Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis
Teodoro J Oscanoa, José Amado, Xavier Vidal, Andrea Savarino, Roman Romero-Ortuno
Clinical Diabetology, doi:10.5603/dk.a2021.0035
background. It has been postulated that metformin could have anti-SARS-CoV-2 action. This raises the hypothesis that people who take metformin may have lower SARS-CoV-2 severity and/or mortality. Objectives. To conduct a meta-analysis of the association between the use of Metformin and risk of severity and mortality in SARS-CoV-2 infection. Methods. we searched PubMed, EMbASE, google scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv and Research Square) for studies published between December 2019 and January 2021. Data was extracted on study location, year of publication, design, number of participants, sex, age at baseline, body mass index, and exposure and outcome definition. Effect statistics were pooled using random effects models with 95% confidence intervals (CI). The quality of included studies was assessed with the newcastle-Ottawa Scale (nOS). Results. Thirty-two observational studies were included, combining to a total sample of 44306 participants. The mean nOS score of included studies was 7.9. Results suggested that metformin use was associated with a reduced risk of SARS-CoV-2 mortality (OR = 0.56, 95% CI: 0.46-0.68, P < 0.001; 22 studies) but not with disease severity (OR = 0.85, 95% CI: 0.71-1.02, P = 0.077; 15 studies). In the subgroup analysis, metformin reduces the risk of mortality (OR = 0.69, 95% CI: 0.55-0.88; P = 0.002) and severity (OR = 0.83, 95% CI: 0.70-0.97, P = 0.023) in patients aged 70 and above. Conclusions. The use of metformin was associated to lower risk of mortality from SARS-CoV-2 infection. This association does not imply causation and further research is required to clarify potential mechanisms.
Conflict of interest None.
Appendix 1
MEDlInE search strategy We searched the NCBI and Medline databases for potentially eligible records. The search terms were as follows:
References
Abu-Jamous, Anisimovich, Baxter, Associations of comorbidities and medications with COVID-19 outcome: A retrospective analysis of real-world evidence data,
doi:10.1101/2020.08.20.20174169Akter, Mannan, Mehedi, Clinical manifestations along with biochemical and psychological outcomes of COVID-19 cases in diabetic individuals in Bangladesh,
doi:10.1101/2020.09.24.20200790Amin, Lux, 'callaghan, The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth, Br J Clin Pharmacol,
doi:10.1111/bcp.13780Bharath, Agrawal, Mccambridge, Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation, Cell Metab,
doi:10.1016/j.cmet.2020.04.015Bo, Van Oekelen, Mouhieddine, A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward, J Hematol Oncol,
doi:10.1186/s13045-020-00934-xBornstein, Rubino, Khunti, Practical recommendations for the management of diabetes in patients with COVID-19, The Lancet Diabetes & Endocrinology,
doi:10.1016/s2213-8587(20)30152-2Bramante, Ingraham, Murray, Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis, The Lancet Healthy Longevity,
doi:10.1016/s2666-7568(20)30033-7Cariou, Hadjadj, Wargny, Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study, Diabetologia,
doi:10.1007/s00125-020-05180-xCernigliaro, Allotta, Scondotto, Can diabetes and its related hypoglycemic drug treatment be considered risk factors for health outcomes in COVID-19 patients? The results of a study in the population residing in Sicily Region (Southern Italy), Epidemiol Prev,
doi:10.19191/EP20.5-6.S2.132Chen, Guo, Li, Immunomodulatory and antiviral activity of metformin and its potential implications in treating coronavirus disease 2019 and lung injury, Front Immunol,
doi:10.3389/fimmu.2020.02056Chen, Jiang, Li, Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: A retrospective cohort study, Diabetes Res Clin Pract,
doi:10.1016/j.diabres.2020.108619Chen, Yang, Yang, Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication, Diabetes Care,
doi:10.2337/dc20-0660Cheng, He, Jung, Suppression of Kaposi's sarcomaassociated herpesvirus infection and replication by 5'-ampactivated protein kinase, J Virol,
doi:10.1128/JVI.00624-16Crouse, Grimes, Li, Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes, Front Endocrinol (Lausanne),
doi:10.3389/fendo.2020.600439Do, Kim, Park, Is there an association between metformin use and clinical outcomes in diabetes patients with COVID-19? Diabetes Metab,
doi:10.1016/j.diabet.2020.10.006Gao, Liu, Zhong, Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report, Clin Transl Sci,
doi:10.1111/cts.12897Gheblawi, Wang, Viveiros, Angiotensin-Converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2, Circ Res,
doi:10.1161/CIRCRESAHA.120.317015Goodall, Reed, Ardissino, Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study, Epidemiol Infect,
doi:10.1017/S0950268820002472Hariyanto, Kurniawan, Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COV-ID-19) infection, Obes Med,
doi:10.1016/j.obmed.2020.100290Higgins, Altman, Gøtzsche, The Cochrane Collaboration's tool for assessing risk of bias in randomised trials, BMJ,
doi:10.1136/bmj.d5928Hippisley-Cox, Young, Coupland, Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people, Heart,
doi:10.1136/heartjnl-2020-317393Izzi-Engbeaya, Distaso, Amin, Severe COVID-19 and diabetes -a retrospective cohort study from three london teaching hospitals. medRxiv,
doi:10.1101/2020.08.07.20160275Lalau, Al-Salameh, Hadjadj, Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19, Diabetes Metab,
doi:10.1016/j.diabet.2020.101216Lally, Tsoukas, Halladay, Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV-2, J Am Med Dir Assoc,
doi:10.1016/j.jamda.2020.10.031Lasbleiz, Cariou, Darmon, Phenotypic characteristics and development of a hospitalization prediction risk score for outpatients with diabetes and COVID-19: the DIABCOVID study, J Clin Med,
doi:10.3390/jcm9113726Li, Han, Xiao, Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal, Clin Cancer Res,
doi:10.1158/1078-0432.CCR-13-2613Li, Qi, Li, Metformin use in diabetes prior to hospitalization: effects on mortality in covid-19, Endocr Pract,
doi:10.4158/EP-2020-0466Liang, Ding, Li, Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies, Crit Care,
doi:10.1186/s13054-019-2346-4Lukito, Pranata, Henrina, The effect of metformin consumption on mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2020.11.006Luo, Qiu, Yi, Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis, Am J Trop Med Hyg,
doi:10.4269/ajtmh.20-0375Mik, Jeon, Kim, The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea, Diabetes Metab J,
doi:10.4093/dmj.2020.0146Mirani, Favacchio, Carrone, Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an Academic Hospital in Lombardy, Italy. Diabetes Care,
doi:10.2337/dc20-1340Mishra, Dingli, Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells, Leukemia,
doi:10.1038/s41375-019-0470-4Moher, Liberati, Tetzlaff, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Int J Surg,
doi:10.1016/j.ijsu.2010.02.007Mueller, Mcnamara, Sinclair, Why does COVID-19 disproportionately affect older people?, Aging (Albany NY),
doi:10.18632/aging.103344Nafakhi, Alareedh, Al-Buthabhak, Predictors of adverse in-hospital outcome and recovery in patients with diabetes mellitus and COVID-19 pneumonia in Iraq, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2020.12.014Orioli, Servais, Belkhir, Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: A retrospective study from an academic center in Belgium, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2020.12.020Oscanoa, Romero-Ortuno, Carvajal, A pharmacological perspective of chloroquine in SARS-CoV-2 infection: An old drug for the fight against a new coronavirus, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106078Oscanoa, Vidal, Kanters, Frequency of long QT in patients with sars-cov-2 infection treated with hydroxychloroquine: a meta-analysis, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106212Philipose, Smati, Wong, Obesity, old age and frailty are the true risk factors for COVID-19 mortality and not chronic disease or ethnicity in Croydon,
doi:10.1101/2020.08.12.20156257Pijls, Jolani, Atherley, Demographic risk factors for COVID-19 infection, severity, ICU admission and death: a metaanalysis of 59 studies, BMJ Open,
doi:10.1136/bmjopen-2020-044640Pérez-Belmonte, Torres-Peña, Md, 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, BMC Med,
doi:10.1186/s12916-020-01832-2Ramos-Rincón, Pérez-Belmonte, Carrasco-Sánchez, Association between prior cardiometabolic therapy and in-hospital mortality in very old patients with type 2 diabetes mellitus hospitalized due to COVID-19. A nationwide observational study in Spain,
doi:10.21203/rs.3.rs-133358/v1Schlesinger, Neuenschwander, Lang, Risk phenotypes of diabetes and association with COVID-19 severity and death -a living systematic review and meta-analysis, SSRN Electronic Journal,
doi:10.2139/ssrn.3730026Shenoy, Coronavirus, Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality, Inflamm Res,
doi:10.1007/s00011-020-01389-zShestakova, Vikulova, Isakov, Diabetes and COV-ID-19: analysis of the clinical outcomes according to the data of the russian diabetes registry, Probl Endokrinol (Mosk),
doi:10.14341/probl12458Shytaj, Procopio, Tarek, Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress, bioRxiv,
doi:10.1101/2020.12.30.424810Soberanes, Misharin, Jairaman, Metformin targets mitochondrial electron transport to reduce air-pollution-induced thrombosis, Cell Metab,
doi:10.1016/j.cmet.2018.09.019Soto-Acosta, Bautista-Carbajal, Cervantes-Salazar, DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target, PLoS Pathog,
doi:10.1371/journal.ppat.1006257Sourij, Aziz, Bräuer, COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission, Diabetes Obes Metab,
doi:10.1111/dom.14256Stang, Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses, Eur J Epidemiol,
doi:10.1007/s10654-010-9491-zThomas, Gregg, Metformin; a review of its history and future: from lilac to longevity, Pediatr Diabetes,
doi:10.1111/pedi.12473Tsaknis, Siempos, Kopterides, Metformin attenuates ventilator-induced lung injury, Crit Care,
doi:10.1186/cc11439Vachharajani, Liu, Brown, SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome, J Leukoc Biol,
doi:10.1189/jlb.3MA0114-034RRValle-Casuso, Angin, Volant, Cellular metabolism is a major determinant of HIV-1 reservoir seeding in CD4 t cells and offers an opportunity to tackle infection, Cell Metab,
doi:10.1016/j.cmet.2018.11.015Wu, Cen, Feng, Metformin activates the protective effects of the AMPK pathway in acute lung injury caused by paraquat poisoning, Oxid Med Cell Longev,
doi:10.1155/2019/1709718Wu, Tian, Huang, Metformin alleviated endotoxemiainduced acute lung injury via restoring AMPK-dependent suppression of mTOR, Chem Biol Interact,
doi:10.1016/j.cbi.2018.05.018Xiang, Wong, So, Exploring drugs and vaccines associated with altered risks and severity of COVID-19: a UK Biobank cohort study of all ATC level-4 drug categories. medRxiv,
doi:10.1101/2020.12.05.20244426Xie, Wang, Dai, Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation, J Mol Cell Cardiol,
doi:10.1016/j.yjmcc.2015.05.021Xu, Du, Zheng, Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review, BMC Womens Health,
doi:10.1186/1472-6874-14-93Xu, Liu, Li, Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes, Cell Metab,
doi:10.1016/j.cmet.2020.08.013Yan, Valdes, Vijay, Role of drugs used for chronic disease management on susceptibility and severity of COVID-19: a large case-control study. medRxiv,
doi:10.1101/2020.04.24.20077875Zhang, Kong, Xia, Impaired fasting glucose and diabetes are related to higher risks of complications and mortality among patients with coronavirus disease, Front Endocrinol (Lausanne),
doi:10.3389/fendo.2020.00525Zhang, Shang, Hui, The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism, Saudi Pharm J,
doi:10.1016/j.jsps.2017.05.001Zhang, Zheng, Yan, Angiotensin-converting enzyme 2 regulates autophagy in acute lung injury through AMPK/ mTOR signaling, Arch Biochem Biophys,
doi:10.1016/j.abb.2019.07.026Zmijewski, Zhao, Mitochondrial respiratory complex I regulates neutrophil activation and severity of lung injury, Am J Respir Crit Care Med,
doi:10.1164/rccm.200710-1602OC{ 'indexed': {'date-parts': [[2022, 3, 29]], 'date-time': '2022-03-29T01:53:46Z', 'timestamp': 1648518826218},
'reference-count': 0,
'publisher': 'VM Media SP. zo.o VM Group SK',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'DOI': '10.5603/dk.a2021.0035',
'type': 'journal-article',
'created': {'date-parts': [[2021, 5, 25]], 'date-time': '2021-05-25T10:36:00Z', 'timestamp': 1621938960000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis',
'prefix': '10.5603',
'author': [ {'given': 'Teodoro J.', 'family': 'Oscanoa', 'sequence': 'first', 'affiliation': []},
{'given': 'José', 'family': 'Amado', 'sequence': 'additional', 'affiliation': []},
{'given': 'Xavier', 'family': 'Vidal', 'sequence': 'additional', 'affiliation': []},
{'given': 'Andrea', 'family': 'Savarino', 'sequence': 'additional', 'affiliation': []},
{'given': 'Roman', 'family': 'Romero-Ortuno', 'sequence': 'additional', 'affiliation': []}],
'member': '3595',
'published-online': {'date-parts': [[2021, 5, 24]]},
'container-title': 'Clinical Diabetology',
'original-title': [],
'link': [ { 'URL': 'https://journals.viamedica.pl/clinical_diabetology/article/viewFile/75056/62969',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 5, 25]],
'date-time': '2021-05-25T10:36:03Z',
'timestamp': 1621938963000},
'score': 1,
'resource': {'primary': {'URL': 'https://journals.viamedica.pl/clinical_diabetology/article/view/75056'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 5, 24]]},
'references-count': 0,
'URL': 'http://dx.doi.org/10.5603/DK.a2021.0035',
'relation': {},
'ISSN': ['2450-8187', '2450-7458'],
'subject': ['Endocrinology, Diabetes and Metabolism', 'Internal Medicine'],
'published': {'date-parts': [[2021, 5, 24]]}}
