Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

WHO. Timeline of WHO’s response to COVID-19. 2020 [cited 2021 Feb 10]. Available from: https://www.who.int/news-room/detail/29-06-2020-covidtimeline.

JHU. Coronavirus Resource Center. 2021 [cited 2021 May 16]. Available from: https://coronavirus.jhu.edu/.

Z Zhu, 2020, From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses., Respir Res., 21, 224, 10.1186/s12931-020-01479-w

AK Singh, 2020, Is metformin ahead in the race as a repurposed host-directed therapy for patients with diabetes and COVID-19?, Diabetes Res Clin Pract, 165, 10.1016/j.diabres.2020.108268

Y Chen, 2020, Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: a systematic review and meta-analysis., medRxiv., 2020

CS Curran, 2020, COVID-19 Usurps Host Regulatory Networks., Front Pharmacol., 11, 1278, 10.3389/fphar.2020.01278

TM Abu Samaan, 2019, Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer., Biomolecules, 9, 10.3390/biom9120789

M Apicella, 2020, COVID-19 in people with diabetes: understanding the reasons for worse outcomes, Lancet Diabetes Endocrinol., 8, 782, 10.1016/S2213-8587(20)30238-2

LC Pinto, 2020, Type 2 diabetes as a major risk factor for COVID-19 severity: a meta-analysis., Arch Endocrinol Metab., 64, 199, 10.20945/2359-3997000000256

ISPAD, 2020, Summary of recommendations regarding COVID-19 in children with diabetes: Keep Calm and Mind your Diabetes Care and Public Health Advice., Pediatr Diabetes., 21, 413, 10.1111/pedi.13013

R Unsworth, 2020, New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K, Diabetes Care, 43, e170, 10.2337/dc20-1551

B Bode, 2020, Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States, J Diabetes Sci Technol, 14, 813, 10.1177/1932296820924469

L Zhu, 2020, Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes., Cell Metab., 31, 1068, 10.1016/j.cmet.2020.04.021

R Gianchandani, 2020, Managing Hyperglycemia in the COVID-19 Inflammatory Storm., Diabetes., 69, 2048, 10.2337/dbi20-0022

SM Samuel, 2017, Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death, Biochem Pharmacol, 132, 118, 10.1016/j.bcp.2017.03.001

SM Samuel, 2019, Treatment with a Combination of Metformin and 2-Deoxyglucose Upregulates Thrombospondin-1 in Microvascular Endothelial Cells: Implications in Anti-Angiogenic Cancer Therapy., Cancers (Basel)., 11

SM Samuel, 2019, Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer., Biomolecules, 9, 10.3390/biom9120846

CR Triggle, 2017, Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium, Acta Physiol (Oxf))., 219, 138, 10.1111/apha.12644

S Varghese, 2019, High Glucose Represses the Anti-Proliferative and Pro-Apoptotic Effect of Metformin in Triple Negative Breast Cancer Cells., Biomolecules, 9, 10.3390/biom9010016

SM Samuel, 2021, Therapeutic Potential of Metformin in COVID-19: Reasoning for its Protective Role, Trends Microbiol

AJ Scheen, Metformin and COVID-19: From cellular mechanisms to reduced mortality, Diabetes Metab. 2020, 46, 423, 10.1016/j.diabet.2020.07.006

R Allard, 2010, Diabetes and the severity of pandemic influenza A (H1N1) infection., Diabetes Care, 33, 1491, 10.2337/dc09-2215

KA Kulcsar, 2019, Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection, JCI Insight, 4, e131774, 10.1172/jci.insight.131774

JK Yang, 2006, Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS, Diabet Med, 23, 623, 10.1111/j.1464-5491.2006.01861.x

S Erener, 2020, Diabetes, infection risk and COVID-19., Mol Metab., 39, 101044, 10.1016/j.molmet.2020.101044

JM Gregory, 2021, COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pandemic’s Impact in Type 1 and Type 2 Diabetes., Diabetes Care., 44, 526, 10.2337/dc20-2260

G Lisco, 2020, Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: a review, Endocrine, 70, 441, 10.1007/s12020-020-02444-9

L-A Teuwen, 2020, COVID-19: the vasculature unleashed, Nat Rev Immunol, 20, 389, 10.1038/s41577-020-0343-0

N Holman, 2020, Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study, Lancet Diabetes Endocrinol., 8, 823, 10.1016/S2213-8587(20)30271-0

E Barron, 2020, Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study., Lancet Diabetes Endocrinol., 8, 813, 10.1016/S2213-8587(20)30272-2

SK Boddu, 2020, New onset diabetes, type 1 diabetes and COVID-19., Diabetes Metab Syndr., 14, 2211, 10.1016/j.dsx.2020.11.012

JA Müller, 2021, SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas, Nat Metab., 3, 149, 10.1038/s42255-021-00347-1

L Yang, 2020, A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids., Cell Stem Cell., 27, 125, 10.1016/j.stem.2020.06.015

AC Codo, 2020, Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis, Cell Metab., 32, 437, 10.1016/j.cmet.2020.07.007

C Junqueira, 2021, SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release., medRxiv

M Zheng, 2021, The Cytokine Profiles and Immune Response Are Increased in COVID-19 Patients with Type 2 Diabetes Mellitus., J Diabetes Res., 2021, 9526701, 10.1155/2021/9526701

RAS Santos, 2018, The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)., Physiol Rev, 98, 505, 10.1152/physrev.00023.2016

N Banu, 2020, Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications, Life Sci, 256, 117905, 10.1016/j.lfs.2020.117905

A Elbadawi, 2021, Incidence and Outcomes of Thrombotic Events in Symptomatic Patients With COVID-19, Arterioscler Thromb Vasc Biol, 41, 545, 10.1161/ATVBAHA.120.315304

E Gavriilaki, 2020, Endothelial Dysfunction in COVID-19: Lessons Learned from Coronaviruses., Curr Hypertens Rep., 22, 63, 10.1007/s11906-020-01078-6

Y Jin, 2020, Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches., Signal Transduct Target Ther, 5, 293, 10.1038/s41392-020-00454-7

A Huertas, 2020, Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?, Eur Respir J, 56, 2001634, 10.1183/13993003.01634-2020

Z Varga, 2020, Endothelial cell infection and endotheliitis in COVID-19, Lancet, 395, 1417, 10.1016/S0140-6736(20)30937-5

A Ribes, 2020, Thromboembolic events and Covid-19., Adv Biol Regul., 77, 100735, 10.1016/j.jbior.2020.100735

G Goshua, 2020, Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study, Lancet Haematol., 7, e575, 10.1016/S2352-3026(20)30216-7

N Tang, 2020, Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia, J Thromb Haemost, 18, 844, 10.1111/jth.14768

AK Singh, 2020, Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review, Diabetes Res Clin Pract, 165, 108266, 10.1016/j.diabres.2020.108266

L He, 2020, Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 –implications for microvascular inflammation and hypercoagulopathy in COVID-19., bioRxiv, 2020

Q Sun, 2014, New insights into insulin: The anti-inflammatory effect and its clinical relevance, World J Diabetes, 5, 89, 10.4239/wjd.v5.i2.89

C Sardu, 2020, Outcomes in Patients With Hyperglycemia Affected by Covid-19: Can We Do More on Glycemic Control?, Diabetes Care, dc200723

Y Chen, 2020, Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication, Diabetes Care, dc200660

ESB Salem, 2014, Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice, Am J Physiol Renal Physiol, 306, F629, 10.1152/ajprenal.00516.2013

S Sharma, 2020, Metformin in COVID-19: A possible role beyond diabetes, Diabetes Res Clin Pract, 164, 108183, 10.1016/j.diabres.2020.108183

AB Crouse, 2021, Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes., Front Endocrinol (Lausanne)., 11, 1081, 10.3389/fendo.2020.600439

TI Hariyanto, 2020, Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection., Obes Med., 19, 100290, 10.1016/j.obmed.2020.100290

AA Lukito, 2020, The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 patients: a systematic review and meta-analysis, Diabetes Metab Syndr., 14, 2177, 10.1016/j.dsx.2020.11.006

S Wang, 2020, Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study, Diabetologia, 63, 2102, 10.1007/s00125-020-05209-1

JD Lalau, 2020, Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19., Diabetes Metab., 47, 101216, 10.1016/j.diabet.2020.101216

CT Bramante, 2021, Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis, Lancet Healthy Longev., 2, e34, 10.1016/S2666-7568(20)30033-7

N Jiang, 2021, Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: A retrospective cohort study, Diabetes Res Clin Pract, 173, 108619, 10.1016/j.diabres.2020.108619

X Cheng, 2020, Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes., Cell Metab., 32, 537, 10.1016/j.cmet.2020.08.013

AR Cameron, 2016, Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status, Circ Res, 119, 652, 10.1161/CIRCRESAHA.116.308445

M Pollak, 2017, The effects of metformin on gut microbiota and the immune system as research frontiers, Diabetologia, 60, 1662, 10.1007/s00125-017-4352-x

NF Wiernsperger, 2000, Metformin: Intrinsic Vasculoprotective Properties., Diabetes Technol Ther, 2, 259, 10.1089/15209150050025230

JK Millet, 2018, Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells, Virology, 517, 3, 10.1016/j.virol.2017.12.015

T Tang, 2020, Coronavirus membrane fusion mechanism offers a potential target for antiviral development, Antiviral Res, 178, 104792, 10.1016/j.antiviral.2020.104792

E Wędrowska, 2020, Coronaviruses fusion with the membrane and entry to the host cell, Ann Agric Environ Med, 27, 175, 10.26444/aaem/122079

W-J Guan, 2020, Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis, Eur Respir J, 2000547, 10.1183/13993003.00547-2020

M Hoffmann, 2020, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, 181, 271, 10.1016/j.cell.2020.02.052

B Rockx, 2020, Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model, Science (New York, NY)., 368, 1012, 10.1126/science.abb7314

L Roncon, 2020, Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome., J Clin Virol., 127, 104354, 10.1016/j.jcv.2020.104354

UM Ashraf, 2020, SARS-CoV-2, ACE2 expression, and systemic organ invasion, Physiol Genomics

IL Kruglikov, 2020, Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions., Elife, 9, e61330, 10.7554/eLife.61330

I Hamming, 2004, Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis, J Pathol, 203, 631, 10.1002/path.1570

X Liu, 2020, COVID-19: Progress in diagnostics, therapy and vaccination., Theranostics, 10, 7821, 10.7150/thno.47987

LA Alanagreh, 2020, The Human Coronavirus Disease COVID-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms., Pathogens., 9, 331, 10.3390/pathogens9050331

A Malhotra, 2020, ACE2, Metformin, and COVID-19., iScience., 23, 101425, 10.1016/j.isci.2020.101425

F Ursini, 2020, COVID-19 and diabetes: Is metformin a friend or foe?, Diabetes Res Clin Pract, 164, 108167, 10.1016/j.diabres.2020.108167

S Bangi, 2020, Protective Effects of CVD and DM Medications in SARS-CoV-2 Infection., SN Compr Clin Med., 1

J Zhang, 2018, AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension, Am J Respir Crit Care Med, 198, 509, 10.1164/rccm.201712-2570OC

M-J Niu, 2008, Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice, Endocrine, 34, 56, 10.1007/s12020-008-9110-x

MA Lally, 2021, Metformin is Associated with Decreased 30-Day Mortality Among Nursing Home Residents Infected with SARS-CoV2, J Am Med Dir Assoc, 22, 193, 10.1016/j.jamda.2020.10.031

DE Gordon, 2020, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature, 583, 459, 10.1038/s41586-020-2286-9

S Hojyo, 2020, How COVID-19 induces cytokine storm with high mortality, Inflamm Regen., 40, 37, 10.1186/s41232-020-00146-3

Y Yan, 2020, Clinical characteristics and outcomes of patients with severe covid-19 with diabetes, BMJ Open Diabetes Res Care, 8, e001343, 10.1136/bmjdrc-2020-001343

KCB Tan, 2002, Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes., Diabetes Care, 25, 1055, 10.2337/diacare.25.6.1055

EM De Francesco, 2020, COVID-19 and Diabetes: The Importance of Controlling RAGE., Front Endocrinol (Lausanne)., 11, 526, 10.3389/fendo.2020.00526

BI Hudson, 2018, Targeting RAGE Signaling in Inflammatory Disease., Annu Rev Med., 69, 349, 10.1146/annurev-med-041316-085215

MAD van Zoelen, 2011, The role of receptor for advanced glycation endproducts (RAGE) in infection., Crit Care., 15, 208, 10.1186/cc9990

JA Menendez, 2020, Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19., Aging (Albany NY)., 12, 8760, 10.18632/aging.103347

S Soberanes, 2019, Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis, Cell Metab, 29, 335, 10.1016/j.cmet.2018.09.019

M Schuiveling, 2018, New Era for an Old Drug in the Treatment of Immune Mediated Disease?, Curr Drug Targets., 19, 945, 10.2174/1389450118666170613081730

KA Adeshara, 2020, Action of metformin therapy against advanced glycation, oxidative stress and inflammation in type 2 diabetes patients: 3 months follow-up study., Diabetes Metab Syndr., 14, 1449, 10.1016/j.dsx.2020.07.036

Z Zhou, 2016, Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression, J Diabetes Res, 2016, 4847812, 10.1155/2016/4847812

XF Chen, 2016, Metformin corrects RAGE overexpression caused signaling dysregulation and NF-κB targeted gene change, Int J Clin Exp Med, 9, 2913

Y Hattori, 2006, Metformin Inhibits Cytokine-Induced Nuclear Factor κB Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells, Hypertension, 47, 1183, 10.1161/01.HYP.0000221429.94591.72

K Isoda, 2006, Metformin Inhibits Proinflammatory Responses and Nuclear Factor-κB in Human Vascular Wall Cells, Arterioscler Thromb Vasc Biol, 26, 611, 10.1161/01.ATV.0000201938.78044.75

R Giannarelli, 2003, Reducing insulin resistance with metformin: the evidence today, Diabetes Metab, 29, 6S28, 10.1016/S1262-3636(03)72785-2

S Lim, 2021, COVID-19 and diabetes mellitus: from pathophysiology to clinical management, Nat Rev Endocrinol., 17, 11, 10.1038/s41574-020-00435-4

P Zimmet, 1999, Clinical Efficacy of Metformin against Insulin Resistance Parameters., Drugs, 58, 21, 10.2165/00003495-199958001-00007

S Tsai, 2018, Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection, Cell Metab, 28, 922, 10.1016/j.cmet.2018.08.003

R Shoemaker, 2015, ACE2 deficiency reduces β-cell mass and impairs β-cell proliferation in obese C57BL/6 mice, Am J Physiol Endocrinol Metab, 309, E621, 10.1152/ajpendo.00054.2015

M Takeda, 2013, Loss of ACE2 exaggerates high-calorie diet-induced insulin resistance by reduction of GLUT4 in mice, Diabetes, 62, 223, 10.2337/db12-0177

H Wang, 2008, SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway, Cell Res, 18, 290, 10.1038/cr.2008.15

E Cure, 2020, Comment on "Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?"., Diabetes Res Clin Pract, 164, 108184, 10.1016/j.diabres.2020.108184

J Kim, 2016, NHX-5, an Endosomal Na+/H+ Exchanger, Is Associated with Metformin Action, J Biol Chem, 291, 18591, 10.1074/jbc.C116.744037

Z Esam, 2020, A proposed mechanism for the possible therapeutic potential of Metformin in COVID-19, Diabetes Res Clin Pract, 167, 10.1016/j.diabres.2020.108282

CA Thaiss, 2018, Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection, Science, 359, 1376, 10.1126/science.aar3318

YK Yeoh, 2021, Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19, Gut, 70, 698, 10.1136/gutjnl-2020-323020

GLV de Oliveira, 2021, Microbiota Modulation of the Gut-Lung Axis in COVID-19., Front Immunol., 12

KF Budden, 2017, Emerging pathogenic links between microbiota and the gut-lung axis, Nat Rev Microbiol, 15, 55, 10.1038/nrmicro.2016.142

M Kyo, 2019, Unique patterns of lower respiratory tract microbiota are associated with inflammation and hospital mortality in acute respiratory distress syndrome, Respir Res, 20, 246, 10.1186/s12931-019-1203-y

PD Cani, 2008, Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice, Diabetes, 57, 1470, 10.2337/db07-1403

H Wu, 2017, Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug, Nat Med, 23, 850, 10.1038/nm.4345

R Amraei, 2020, COVID-19, Renin-Angiotensin System and Endothelial Dysfunction., Cells., 9, 10.3390/cells9071652

G Xin, 2016, Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release., Sci Rep., 6, 36222, 10.1038/srep36222

X Jin, 2015, Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway, Biomed Res Int, 2015, 732450

Y Hattori, 2006, Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells, Hypertension, 47, 1183, 10.1161/01.HYP.0000221429.94591.72

DE Gordon, 2020, A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing., bioRxiv, 2020

M Voysey, 2021, Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK., Lancet, 397, 99, 10.1016/S0140-6736(20)32661-1

FP Polack, 2020, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, N Engl J Med, 383, 2603, 10.1056/NEJMoa2034577

CDC. Emerging SARS-CoV-2 Variants. 2021 [cited 2021 Feb 10]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html.

LJ Abu-Raddad, 2021, Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants, N Engl J Med

EJ Haas, 2021, Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data, Lancet

A Liskova, 2021, Flavonoids against the SARS-CoV-2 induced inflammatory storm, Biomed Pharmacother, 138, 111430, 10.1016/j.biopha.2021.111430

N Tang, 2020, Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy., J Thromb Haemost, 18, 1094, 10.1111/jth.14817

ClinicalTrials.gov. MET-COVID Trial—Metformin for Outpatient Treatment and Post-exposure Prophylaxis (PEP) of COVID-19. 2020 [cited 2021 Feb 10]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04510194?term=metformin&cond=COVID&draw=2&rank=2.

CT Bramante, 2021, Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity, J Med Virol

ClinicalTrials.gov. Adaptive Study to Demonstrate Efficacy and Safety of Metformin Glycinate for the Treatment of Hospitalized Patients With Severe Acute Respiratory Syndrome Secondary to SARS-CoV-2. Randomized, Double-Blind, Phase IIIb. 2021 [cited 2021 Feb 10]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04625985?term=metformin&cond=COVID&draw=2&rank=3.

Ahmad W, Shabbiri K, Islam, N. O-β-GlcNAcylation, Chloroquine and 2-Hydroxybenzohydrazine May Hamper SARS-CoV-2 entry to Human via Inhibition of ACE2 Phosphorylation at Ser787 but Also Induce Disruption of Virus-ACE2 Binding. Preprints. 2020;2020040390 1020944/preprints2020040390v1

Y Gao, 2020, Risk of Metformin in Patients With Type 2 Diabetes With COVID-19: A Preliminary Retrospective Report., Clin Transl Sci.

JY Do, 2020, Is there an association between metformin use and clinical outcomes in diabetes patients with COVID-19?, Diabetes Metab., 101208

W Saenwongsa, 2020, Metformin-induced suppression of IFN-α via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes, Sci Rep., 10, 3229, 10.1038/s41598-020-60213-0

Y Han, 2019, Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis, Cardiovasc Diabetol, 18, 96, 10.1186/s12933-019-0900-7

IA Ekeruo, 2013, Metformin in Diabetic Patients with Heart Failure: Safe and Effective?, Curr Cardiovasc Risk Rep., 7, 417, 10.1007/s12170-013-0355-4