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All Studies   Meta Analysis    Recent:   
0 0.5 1 1.5 2+ ICU admission, both cohor.. 37% Improvement Relative Risk ICU admission, cohort 1 43% ICU admission, cohort 2 31% Metformin for COVID-19  Miguel et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 132 patients in Spain (March - June 2020) Lower ICU admission with metformin (not stat. sig., p=0.24) c19early.org Miguel et al., Redox Biology, November 2023 Favors metformin Favors control

Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney

Miguel et al., Redox Biology, doi:10.1016/j.redox.2023.102957
Nov 2023  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
 
*, now known with p < 0.00000000001 from 84 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments. c19early.org
Mouse models showing reduced lung and kidney injury with metformin. Metformin minimized lung damage and fibrosis in a mouse model of LPS-induced ARDS, and reduced UUO and FAN-induced kidney fibrosis. In Vitro study showing that metformin increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells.
Authors also include a retrospective study showing lower ICU admission with metformin without statistical significance.
6 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) 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.
risk of ICU admission, 37.4% lower, RR 0.63, p = 0.24, treatment 49, control 40, both cohorts combined.
risk of ICU admission, 42.9% lower, RR 0.57, p = 0.34, treatment 3 of 15 (20.0%), control 14 of 40 (35.0%), NNT 6.7.
risk of ICU admission, 31.4% lower, RR 0.69, p = 0.52, treatment 6 of 49 (12.2%), control 5 of 28 (17.9%), NNT 18.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Miguel et al., 17 Nov 2023, retrospective, Spain, peer-reviewed, 19 authors, study period March 2020 - June 2020. Contact: veronica.miguel@cnic.es, slamas@cbm.csic.es.
This PaperMetforminAll
Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney
Verónica Miguel, Carlos Rey-Serra, Jessica Tituaña, Belén Sirera, Elena Alcalde-Estévez, J Ignacio Herrero, Irene Ranz, Laura Fernández, Carolina Castillo, Lucía Sevilla, James Nagai, Katharina C Reimer, Jitske Jansen, Rafael Kramann, Ivan G Costa, Ana Castro, David Sancho, José Miguel Rodríguez González-Moro, Santiago Lamas
Redox Biology, doi:10.1016/j.redox.2023.102957
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.
Author contributions SL conceived and directed research. VM designed, performed and analyzed the majority of experiments. CRS, JT, BS, EA, IR and LF performed experiments. JIH provided technical assistance for mouse experiments. CC performed histological evaluation. KCR, JJ, RK and DS provided intellectual insight and resources. LS and JMRGM collected information about COVID-19 patient cohorts. JN and IC performed bioinformatic studies. AC provided indol-based compounds. All authors helped with the discussion of the results and SL and VM wrote the manuscript. Declaration of competing interest The authors have no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.redox.2023.102957.
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