{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:40:30Z","timestamp":1788950430847,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,19]],"date-time":"2022-02-19T00:00:00Z","timestamp":1645228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Background: Obesity is a risk factor for the development of influenza by leading to a chronic inflammatory state and T-cell dysfunction. Based upon preclinical research, metformin has influenza activity by restoring T-cell function and improving the immune response. Objective: We aimed to evaluate the potential drug repurposing of metformin for the management of influenza among patients with obesity utilizing national claims data in an electronic health record database. Methods: The VA Informatics and Computing Infrastructure (VINCI) was utilized to obtain individual-level information on demographics, administrative claims, and pharmacy dispensation. A cohort was created among individuals with laboratory confirmed diagnosis of influenza with a diagnosis of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome was death after diagnosis of influenza. Cohorts were formed using diabetes status and metformin exposure prior to a positive influenza diagnosis. Hazard ratios for mortality were estimated using a cox proportional hazards model adjusting for baseline covariates and a sub-analysis was conducted utilizing propensity score matching. A greedy nearest neighbor algorithm was utilized to match 1 to 1 non-metformin diabetic controls and non-diabetic controls to diabetic patients receiving metformin. Results: A total of 3551 patients met the inclusion criteria and were evaluated in our study. The cohorts consisted of 1461 patients in the non-diabetic cohort, 1597 patients in the diabetic \/ metformin cohort, and 493 patients in the diabetic no metformin cohort. Compared to non-diabetic patients, diabetic patients with metformin had a lower rate of death (aHR 0.78, 95% CI 0.609\u20130.999). There was not a statistical difference between the non-diabetic patients and the diabetic patients without metformin (aHR 1.046, 95% CI 0.781\u20131.400). The propensity score matched cohorts revealed consistent results with the primary analysis. Conclusion: Our results demonstrated patients with obesity and a history of metformin treatment have lower influenza mortality.<\/jats:p>","DOI":"10.3390\/pathogens11020270","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:23:29Z","timestamp":1645431809000},"page":"270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Patients with Obesity and a History of Metformin Treatment Have Lower Influenza Mortality: A Retrospective Cohort Study"],"prefix":"10.3390","volume":"11","author":[{"given":"Tammy H.","family":"Cummings","sequence":"first","affiliation":[{"name":"Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209, USA"},{"name":"Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Magagnoli","sequence":"additional","affiliation":[{"name":"Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209, USA"},{"name":"Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Hardin","sequence":"additional","affiliation":[{"name":"Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209, USA"},{"name":"Department of Epidemiology & Biostatistics, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3889-6178","authenticated-orcid":false,"given":"S. Scott","family":"Sutton","sequence":"additional","affiliation":[{"name":"Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209, USA"},{"name":"Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,19]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, January 26). Global influenza strategy 2019\u20132030. Available online: https:\/\/apps.who.int\/iris\/handle\/10665\/311184."},{"key":"ref_2","unstructured":"CDC (2022, January 26). Pandemic Basics, Available online: https:\/\/www.cdc.gov\/flu\/pandemic-resources\/basics\/faq.html."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Morgan, O.W., Bramley, A., Fowlkes, A., Freedman, D.S., Taylor, T.H., Gargiullo, P., Belay, B., Jain, S., Cox, C., and Kamimoto, L. (2010). Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009694"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/cid\/ciq152","article-title":"A novel risk factor for a novel virus: Obesity and 2009 pandemic influenza a (H1N1)","volume":"52","author":"Louie","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/ijo.2017.131","article-title":"Increased risk of influenza among vaccinated adults who are obese","volume":"41","author":"Neidich","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ijo.2011.208","article-title":"Obesity is associated with impaired immune response to influenza vaccination in humans","volume":"36","author":"Sheridan","year":"2012","journal-title":"Int. J. Obes."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S406","DOI":"10.1513\/AnnalsATS.201706-447AW","article-title":"Obesity impairs the adaptive immune response to influenza virus","volume":"14","author":"Green","year":"2017","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1002\/oby.20383","article-title":"Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 Influenza a virus","volume":"21","author":"Paich","year":"2013","journal-title":"Obesity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1038\/s41366-020-00692-3","article-title":"Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity","volume":"44","author":"Alwarawrah","year":"2020","journal-title":"Int. J. Obes."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1093\/infdis\/jiy700","article-title":"Obesity-induced changes in T-cell metabolism are associated with impaired memory T-cell response to influenza and are not reversed with weight loss","volume":"219","author":"Rebeles","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S133","DOI":"10.1086\/507548","article-title":"Prevention and treatment of influenza in high-risk groups: Children, pregnant women, immunocompromised hosts, and nursing home residents","volume":"194","author":"Whitley","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1086\/527391","article-title":"A prospective, comparative study of the immune response to inactivated influenza vaccine in pediatric liver transplant recipients and their healthy siblings","volume":"46","author":"Madan","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11756","DOI":"10.1128\/JVI.01460-06","article-title":"Cellular Immune Responses in Children and Adults Receiving Inactivated or Live Attenuated Influenza Vaccines","volume":"80","author":"He","year":"2006","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/ijo.2012.62","article-title":"Obesity and the risk and outcome of infection","volume":"37","author":"Huttunen","year":"2013","journal-title":"Int. J. Obes."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1017\/S0029665112000158","article-title":"The impact of obesity on the immune response to infection","volume":"71","author":"Milner","year":"2012","journal-title":"Nutr. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.3389\/fimmu.2019.01071","article-title":"Impact of obesity on influenza A virus pathogenesis, immune response, and evolution","volume":"10","author":"Honce","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Benedetti, F., Sorrenti, V., Buriani, A., Fortinguerra, S., Scapagnini, G., and Zella, D. (2020). Resveratrol, rapamycin and metformin as modulators of antiviral pathways. Viruses, 12.","DOI":"10.3390\/v12121458"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1146\/annurev-immunol-032713-120236","article-title":"Metabolic regulation of immune responses","volume":"32","author":"Ganeshan","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.3389\/fimmu.2018.01055","article-title":"Changes in nutritional status impact immune cell metabolism and function","volume":"9","author":"Alwarawrah","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1038\/s41467-018-05116-5","article-title":"Network-based approach to prediction and population-based validation of in silico drug repurposing","volume":"9","author":"Cheng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-10914-6","article-title":"Country-wide medical records infer increased allergy risk of gastric acid inhibition","volume":"10","author":"Jordakieva","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/cpt.512","article-title":"Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making","volume":"100","author":"Schneeweiss","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jclinepi.2004.10.012","article-title":"A review of uses of health care utilization databases for epidemiologic research on therapeutics","volume":"58","author":"Schneeweiss","year":"2005","journal-title":"J. Clin. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/EDE.0b013e3181a663cc","article-title":"High-dimensional propensity score adjustment in studies of treatment effects using health care claims data","volume":"20","author":"Schneeweiss","year":"2009","journal-title":"Epidemiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.amjmed.2015.10.015","article-title":"Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration","volume":"129","author":"Brilliant","year":"2016","journal-title":"Am. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/irv.12470","article-title":"The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection","volume":"11","author":"Sellers","year":"2017","journal-title":"Influenza Other Respi. Viruses"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1093\/infdis\/jir171","article-title":"Circulating influenza virus, climatic factors, and acute myocardial infarction: A time series study in England and Wales and Hong Kong","volume":"203","author":"Bhaskaran","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1093\/infdis\/jis597","article-title":"Influenza infection and risk of acute myocardial infarction in england and wales: A CALIBER self-controlled case series study","volume":"206","author":"Hayward","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S1473-3099(09)70233-6","article-title":"Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: A systematic review","volume":"9","author":"Smeeth","year":"2009","journal-title":"Lancet Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"A9819","DOI":"10.1161\/circ.144.suppl_1.9819","article-title":"Abstract 9819: Real World Data: Off-Label Metformin in Patients with Prediabetes is Associated with Improved Cardiovascular Outcomes","volume":"144","author":"Murillo","year":"2021","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-71946-3","article-title":"Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis","volume":"10","author":"Nojima","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.2337\/diacare.25.12.2244","article-title":"Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes","volume":"25","author":"Johnson","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1001\/archinternmed.2010.409","article-title":"Metformin use and mortality among patients with diabetes and atherothrombosis","volume":"170","author":"Roussel","year":"2010","journal-title":"Arch. Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1016\/S2666-7568(20)30033-7","article-title":"Metformin and risk of mortality in patients hospitalised with COVID-19: A retrospective cohort analysis","volume":"2","author":"Bramante","year":"2021","journal-title":"Lancet Healthy Longev."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/2\/270\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:22:58Z","timestamp":1760134978000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/2\/270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,19]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["pathogens11020270"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11020270","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,19]]}}}