Outpatient metformin use is associated with reduced severity of COVID‐19 disease in adults with overweight or obesity
MD, MPH Carolyn T Bramante, MD John Buse, MD Leonardo Tamaritz, MD Ana Palacio, MD Ken Cohen, Deneen Vojta, MD David Liebovitz, MD, MPH Nia Mitchell, MD Jacinda Nicklas, MD, MPH, MSCS Ildiko Lingvay, MD, MPH Jeanne M Clark, Louis J Aronne, MD, MPH Erik Anderson, Michael Usher, PhD, MPH Ryan Demmer, MD Genevieve B Melton, MD Nicholas Ingraham, Christopher J Tignanelli
Journal of Medical Virology, doi:10.1002/jmv.26873
Observational studies suggest outpatient metformin use is associated with reduced mortality from coronavirus disease-2019 (COVID-19). Metformin is known to decrease interleukin-6 and tumor-necrosis factor-α, which appear to contribute to morbidity in COVID-19. We sought to understand whether outpatient metformin use was associated with reduced odds of severe COVID-19 disease in a large US healthcare data set. Retrospective cohort analysis of electronic health record (EHR) data that was pooled across This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
AUTHOR CONTRIBUTIONS Dr. Tignanelli is the guarantor with responsibility for the work as a whole given his full access to the data. Carolyn T. Bramante Michael Usher contributed to design and analysis. Ryan Demmer contributed to design, analysis, and critical review. Genevieve B. Melton contributed to design and analysis and writing. Nicholas Ingraham contributed to analysis and writing. Christopher J. Tignanelli contributed to study design, analysis, interpretation, and critical review.
SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article.
References
Afshari, Haddadi, Anti-inflammatory effects of metformin improve the neuropathic pain and locomotor activity in spinal cord injured rats: introduction of an alternative therapy, Spinal Cord
Alwarawrah, Nichols, Green, Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity, Int J Obes
Atzeni, Gerratana, Giallanza, The effect of drugs used in rheumatology for treating SARS-CoV2 infection, Expert Opin Biol Ther
Babinski, Giermaziak, Influenza epidemic in 1971 in diabetics treated with 1-butyl-biguanidine hydrochloride (Silubin retard) and 1-phenylethyl-biguanidine hydrochloride (Phenformin), Pol Tyg Lek
Bailey, Metformin: historical overview, Diabetologia
Barbaro, Hoffman, The Vaccine Trust Problem [Internet
Berlin, Gulick, Martinez, Severe COVID-19, N Engl J Med
Bramante, Ingraham, Murray, Observational study of metformin and risk of mortality in patients hospitalized with COVID-19
Brookhart, Schneeweiss, Rothman, Glynn, Avorn et al., Variable selection for propensity score models, Am J Epidemiol
Cameron, Morrison, Levin, Anti-inflammatory effects of metformin irrespective of diabetes status, Circ Res
Campo, García-Valdecasas, Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy, PLOS One
Campo, García-Valdecasas, Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy, PLOS One
Cariou, Hadjadj, Wargny, Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study, Diabetologia
Chen, Sang, Jiang, Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China, J Allergy Clin Immunol
Crouse, Grimes, Peng, Might, Ovalle et al., Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes
De Macedo, Brazil and COVID-19-A fleeting glimpse of what is to come, JAMA Health Forum
Dehkordi, Abbaszadeh, Mir, Hasanvand, Metformin and its anti-inflammatory and anti-oxidative effects; new concepts, J Renal Inj Prev
Flory, Lipska, Metformin in 2019, JAMA
Gordon, Jang, Bouhaddou, A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing, bioRxiv
Hyun, Shin, Lee, Metformin down-regulates TNF-α secretion via suppression of scavenger receptors in macrophages, Immune Netw
Ingraham, Lotfi-Emran, Thielen, Immunomodulation in COVID-19, Lancet Respir Med
Karam, Morris, Bramante, mTOR inhibition in COVID-19: A commentary and review of efficacy in RNA viruses, J Med Virol
Krysiak, Gdula-Dymek, Okopień, Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance, Pharmacol Rep
Kuo, Pilling, Atkins, COVID-19 severity is predicted by earlier evidence of accelerated aging, medRxiv
Little, Agostino, Cohen, The prevention and treatment of missing data in clinical trials, N Engl J Med
Lunt, Selecting an appropriate caliper can be essential for achieving good balance with propensity score matching, Am J Epidemiol
Luo, Qiu, Liu, Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis, Am J Trop Med Hyg
Mehta, Mcauley, Brown, Sanchez, Tattersall et al., COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet
Mishra, Dingli, Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells, Leukemia
Nakashima, Takeuchi, Chihara, Hotta, Sada, Inhibition of hepatitis C virus replication through adenosine monophosphateactivated protein kinase-dependent and -independent pathways, Microbiol Immunol
Rangarajan, Bone, Zmijewska, Metformin reverses established lung fibrosis in a bleomycin model, Nat Med
Salber, Wang, Lynch, Metformin use in practice: compliance with guidelines for patients with diabetes and preserved renal function, Clinical Diabetes
Salpeter, Greyber, Pasternak, Posthumous, Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus, Cochrane Database Syst Rev
Singh, Singh, Suhail, AMP-activated protein kinase restricts zika virus replication in endothelial cells by potentiating innate antiviral responses and inhibiting glycolysis, J Immunol
Ursini, Russo, Pellino, Metformin and autoimmunity: a "new deal" of an old drug, Front Immunol
Vanderweele, Ding, Sensitivity analysis in observational research: introducing the E-value, Ann Intern Med
Verdura, Cuyàs, Martin-Castillo, Menendez, Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy, Oncoimmunology
Wang, Li, Chen, Gu, Ye, Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin, Arthritis Rheumatol
Warnakulasuriya, Fernando, Adikaram, Metformin in the management of childhood obesity: a randomized control trial, Childhood Obesity
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