Is metformin use associated with low mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19? a multivariable and propensity score-adjusted meta-analysis
Zhiyuan Ma, Mahesh Krishnamurthy
PLOS ONE, doi:10.1371/journal.pone.0282210
Background Coronavirus disease 2019 (COVID-19) is a new pandemic that the entire world is facing since December of 2019. Increasing evidence has shown that metformin is linked to favorable outcomes in patients with COVID-19. The aim of this study was to address whether outpatient or inpatient metformin therapy for type 2 diabetes mellitus is associated with low inhospital mortality in patients hospitalized for COVID-19.
Methods We searched studies published in PubMed, Embase, Google Scholar and Cochrane Library up to November 1, 2022. Raw event data extracted from individual study were pooled using the Mantel-Haenszel approach. Odds ratio (OR) or hazard ratio (HR) adjusted for covariates that potentially confound the association using multivariable regression or propensity score matching was pooled by the inverse-variance method. Random effect models were applied for meta-analysis due to variance among studies.
Results Twenty-two retrospective observational studies were selected. The pooled unadjusted OR for outpatient metformin therapy and in-hospital mortality was 0.48 (95% CI, 0.37-0.62) and the pooled OR adjusted with multivariable regression or propensity score matching was 0.71 (95% CI, 0.50-0.99). The pooled unadjusted OR for inpatient metformin therapy and in-hospital mortality was 0.18 (95% CI, 0.10-0.31), whereas the pooled adjusted HR was 1.10 (95% CI, 0.38-3.15).
References
Abu-Jamous, Anisimovich, Baxter, Mackillop, Vizcaychipi et al., Associations of comorbidities and medications with COVID-19 outcome: A retrospective analysis of real-world evidence data, medRxiv,
doi:10.1101/2020.08.20.20174169
Bramante, Buse, Tamaritz, Palacio, Cohen et al., Outpatient metformin use is associated with reduced severity of COVID-19 disease in adults with overweight or obesity, J Med Virol,
doi:10.1002/jmv.26873
Bramante, Ingraham, Murray, Marmor, Hovertsen et al., Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis, Lancet Healthy Longev,
doi:10.1016/S2666-7568%2820%2930033-7
Cameron, Morrison, Levin, Mohan, Forteath et al., Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status, Circ Res,
doi:10.1161/CIRCRESAHA.116.308445
Cariou, Hadjadj, Wargny, Pichelin, Al-Salameh et al., Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study, Diabetologia,
doi:10.1007/s00125-020-05180-x
Chen, Yang, Cheng, Chen, Peng et al., Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication, Diabetes Care,
doi:10.2337/dc20-0660
Cheng, Liu, Li, Zhang, Lei et al., 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.2020.08.013
Crouse, Grimes, Li, Might, Ovalle et al., Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes, Front Endocrinol,
doi:10.3389/fendo.2020.600439
Cummings, Baldwin, Abrams, Jacobson, Meyer et al., Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study, Lancet,
doi:10.1016/S0140-6736%2820%2931189-2
Garcia, Flumamine, a new synthetic analgesic and anti-flu drug, J Philipp Med Assoc
Ghany, Palacio, Dawkins, Chen, Mccarter et al., Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2021.02.022
Grasselli, Zangrillo, Zanella, Antonelli, Cabrini et al., Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, JAMA,
doi:10.1001/jama.2020.5394
Guan, Ni, Hu, Liang, Ou et al., Clinical Characteristics of Coronavirus Disease 2019 in China, N Engl J Med,
doi:10.1056/NEJMoa2002032
Huang, Lim, Pranata, Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia-A systematic review, meta-analysis, and meta-regression, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2020.04.018
Jiang, Chen, Liu, Yin, Yang et al., 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.2020.108619
Lalau, Al-Salameh, Hadjadj, Goronflot, Wiernsperger et al., 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.2020.101216
Li, Wei, Li, Mccowen, Xiong et al., Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19, Endocr Pract,
doi:10.4158/EP-2020-0466
Li, Wei, Mccowen, Xiong, Liu et al., Inpatient use of metformin and acarbose is associated with reduced mortality of COVID-19 patients with type 2 diabetes mellitus, Endocrinol Diabetes Metab,
doi:10.1002/edm2.301
Li, Yang, Yan, Sun, Zeng et al., Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis, Front Med,
doi:10.3389/fmed.2021.704666
Lighter, Phillips, Hochman, Sterling, Johnson et al., Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission, Clin Infect Dis,
doi:10.1093/cid/ciaa415
Luk, Yip, Zhang, Kong, Wong et al., Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong, BMJ Open,
doi:10.1136/bmjopen-2021-052310
Luo, Qiu, Liu, Liu, Zheng et al., 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.20-0375
Ma, Fan, Cheng, Does sleeve lobectomy concomitant with or without pulmonary artery reconstruction (double sleeve) have favorable results for non-small cell lung cancer compared with pneumonectomy? A meta-analysis, Eur J Cardiothorac Surg,
doi:10.1016/j.ejcts.2007.03.018
Ma, Patel, Vemparala, Krishnamurthy, Metformin is associated with favorable outcomes in patients with COVID-19 and type 2 diabetes mellitus, Sci Rep,
doi:10.1038/s41598-022-09639-2
Mirani, Favacchio, Carrone, Betella, Biamonte et al., 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/dc20-1340
Oh, Song, Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study, Acta Diabetol,
doi:10.1007/s00592-020-01666-7
Ojeda-Fernandez, Foresta, Macaluso, Colacioppo, Tettamanti et al., Metformin use is associated with a decrease in the risk of hospitalization and mortality in COVID-19 patients with diabetes: A population-based study in Lombardy, Diabetes Obes Metab,
doi:10.1111/dom.14648
Ong, Tan, Canete, Lim, Robles, Association Between Metformin Use and Mortality among Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19 Infection, J ASEAN Fed Endocr Soc,
doi:10.15605/jafes.036.02.20
Oscanoa, Amado, Vidal, Savarino, Romero-Ortuno, Metformin therapy, severity and mortality of SARS-CoV-2 infection: a meta-analysis, Clin Diabetol
Perez-Belmonte, Torres-Pena, Lopez-Carmona, Ayala-Gutierrez, Fuentes-Jimenez 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, BMC Med,
doi:10.1186/s12916-020-01832-2
Ramos-Rinco ´n, ´rez-Belmonte, ´nchez, Jansen-Chaparro, De-Sousa-Baena, type 2 diabetes mellitus hospitalized due to COVID-19. A nationwide observational study in Spain,
doi:10.21203/rs.3.rs-133358/v1
Roncon, Zuin, Rigatelli, Zuliani, Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome, J Clin Virol,
doi:10.1016/j.jcv.2020.104354
Siddiqi, Mehra, COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, J Heart Lung Transplant,
doi:10.1016/j.healun.2020.03.012
Stang, Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses, Eur J Epidemiol,
doi:10.1007/s10654-010-9491-z
Tamura, Said, De Freitas, Rubio, Outcome and death risk of diabetes patients with Covid-19 receiving pre-hospital and in-hospital metformin therapies, Diabetol Metab Syndr,
doi:10.1186/s13098-021-00695-8
Thomas, Li, Pencina, Overlap Weighting: A Propensity Score Method That Mimics Attributes of a Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2020.7819
Ursini, Russo, Pellino, Angelo, Chiaravalloti et al., Metformin and Autoimmunity: A "New Deal" of an Old Drug, Front Immunol,
doi:10.3389/fimmu.2018.01236
Wiernsperger, Al-Salameh, Cariou, Lalau, Protection by metformin against severe Covid-19: An in-depth mechanistic analysis, Diabetes Metab,
doi:10.1016/j.diabet.2022.101359
Wu, Mcgoogan, Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention, JAMA,
doi:10.1001/jama.2020.2648
Yang, Sun, Zhang, Zhang, The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus, Diabetes Res Clin Pract,
doi:10.1016/j.diabres.2021.108977
Yang, Yu, Xu, Shu, Xia et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lan, cet Respir Med,
doi:10.1016/S2213-2600%2820%2930079-5
Zhou, Yu, Du, Fan, Liu et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet,
doi:10.1016/S0140-6736%2820%2930566-3