year":"2022","journal-title":"Diabetes Metab Res Rev"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1769013","article-title":"Neurotoxicity of immune checkpoint inhibitors: a retrospective pharmacovigilance study using FAERS database","volume":"17","author":"Cao","year":"2026","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2024.0036","article-title":"Diabetic ketoacidosis as an effect of sodium-glucose cotransporter 2 inhibitor: real world insights","volume":"48","author":"Baek","year":"2024","journal-title":"Diabetes Metab J"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1917352\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:19Z","timestamp":1788496039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1917352\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":48,"alternative-id":["10.3389\/fendo.2026.1917352"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1917352","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]},"article-number":"1917352"}}