Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial
et al., Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223, Aug 2022
Metformin for COVID-19
3rd treatment shown to reduce risk in
July 2020, now with p < 0.00000000001 from 107 studies.
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
RCT 20 hospitalized COVID-19 patients showing faster viral load reduction and lower oxygen use with metformin glycinate 620mg twice daily for 14 days compared to placebo. The in vitro portion demonstrated inhibition of viral replication and cytopathic effects with metformin glycinate pretreatment.
17 preclinical studies support the efficacy of metformin for COVID-19:
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI)14.
Metformin inhibits SARS-CoV-2 in vitro11,12, minimizes LPS-induced cytokine storm in a mouse model13, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS10, may protect against SARS-CoV-2-induced neurological disorders9, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation15, reduces UUO and FAN-induced kidney fibrosis10, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells10, may reduce inflammation, oxidative stress, and thrombosis via regulating glucose metabolism2, attenuates spike protein S1-induced inflammatory response and α-synuclein aggregation8, may reduce COVID-19 severity and long COVID by inhibiting NETosis via suppression of protein kinase C activation16, enhances interferon responses and reduces SARS-CoV-2 infection and inflammation in diabetic models by suppressing HIF-1α signaling7, may improve COVID-19 outcomes by preventing VDAC1 mistargeting to the plasma membrane, reducing ATP loss, and preserving immune cell function during cytokine storm17, reduces hyperglycemia-induced hepatic ACE2/TMPRSS2 up-regulation and SARS-CoV-2 entry6, may reduce COVID-19 severity by suppressing monocyte inflammatory responses and glycolytic activation via AMPK pathway modulation5, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity18.
|
oxygen time, 44.3% lower, relative time 0.56, p = 0.03, treatment mean 5.9 (±4.6) n=10, control mean 10.6 (±6.2) n=10.
|
|
hospitalization time, 10.2% lower, relative time 0.90, p = 0.35, treatment mean 8.8 (±6.1) n=10, control mean 9.8 (±5.4) n=10.
|
|
time to viral-, 41.1% lower, relative time 0.59, p = 0.03, treatment mean 3.3 (±2.16) n=10, control mean 5.6 (±0.89) n=10.
|
| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
Tavares et al., Investigation of Interactions Between the Protein MPro and the Vanadium Complex VO(metf)2∙H2O: A Computational Approach for COVID-19 Treatment, Biophysica, doi:10.3390/biophysica5010004.
2.
Hou et al., Metformin is a potential therapeutic for COVID-19/LUAD by regulating glucose metabolism, Scientific Reports, doi:10.1038/s41598-024-63081-0.
3.
Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.
4.
Lockwood, T., Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent, BioMetals, doi:10.1007/s10534-024-00590-5.
5.
Maurmann et al., Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1, bioRxiv, doi:10.1101/2025.09.12.675877.
6.
Rao et al., Pathological Glucose Levels Enhance Entry Factor Expression and Hepatic SARS‐CoV‐2 Infection, Journal of Cellular and Molecular Medicine, doi:10.1111/jcmm.70581.
7.
Joshi et al., Severe SARS‐CoV‐2 infection in diabetes was rescued in mice supplemented with metformin and/or αKG, and patients taking metformin, via HIF1α‐IFN axis, Clinical and Translational Medicine, doi:10.1002/ctm2.70275.
8.
Chang et al., SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin, Biomedicines, doi:10.3390/biomedicines12061223.
9.
Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.
10.
Miguel et al., Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney, Redox Biology, doi:10.1016/j.redox.2023.102957.
11.
Ventura-López et al., Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial, Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223.
12.
Parthasarathy et al., Metformin Suppresses SARS-CoV-2 in Cell Culture, bioRxiv, doi:10.1101/2021.11.18.469078.
13.
Taher et al., Anti‑inflammatory effect of metformin against an experimental model of LPS‑induced cytokine storm, Experimental and Therapeutic Medicine, doi:10.3892/etm.2023.12114.
14.
Wang et al., Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1215307.
15.
Zhang et al., SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects, Pathogens, doi:10.3390/pathogens13010075.
16.
Monsalve et al., NETosis: A key player in autoimmunity, COVID-19, and long COVID, Journal of Translational Autoimmunity, doi:10.1016/j.jtauto.2025.100280.
Ventura-López et al., 31 Aug 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, peer-reviewed, mean age 47.5, 14 authors, study period January 2020 - August 2021.
Contact: cventura@cicese.mx, kcervates@cicese.mx, janetaguirre@yahoo.com, juancarlosfl18@hotmail.com, alvarezc@cicese.mx, jbernald@cicese.mx, lsanchez@cicese.mx, llugo@silanes.com.mx, icrodriguez@silanes.com.mx, jgsander@silanes.com.mx, yromero@silanes.com.mx, marguedas@silanes.com.mx, jogonzalez@silanes.com.mx, alicea@cicese.mx.
Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial
Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223
The health crisis caused by the new coronavirus SARS-CoV-2 highlights the need to identify new treatment strategies for this viral infection. During the past year, over 400 coronavirus disease (COVID-19) treatment patents have been registered; nevertheless, the presence of new virus variants has triggered more severe disease presentations and reduced treatment effectiveness, highlighting the need for new treatment options for the COVID-19. This study evaluates the Metformin Glycinate (MG) effect on the SARS-CoV-2 in vitro and in vivo viral load. The in vitro study was conducted in a model of Vero E6 cells, while the in vivo study was an adaptive, twoarmed, randomized, prospective, longitudinal, double-blind, multicentric, and phase IIb clinical trial. Our in vitro results revealed that MG effectively inhibits viral replication after 48 h of exposure to the drug, with no cytotoxic effect in doses up to 100 µM. The effect of the MG was also tested against three variants of interest (alpha, delta, and epsilon), showing increased survival rates in cells treated with MG. These results are aligned with our clinical data, which indicates that MG treatment reduces SARS-CoV2-infected patients´viral load in just 3.3 days and supplementary oxygen requirements compared with the control group. We expect our results can guide efforts to position MG as a therapeutic option for COVID-19 patients.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
Ali, Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19, J. Med. Virol, doi:10.1002/jmv.26097
Alothaid, Aldughaim, Bakkouri, Almashhadi, Al-Qahtani, Similarities between the effect of SARS-CoV-2 and HCV on the cellular level, and the possible role of ion channels in COVID19 progression: a review of potential targets for diagnosis and treatment, Channels, doi:10.1080/19336950.2020.1837439
Altan-Bonnet, Lipid tales of viral replication and transmission, Trends Cell Biol, doi:10.1016/j.tcb.2016.09.011
Amako, Syed, Siddiqui, Protein kinase D negatively regulates hepatitis C virus secretion through phosphorylation of oxysterol-binding protein and ceramide transfer protein, J. Biol. Chem, doi:10.1074/jbc.M110.182097
Ceriello, Hyperglycemia and COVID-19: what was known and what is really new?, Diabetes Res. Clin. Pract, doi:10.1016/j.diabres.2020.108383
Corman, Landt, Kaiser, Molenkamp, Meijer et al., Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR, Eur. Surveill, doi:10.2807/1560-7917.ES.2020.25.3.2000045
Cory, Owen, Barltrop, Cory, Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture, Cancer Commun, doi:10.3727/095535491820873191
Díaz, Aguilar-Jiménez, Flórez-Álvarez, Valencia, Laiton-Donato et al., Isolation and characterization of an early SARS-CoV-2 isolate from the 2020 epidemic in Medellín, Colombia. Aislamiento y caracterización de una cepa temprana de SARS-CoV-2 durante la epidemia de 2020 en Medellín, Colombia, Biomed.: Rev. Inst. Nac. Salud, doi:10.7705/biomedica.5834
Egger, Wolk, Gosert, Bianchi, Blum et al., Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex, J. Virol, doi:10.1128/jvi.76.12.5974-5984.2002
Florin, Pegel, Becker, Hausser, Olayioye et al., Heterologous expression of the lipid transfer protein CERT increases therapeutic protein productivity of mammalian cells, J. Biotechnol, doi:10.1016/j.jbiotec.2009.02.014
Ford, Fullerton, Pinkosky, Day, Scott et al., Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity, Biochem. J, doi:10.1042/BJ20150125
Foster, Weir, Lim, Liu, Trimble et al., A functional role for VAP-33 in insulin-stimulated GLUT4 traffic, Traffic, doi:10.1034/j.1600-0854.2000.010609.x
Fung, Liu, Human coronavirus: host-pathogen interaction, Annu. Rev. Microbiol, doi:10.1146/annurev-micro-020518-115759
Garcia-Sastre, Ten strategies of interferon evasion by viruses, Cell Host Microbe, doi:10.1016/j.chom.2017.07.012
Gewaid, Aoyagi, Arita, Watashi, Suzuki et al., Sphingomyelin is essential for the structure and function of the double-membrane vesicles in hepatitis C virus RNA replication factories, J. Virol, doi:10.1128/JVI.01080-20
González-Canudas, Comet Group, 146-LB: efficacy and safety of metformin glycinate vs. metformin hydrochloride in metabolic control and inflammatory mediators in Type 2 diabetes mellitus patients (T2DM), ADA, doi:10.2337/db19-146-LB
Hardie, Ross, Hawley, AMPK: a nutrient and energy sensor that maintains energy homeostasis, Nat. Rev. Mol. Cell Biol, doi:10.1038/nrm3311
Kao, Lai, Yu, How dengue virus circumvents innate immunity, Front. Immunol, doi:10.3389/fimmu.2018.02860
Kawano, Kumagai, Nishijima, Hanada, Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT, J. Biol. Chem, doi:10.1074/jbc.M605032200
Kikkert, Innate immune evasion by human respiratory RNA viruses, J. Innate Immun, doi:10.1159/000503030
Ojeda-Fernández, Foresta, Macaluso, Colacioppo, Tettamanti et al., Metformin use is associated with a decrease in the risk of hospitalization and mortality in COVID-19 patients with diabetes: a population-based study in Lombardy, Diabetes Obes. Metab, doi:10.1111/dom.14648
Prosser, Tran, Gougeon, Verly, Ngsee, FFAT rescues VAPAmediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation, J. Cell Sci, doi:10.1242/jcs.028696
Rada, Mosquera, Mutané, Ferrandiz, Rodríguez-Mañas et al., Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice, Food Chem. Toxicol, doi:10.1016/j.fct.2018.11.019
Ramakrishnan, Determination of 50 % endpoint titer using a simple formula, World J. Virol, doi:10.5501/wjv.v5.i2.85
Raya, Revert-Ros, Martinez-Martinez, Navarro, Rosello et al., Goodpasture antigen-binding protein, the kinase that phosphorylates the goodpasture antigen, is an alternatively spliced variant implicated in autoimmune pathogenesis, J. Biol. Chem, doi:10.1074/jbc.M002769200
Reed, Muench, A simple method of estimating fifty per cent endpoints, Am. J. Epidemiol, doi:10.1093/oxfordjournals.aje.a118408
Riss, Moravec, Comparison of MTT, XTT, and a novel tetrazolium compound for MTS for in vitro proliferation and chemosensitivity assays, Mol. Biol. Cell
Romero-Brey, Bartenschlager, Membranous replication factories induced by plus-strand RNA viruses, Viruses, doi:10.3390/v6072826
Sachs, Schnurr, Yagi, Lachowicz-Scroggins, Widdicombe, Quantitative real-time PCR for rhinovirus, and its use in determining the relationship between TCID50 and the number of viral particles, J. Virol. Methods, doi:10.1016/j.jviromet.2010.10.027
Saito, Matsui, Kawano, Kumagai, Tomishige et al., Protein phosphatase 2Cepsilon is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes, J. Biol. Chem, doi:10.1074/jbc.M707691200
Samuel, Varghese, Büsselberg, Therapeutic potential of metformin in COVID-19: reasoning for its protective role, Trends Microbiol, doi:10.1016/j.tim.2021.03.004
Varghese, Samuel, Liskova, Kubatka, Büsselberg, Diabetes and coronavirus (SARS-CoV-2): molecular mechanism of metformin intervention and the scientific basis of drug repurposing, PLoS Pathog, doi:10.1371/journal.ppat.1009634
Wang, Tai, Mechanisms of cellular membrane reorganization to support hepatitis C virus replication, Viruses, doi:10.3390/v8050142
Yao, Cao, Wang, Shi, Liu et al., Ddimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study, J. Intensive Care, doi:10.1186/s40560-020-00466-z
Zhang, Wang, Bao, Xu, Shen et al., Metformin interacts with AMPK through binding to gamma subunit, Mol. Cell. Biochem, doi:10.1007/s11010-012-1344-5
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"DOI": "10.1016/j.jviromet.2010.10.027",
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"first-page": "85",
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{
"DOI": "10.2807/1560-7917.ES.2020.25.3.2000045",
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"first-page": "207",
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"article-title": "Comparison of MTT, XTT, and a novel tetrazolium compound for MTS for in vitro proliferation and chemosensitivity assays",
"author": "Riss",
"first-page": "S184a",
"issue": "Suppl.",
"journal-title": "Mol. Biol. Cell",
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"year": "1992"
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"DOI": "10.1111/dom.14648",
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"DOI": "10.1016/j.tim.2021.03.004",
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"first-page": "894",
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"volume": "29",
"year": "2021"
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{
"DOI": "10.1371/journal.ppat.1009634",
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"DOI": "10.1016/j.tcb.2016.09.011",
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"first-page": "201",
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"year": "2017"
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{
"DOI": "10.1080/19336950.2020.1837439",
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"DOI": "10.1128/JVI.76.12.5974-5984.2002",
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"author": "Egger",
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"first-page": "5974",
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"year": "2002"
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{
"DOI": "10.3390/v8050142",
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"first-page": "142",
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"first-page": "4",
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"DOI": "10.3390/v6072826",
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"DOI": "10.1016/j.diabres.2020.108383",
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Late treatment
is less effective
is less effective
