The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus

  • Author Footnotes
    1 These authors contributed equally to this work.
    Wenxing Yang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Physiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Xuehong Sun
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China
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  • Jun Zhang
    Affiliations
    Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China
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  • Kui Zhang
    Correspondence
    Corresponding author.
    Affiliations
    Department of Forensic Pathology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Aim

      COVID-19 has spread globally with heavy impact on most countries and our therapeutic strategies in COVID-19 patients with diabetes are still limited. Recently, some new information was added to this field. We performed this updated meta-analysis to reveal the underlying effect of metformin on COVID-19 patients with diabetes.

      Methods

      We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the effect of metformin on COVID-19 patients with diabetes. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics.

      Results

      We collected 17 studies including 20,719 COVID-19 patients with diabetes. Our results found that metformin was associated with significantly decreased mortality and severity in COVID-19 patients with diabetes (OR = 0.64, 95% CI = 0.51–0.79 for mortality, and OR = 0.81, 95% CI = 0.66–0.99 for severity).

      Conclusions

      Our meta-analysis indicated that following metformin treatment might benefit the patients with T2DM, both the mortality and severity. However, patients with severe COVID-19 should be monitored closely for the development of lactic acidosis, acidosis, and decreased kidney function.

      Keywords

      1. Introduction

      COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread throughout the world, afflicting more than 174.4 million people, resulting in more than 3.7 million deaths globally as of June 9, 2021, and with a mortality rate of about 2.1%. The epidemic of diabetes mellitus and its complications poses a major global health threat. The International Diabetes Federation (IDF) estimated that 1 in 11 adults had diabetes mellitus, the estimate is projected to rise to 642 million by 2040 globally [
      • Holman N.
      • Knighton P.
      • Kar P.
      • O'Keefe J.
      • Curley M.
      • Weaver A.
      • et al.
      Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.
      ]. The presence of diabetes mellitus, the individual degree of hyperglycaemia and the presence of typical complications of diabetes mellitus seem to be independently associated with COVID-19 severity and increased mortality [
      • Holman N.
      • Knighton P.
      • Kar P.
      • O'Keefe J.
      • Curley M.
      • Weaver A.
      • et al.
      Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study.
      ,
      • Zhu L.
      • She Z.-G.
      • Cheng X.u.
      • Qin J.-J.
      • Zhang X.-J.
      • Cai J.
      • et al.
      Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes.
      ]. Especially the hyperglycaemia might modulate immune and inflammatory responses, thus predisposing patients to severe COVID-19 and possible lethal outcomes [
      • Zhu L.
      • She Z.-G.
      • Cheng X.u.
      • Qin J.-J.
      • Zhang X.-J.
      • Cai J.
      • et al.
      Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes.
      ,
      • Lim S.
      • Bae J.H.
      • Kwon H.-S.
      • Nauck M.A.
      COVID-19 and diabetes mellitus: from pathophysiology to clinical management.
      ].
      Glucose-lowering medications might have effects on COVID-19 pathogenesis, and these effects could have implications for the management of patients with diabetes mellitus and COVID-19 [
      • Lim S.
      • Bae J.H.
      • Kwon H.-S.
      • Nauck M.A.
      COVID-19 and diabetes mellitus: from pathophysiology to clinical management.
      ]. Dipeptidyl peptidase 4 (DPP4) and the renin–angiotensin–aldosterone system (RAAS) are linked genetically and are associated with the risk of SARS-CoV-2 infection and possibly severity of COVID-19[
      • Valencia I.
      • Peiró C.
      • Lorenzo Ó.
      • Sánchez-Ferrer C.F.
      • Eckel J.
      • Romacho T.
      DPP4 and ACE2 in diabetes and COVID-19: therapeutic targets for cardiovascular complications?.
      ]. Glucagon-like peptide 1 (GLP1) analogues are not recommended in severe COVID-19 patients, because they will take time to become effective [
      • Nauck M.A.
      • Meier J.J.
      Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes?.
      ]. Sodium–glucose cotransporter 2 (SGLT2) inhibitors might cause adverse effects such as osmotic diuresis and dehydration in patients with COVID-19 and so cannot be recommended [
      • Hahn K.
      • Ejaz A.A.
      • Kanbay M.
      • Lanaspa M.A.
      • Johnson R.J.
      Acute kidney injury from SGLT2 inhibitors: potential mechanisms.
      ].
      Metformin is a widely used oral glucose-lowering drug and is recommended as a first-line drug in recent treatment guidelines of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) [
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • Diamant M.
      • Ferrannini E.
      • Nauck M.
      • et al.
      Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
      ]. The clinical science of the potential relationships between metformin and COVID-19 patients with diabetes mellitus has been widely studied. However, knowledge in this field is emerging rapidly, with numerous publications appearing frequently. In the present study, we carried out this meta-analysis to detect the overall effects of metformin on COVID-19 patients with diabetes. This study was reported in accordance with the PRISMA statement for reporting systematic reviews and meta-analysis [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      2. Methods

      2.1 Publication search and inclusion criteria

      We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles within a range of published years from 2019 to 2021 on the effect of metformin on COVID-19 patients with diabetes (last search was June 6, 2021). The following terms were used in this search: ‘metformin’, ‘diabetes’ and ‘COVID-19’. In order to identify the relevant publications, the references cited in the research papers were also scanned. Combining searches resulted in 47 abstracts. In addition, eight studies were identified through review articles and meta-analysis, for a total of 55 studies were screened after duplicated records were removed. After screening the titles and abstracts, 24 were retrieved for more detailed evaluation (Fig. 1). We used the Newcastle-Ottawa Scale (NOS) for assessing the quality of cohort studies and case-control studies based on three categories and eight items.
      Figure thumbnail gr1
      Fig. 1Flowchart for identification of studies.
      We evaluated the eligible studies if all the following conditions were met: (1) evaluation on the effect of metformin on COVID-19 patients with diabetes; (2) inclusion of sufficient data or the data can be acquired from the manuscript or supplementary materials to calculate ORs and 95% CIs; and (3) the study was published in English.

      2.2 Data extraction

      Two authors (Kui Zhang and Wenxing Yang) independently reviewed and extracted the data needed. Disagreements were resolved through discussion among the authors to achieve a consensus. The following information was recorded for each study: first author, year of publication, region, outcome, number of metformin users, and number of patients (all of the data are shown in table 1).
      Table 1Characteristics of literatures included in the meta-analysis.
      ReferenceYearRegionOutcomeNo. of metformin usersNo. of patientsAdjustment for covariates
      Jiang N
      • Jiang N.
      • Chen Z.
      • Liu L.i.
      • Yin X.
      • Yang H.
      • Tan X.
      • et al.
      Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: a retrospective cohort study.
      2021ChinaMortality

      ARDS
      100328age, gender, weight, FBG, severity of COVID-19, Charlson comorbidity index, CHD, metformin therapy prior to hospitalization, DDI, creatinine and site
      Li W
      • Li W.
      • Li J.
      • Wei Q.
      • McCowen K.
      • Xiong W.
      • Liu J.
      • et al.
      Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus.
      2021ChinaMortality37131age, BMI, glucose, triglyceride, CRP, D-dimer, and steroid use
      Bramante CT
      • Bramante C.T.
      • Ingraham N.E.
      • Murray T.A.
      • Marmor S.
      • Hovertsen S.
      • Gronski J.
      • et al.
      Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.
      2021USAMortality23336256age, sex, comorbidities, alcohol abuse, HIV, asthma, inflammatory bowel disease, dementia, Charlson comorbidity index, and medications, and state
      Lally MA
      • Lally M.A.
      • Tsoukas P.
      • Halladay C.W.
      • O'Neill E.
      • Gravenstein S.
      • Rudolph J.L.
      Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV2.
      2021USAMortality127775age, body mass index, hemoglobin A1c, estimated glomerular filtration rate, long stay (>90 days), and underlying psychoses
      Cheng X
      • Cheng X.u.
      • Liu Y.-M.
      • Li H.
      • Zhang X.
      • Lei F.
      • Qin J.-J.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      2020ChinaMortality

      ARDS

      DIC

      Heart failure

      Acute kidney injury

      Acute heart injury
      6781213age, gender, comorbidities, blood glucose, C-reactive protein, estimated glomerular filtration rate, alanine aminotransferase, and creatinine
      Ghany R
      • Ghany R.
      • Palacio A.
      • Dawkins E.
      • Chen G.
      • McCarter D.
      • Forbes E.
      • et al.
      Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA.
      2021USAMortality

      ARDS
      3921139age, gender, Charlson score, diabetes, hypertension and ejection fraction
      Luo P
      • Luo P.
      • Qiu L.
      • Liu Y.
      • Liu X.-L.
      • Zheng J.-L.
      • Xue H.-Y.
      • et al.
      Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis.
      2020ChinaMortality104283age, gender, underlying diseases, clinical severity
      Oh TK
      • Oh T.K.
      • Song I.-A.
      Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study.
      2021KoreaMortality4802047age, sex, underlying disability, Charlson Comorbidity Index
      Li J
      • Li J.
      • Wei Q.i.
      • Li W.X.
      • McCowen K.C.
      • Xiong W.
      • Liu J.
      • et al.
      Metformin use in diabetes prior to hospitalization: effects on mortality in Covid-19.
      2020ChinaMortality

      ventilation
      37131age, body weight, BMI, oxygen desaturation, glucose, triglyceride, CRP, and D-dimers
      Lalau J-D
      • Lalau J.-D.
      • Al-Salameh A.
      • Hadjadj S.
      • Goronflot T.
      • Wiernsperger N.
      • Pichelin M.
      • et al.
      Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.
      2020FranceMortality

      IMV
      14962449sex, age, BMI, arterial hypertension, history of disease, active cancer, treated obstructive sleep apnoea, use of any of anti-diabetes drugs
      Crouse A

      Crouse A, Grimes T, Li P, Might M, Ovalle F, Shalev A. metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. medRxiv. 2020.

      2020USAMortality76239age, race, sex, obesity and hypertension
      Pérez-Belmonte LM
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      2020SpainMortality

      ICU admission mechanical ventilation in-hospital death
      8251488age; gender; history of smoking, hypertension; dyslipidemia; chronic kidney disease; cerebrovascular disease; chronic obstructive pulmonary disease; atrial fibrillation; coronary artery disease; heart failure; obesity; dementia; Barthel Index score; and Charlson Comorbidity Index score
      Wargny M
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • Pichelin M.
      • Amadou C.
      • Benhamou P.-Y.
      • et al.
      Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      2021FranceMortality15532794sex, age, BMI, the patient’s history, routine medication, symptoms on admission, biological features
      Chen Y
      • Chen Y.
      • Yang D.
      • Cheng B.
      • Chen J.
      • Peng A.
      • Yang C.
      • et al.
      Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
      2020ChinaMortality

      Poor prognosis
      43120age, albumin, creatinine, glucose, CRP, and usage of a specific medication
      Goodall JW
      • Goodall J.W.
      • Reed T.A.N.
      • Ardissino M.
      • Bassett P.
      • Whittington A.M.
      • Cohen D.L.
      • et al.
      Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study.
      2020UKMortality210981age, sex, comorbidities and medication usage
      Kim MK
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      2020KoreaMortality

      severe disease
      113235age, sex, and the presence of underlying diseases
      Gao Y
      • Gao Y.
      • Liu T.
      • Zhong W.
      • Liu R.
      • Zhou H.
      • Huang W.
      • et al.
      Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report.
      2020ChinaLife threatening complications56110age, gender, blood glucose and LDH levels
      IMV, tracheal intubation for mechanical ventilation; severe disease, the necessity for the use of a high-flow nasal cannula, mechanical ventilation, CRRT, or ECMO, or admission to an ICU; CRP, C-reactive protein; BMI, body mass index.

      2.3 Statistical analysis

      The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the effect of metformin on COVID-19 patients with diabetes. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics [
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ]. If there was no obvious heterogeneity, the fixed-effects model (the Mantel-Haenszel method) was used to estimate the summary OR [
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ]; otherwise, the random-effects model (the DerSimonian and Laird method) was used [
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ]. Finally, random effects models were used to calculate the overall OR estimates and 95% CIs to assess the effect of metformin on mortality and severity in COVID-19 patients with diabetes. To explore sources of heterogeneity across studies, we did logistic meta-regression analyses. We examined the following study characteristics: publication year, region, number of metformin users, and number of patients. Publication bias was evaluated with funnel plot and Begg’s rank correlation method [
      • Begg C.B.
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      ]. The statistical analyses were performed by STATA 12.0 software (Stata Corp., College Station, TX).

      3. Results

      3.1 Characteristics of studies

      Out of a total of 55 titles and abstracts, 24 were retrieved for more detail evaluation. Of the seven excluded studies, two papers were reviews, three papers lacked enough data, and two papers were excluded with duplicated data [
      • Cariou B.
      • Hadjadj S.
      • Wargny M.
      • Pichelin M.
      • Al-Salameh A.
      • Allix I.
      • et al.
      Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.
      ,
      • Bramante C.T.
      • Ingraham N.E.
      • Murray T.A.
      • Marmor S.
      • Hovertsen S.
      • Gronski J.
      • et al.
      Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19.
      ] and the updated data were included. Finally, 17 studies met the inclusion criteria for this study, including 20,719 COVID-19 patients with diabetes. The details including first author, year of publication, region, outcome, number of metformin users, and number of patients in selected studies were listed in Table 1.

      3.2 Quantitative synthesis

      Overall, metformin was associated with significantly decreased mortality and severity in COVID-19 patients with diabetes (OR = 0.64, 95% CI = 0.51–0.79 for mortality, and OR = 0.81, 95% CI = 0.66–0.99 for severity, shown in Fig. 2 and Fig. 3)
      Figure thumbnail gr2
      Fig. 2Forest plot of mortality following metformin treatment in COVID-19 patients with diabetes.
      Figure thumbnail gr3
      Fig. 3Forest plot of severity following metformin treatment in COVID-19 patients with diabetes.

      3.3 Evaluation of heterogeneity

      There was heterogeneity among studies in comparisons (P heterogeneity < 0.001, I2 = 65.6 %, Tau2 = 0.0996 for mortality, and P heterogeneity = 0.047, I2 = 42.2 %, Tau2 = 0.0493 for severity). Logistic meta-regression analyses found no possible factors that may substantially influence the initial heterogeneity.

      3.4 Sensitivity analysis

      The influence of a single study on the overall meta-analysis estimate was investigated by omitting one study at a time, and the omission of any study made no significant difference, indicating that our results were statistically reliable.

      3.5 Publication bias

      The Begg’s test was performed to evaluate the publication bias of selected literatures. No evidence of publication bias in our study was observed (P = 0.064 for mortality and P = 0.827 for severity).

      4. Discussion

      COVID-19 has spread globally with heavy impact on most countries and our therapeutic strategies in COVID-19 patients with diabetes are still limited. Diabetes was associated with poorer outcomes in COVID-19 patients [
      • Lim S.
      • Bae J.H.
      • Kwon H.-S.
      • Nauck M.A.
      COVID-19 and diabetes mellitus: from pathophysiology to clinical management.
      ,
      • Erener S.
      Diabetes, infection risk and COVID-19.
      ]. Previous meta-analysis indicated that metformin consumption was associated with lower mortality in COVID-19 patients among diabetic populations [
      • Lukito A.A.
      • Pranata R.
      • Henrina J.
      • Lim M.A.
      • Lawrensia S.
      • Suastika K.
      The effect of metformin consumption on mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Lazarus G.
      • Suhardi I.P.
      • Wiyarta E.
      • Rasyidah R.A.
      • Barliana J.D.
      Is there a need to reconsider the use of metformin in COVID-19 patients with type 2 diabetes mellitus?.
      ]. However, whether to continue or withdraw metformin therapy in COVID-19 patients with diabetes remains contentious. Knowledge in this field is emerging rapidly, with numerous publications appearing frequently. Recently, some new information was added to this field [
      • Bramante C.T.
      • Ingraham N.E.
      • Murray T.A.
      • Marmor S.
      • Hovertsen S.
      • Gronski J.
      • et al.
      Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.
      ,
      • Ghany R.
      • Palacio A.
      • Dawkins E.
      • Chen G.
      • McCarter D.
      • Forbes E.
      • et al.
      Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA.
      ,
      • Jiang N.
      • Chen Z.
      • Liu L.i.
      • Yin X.
      • Yang H.
      • Tan X.
      • et al.
      Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: a retrospective cohort study.
      ,
      • Lally M.A.
      • Tsoukas P.
      • Halladay C.W.
      • O'Neill E.
      • Gravenstein S.
      • Rudolph J.L.
      Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV2.
      ,
      • Li W.
      • Li J.
      • Wei Q.
      • McCowen K.
      • Xiong W.
      • Liu J.
      • et al.
      Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus.
      ,
      • Oh T.K.
      • Song I.-A.
      Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study.
      ,
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • Pichelin M.
      • Amadou C.
      • Benhamou P.-Y.
      • et al.
      Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      ], so we performed this updated meta-analysis to reveal the underlying effect of metformin on COVID-19 patients with diabetes.
      Metformin can promote lifespan [
      • Chen J.
      • Ou Y.
      • Li Y.
      • Hu S.
      • Shao L.W.
      • Liu Y.
      Metformin extends C. elegans lifespan through lysosomal pathway.
      ] and facilitates health [
      • Rizos C.V.
      • Elisaf M.S.
      Metformin and cancer.
      ,
      • Li J.
      • Deng J.
      • Sheng W.
      • Zuo Z.
      Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice.
      ] through mitohormesis [
      • De Haes W.
      • Frooninckx L.
      • Van Assche R.
      • Smolders A.
      • Depuydt G.
      • Billen J.
      • et al.
      Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.
      ] and lysosomal pathway [
      • Chen J.
      • Ou Y.
      • Li Y.
      • Hu S.
      • Shao L.W.
      • Liu Y.
      Metformin extends C. elegans lifespan through lysosomal pathway.
      ] to coordinate mTORC1 and AMPK [
      • Zhang C.-S.
      • Li M.
      • Ma T.
      • Zong Y.
      • Cui J.
      • Feng J.-W.
      • et al.
      Metformin activates AMPK through the lysosomal pathway.
      ] via host-microbe- metformin -nutrient interactions [
      • Wu H.
      • Esteve E.
      • Tremaroli V.
      • Khan M.T.
      • Caesar R.
      • Mannerås-Holm L.
      • et al.
      Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.
      ,
      • Pryor R.
      • Norvaisas P.
      • Marinos G.
      • Best L.
      • Thingholm L.B.
      • Quintaneiro L.M.
      • et al.
      Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy.
      ]. Metformin has been reported to have anti-inflammation properties and reduced oxidative damage [
      • Schuiveling M.
      • Vazirpanah N.
      • Radstake T.R.D.J.
      • Zimmermann M.
      • Broen J.C.A.
      Metformin, a new era for an old drug in the treatment of immune mediated disease?.
      ]. Metformin’s ability to reduce neutrophil counts and to reduce neutrophil extracellular traps have also been proposed as potential mechanisms for its beneficial use in patients with diabetes and COVID-19[
      • Dalan R.
      Metformin, neutrophils and COVID-19 infection.
      ]. In previous clinical researches, some studies found that metformin use was not significantly associated with lower mortality in COVID-19 patients with diabetes [
      • Bramante C.T.
      • Ingraham N.E.
      • Murray T.A.
      • Marmor S.
      • Hovertsen S.
      • Gronski J.
      • et al.
      Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.
      ,
      • Jiang N.
      • Chen Z.
      • Liu L.i.
      • Yin X.
      • Yang H.
      • Tan X.
      • et al.
      Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: a retrospective cohort study.
      ,
      • Oh T.K.
      • Song I.-A.
      Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study.
      ,
      • Chen Y.
      • Yang D.
      • Cheng B.
      • Chen J.
      • Peng A.
      • Yang C.
      • et al.
      Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
      ,
      • Cheng X.u.
      • Liu Y.-M.
      • Li H.
      • Zhang X.
      • Lei F.
      • Qin J.-J.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      ,
      • Lalau J.-D.
      • Al-Salameh A.
      • Hadjadj S.
      • Goronflot T.
      • Wiernsperger N.
      • Pichelin M.
      • et al.
      Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.
      ,
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      ,
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      ,
      • Goodall J.W.
      • Reed T.A.N.
      • Ardissino M.
      • Bassett P.
      • Whittington A.M.
      • Cohen D.L.
      • et al.
      Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study.
      ]. However, others found that patients using metformin after admission were significantly more likely to survive than those who did not use [
      • Ghany R.
      • Palacio A.
      • Dawkins E.
      • Chen G.
      • McCarter D.
      • Forbes E.
      • et al.
      Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA.
      ,
      • Lally M.A.
      • Tsoukas P.
      • Halladay C.W.
      • O'Neill E.
      • Gravenstein S.
      • Rudolph J.L.
      Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV2.
      ,
      • Li W.
      • Li J.
      • Wei Q.
      • McCowen K.
      • Xiong W.
      • Liu J.
      • et al.
      Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus.
      ,
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • Pichelin M.
      • Amadou C.
      • Benhamou P.-Y.
      • et al.
      Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      ,
      • Luo P.
      • Qiu L.
      • Liu Y.
      • Liu X.-L.
      • Zheng J.-L.
      • Xue H.-Y.
      • et al.
      Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis.
      ,
      • Li J.
      • Wei Q.i.
      • Li W.X.
      • McCowen K.C.
      • Xiong W.
      • Liu J.
      • et al.
      Metformin use in diabetes prior to hospitalization: effects on mortality in Covid-19.
      ,

      Crouse A, Grimes T, Li P, Might M, Ovalle F, Shalev A. metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. medRxiv. 2020.

      ]. Significantly, Oh TK et al found that metformin therapy might have potential benefits for the prevention of COVID-19 in Korean population [
      • Oh T.K.
      • Song I.-A.
      Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study.
      ]. Bramante CT et al revealed that metformin was associated with decreased mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19, but not in men [
      • Bramante C.T.
      • Ingraham N.E.
      • Murray T.A.
      • Marmor S.
      • Hovertsen S.
      • Gronski J.
      • et al.
      Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.
      ], and they contributed the results to different cytokine responses to COVID-19 between genders. Most strikingly, research revealed that metformin use prior to the diagnosis of COVID-19 have more potential benefits in subjects with diabetes [

      Crouse A, Grimes T, Li P, Might M, Ovalle F, Shalev A. metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. medRxiv. 2020.

      ]. Our results with accumulated data indicated that metformin was associated with significantly decreased mortality in COVID-19 patients with diabetes.
      Acute respiratory distress syndrome (ARDS) is one of the most common complications in patients with COVID-19. It is of great significance to prevent the incidence of ARDS for improving the outcome of patients [
      • Zangrillo A.
      • Beretta L.
      • Scandroglio A.M.
      • Monti G.
      • Fominskiy E.
      • Colombo S.
      • et al.
      Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy.
      ]. The effect of metformin on the incidence of ARDS was controversial [
      • Ghany R.
      • Palacio A.
      • Dawkins E.
      • Chen G.
      • McCarter D.
      • Forbes E.
      • et al.
      Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA.
      ,
      • Jiang N.
      • Chen Z.
      • Liu L.i.
      • Yin X.
      • Yang H.
      • Tan X.
      • et al.
      Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: a retrospective cohort study.
      ]. Significantly, metformin use was significantly associated with reduced heart failure and inflammation [
      • Cheng X.u.
      • Liu Y.-M.
      • Li H.
      • Zhang X.
      • Lei F.
      • Qin J.-J.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      ]. However, some researches did not find any significant results of metformin use on clinical severity of the disease [
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      ], and adverse outcomes [
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      ]. Another study found that antidiabetic therapy with metformin was associated with a higher risk of disease progression in COVID-19 patients with diabetes during hospitalization [
      • Gao Y.
      • Liu T.
      • Zhong W.
      • Liu R.
      • Zhou H.
      • Huang W.
      • et al.
      Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report.
      ], and the reason was that blood glucose and lactate dehydrogenase (LDH) levels of the metformin group were higher than those of the non-metformin group at admission [
      • Gao Y.
      • Liu T.
      • Zhong W.
      • Liu R.
      • Zhou H.
      • Huang W.
      • et al.
      Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report.
      ]. Our results with accumulated data indicated that metformin was associated with significantly decreased severity in COVID-19 patients with diabetes.
      A few limitations of our study should be considered. Although we did not observe significant publication bias, publication bias is possible in any meta-analysis. Moreover, there was heterogeneity among studies in overall comparisons. Although we performed logistic meta-regression analyses and stratified analysis to explore sources of heterogeneity across studies, we still found no possible factors that may substantially influence the initial heterogeneity, and the heterogeneity may potentially affect the results.
      In conclusion, our meta-analysis indicated that following metformin treatment in COVID-19 patients with diabetes might decrease the mortality and severity. However, metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID19 [
      • Cheng X.u.
      • Liu Y.-M.
      • Li H.
      • Zhang X.
      • Lei F.
      • Qin J.-J.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      ]. Thus, patients with severe COVID-19 should be monitored closely for the development of lactic acidosis, acidosis, and decreased kidney function.

      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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