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Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial

Ventura-López et al., Biomedicine & Pharmacotherapy, doi:10.1016/j.biopha.2022.113223

Aug 2022

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Metformin for COVID-19

3rd treatment shown to reduce risk in July 2020

^*, now known with p < 0.00000000001 from 88 studies.

Lower risk for mortality, ventilation, ICU admission, hospitalization, progression, and recovery.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ 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.

7 preclinical studies support the efficacy of metformin for COVID-19:

1 In Silico study Lockwood

4 In Vitro studies Miguel, Parthasarathy, Ventura-López, Yang

2 In Vivo animal studies Miguel, Taher

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) Wang. Metformin inhibits SARS-CoV-2 in vitro Parthasarathy, Ventura-López, minimizes LPS-induced cytokine storm in a mouse model Taher, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS Miguel, may protect against SARS-CoV-2-induced neurological disorders Yang, may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation Zhang, reduces UUO and FAN-induced kidney fibrosis Miguel, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells Miguel, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity Petakh.

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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. 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.springer.com, doi.org.

2. 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.sciencedirect.com, doi.org.

3. Parthasarathy et al., Metformin Suppresses SARS-CoV-2 in Cell Culture, bioRxiv, doi:10.1101/2021.11.18.469078.biorxiv.org, doi.org.

4. Petakh et al., Metformin Alters mRNA Expression of FOXP3, RORC, and TBX21 and Modulates Gut Microbiota in COVID-19 Patients with Type 2 Diabetes, Viruses, doi:10.3390/v16020281.mdpi.com, doi.org.

5. 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.spandidos-publications.com, doi.org.

6. 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.sciencedirect.com, doi.org.

7. 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.frontiersin.org, doi.org.

8. Yang et al., SARS-CoV-2 infection causes dopaminergic neuron senescence, Cell Stem Cell, doi:10.1016/j.stem.2023.12.012.sciencedirect.com, doi.org.

9. 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.mdpi.com, doi.org.

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.

This Paper Metformin All

Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial

Claudia Ventura-López, Karla Cervantes-Luevano, Janet S Aguirre-Sánchez, Juan C Flores-Caballero, Carolina Alvarez-Delgado, Johanna Bernaldez-Sarabia, Noemí Sánchez-Campos, Laura A Lugo-Sánchez, Ileana C Rodríguez-Vázquez, Jose G Sander-Padilla, Yulia Romero-Antonio, María M Arguedas-Núñez, Jorge González-Canudas, Alexei F Licea-Navarro

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.

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Late treatment
is less effective

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