Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19
Jean-Daniel Lalau, Abdallah Al-Salameh, Samy Hadjadj, Thomas Goronflot, Nicolas Wiernsperger, Matthieu Pichelin, Ingrid Allix, Coralie Amadou, Olivier Bourron, Thierry Duriez, Jean-François Gautier, Anne Dutour, Céline Gonfroy, Didier Gouet, Michael Joubert, Ingrid Julier, Etienne Larger, Lucien Marchand, Michel Marre, Laurent Meyer, Frédérique Olivier, Gaëtan Prevost, Pascale Quiniou, Christelle Raffaitin-Cardin, Ronan Roussel, Pierre-Jean Saulnier, Dominique Seret-Begue, Charles Thivolet, Camille Vatier, Rachel Desailloud, Matthieu Wargny, Pierre Gourdy, Bertrand Cariou
Diabetes & Metabolism, doi:10.1016/j.diabet.2020.101216
Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. Methods. -CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. Results. -Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P < 0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649À1.082] and 0.688 [0.470À1.007] on day 7, then 0.783 [0.615À0.996] and 0.710 [0.537À0.938] on day 28, respectively. Conclusion. -Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
Conflict of interest JDL reports personal fees from AstraZeneca, Brothier, Lilly, MSD, Novo Nordisk, Pfizer, and Sanofi. AAS reports personal fees from AstraZeneca and Novo Nordisk. SH reports personal fees and non-financial support from AstraZeneca, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, grants from Dinno Sante ´, personal fees from Eli Lilly, non-financial support from LVL, personal fees and non-financial support from MSD, personal fees from Novartis, grants from Pierre Fabre Sante ´, personal fees and non-financial support from Sanofi, personal fees and non-financial support from Servier, and personal fees from Valbiotis. MP reports personal fees and non-financial support from Novo Nordisk, nonfinancial support from Sanofi, and non-financial support from Amgen. JFG reports personal fees and non-financial support from Eli Lilly, personal fees and non-financial support from Novo Nordisk, personal fees and non-financial support from Gilead, and personal fees and non-financial support from AstraZeneca. MJ reports personal fees and non-financial support from Sanofi, personal fees and non-financial support from Eli Lilly, personal fees and non-financial support from Novo Nordisk, grants and personal fees from Boehringer Ingelheim, grants, personal fees and non-financial support from Medtronic, personal fees and non-financial support from Abbott, personal fees and non-financial support from BMS, personal fees and non-financial support from..
References
Ac (african Or Caribbean, As, HbA1c corresponds to the glycated haemoglobin determined in the first 7 days following hospital admission or in the 6 months prior hospitalisation
Arb, angiotensin-2 receptor-blocker
Austin, The performance of different propensity-score methods for estimating differences in proportions (risk differences or absolute risk reductions) in observational studies, Stat Med,
doi:10.1002/sim.3854Austin, The relative ability of different propensity score methods to balance measured covariates between treated and untreated subjects in observational studies, Med Decis Mak Int J Soc Med Decis Mak,
doi:10.1177/0272989X09341755Bramante, Ingraham, Murray, Marmor, Hoversten et al., Observational study of metformin and risk of mortality in patients hospitalized with Covid-19, MedRxiv Prepr Serv Health Sci,
doi:10.1101/2020.06.19.20135095Buse, Wexler, Tsapas, Rossing, Mingrone et al., Update to: management of hyperglycemia in Type 2 diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), Diabetes Care,
doi:10.2337/dci19-0066Cariou, Goronflot, Rimbert, Boullu, May et al., Routine use of statins and increased mortality related to COVID-19 in inpatients with type 2 diabetes: results from the CORONADO study, Diabetes Metab,
doi:10.1016/j.diabet.2020.10.001Cariou, 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-xCheng, 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.2020.08.013Crouse, Grimes, Li, Might, Ovalle et al., Metformin use is associated with reduced mortality in a diverse population with covid-19 and diabetes, MedRxiv Prepr Serv Health Sci,
doi:10.1101/2020.07.29.20164020Crowley, Diamantidis, Mcduffie, Cameron, Stanifer et al., Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review, Ann Intern Med,
doi:10.7326/M16-1901Do, Kim, Park, Cho, Kang, Is there an association between metformin use and clinical outcomes in diabetes patients with COVID-19?, Diabetes Metab,
doi:10.1016/j.diabet.2020.10.006Foretz, Guigas, Viollet, Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus, Nat Rev Endocrinol,
doi:10.1038/s41574-019-0242-2Gao, Liu, Zhong, Liu, Zhou et al., Risk of metformin in patients with type 2 diabetes with Covid-19: a preliminary retrospective report, Clin Transl Sci,
doi:10.1111/cts.12897Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature,
doi:10.1038/s41586-020-2286-9Hariyanto, Kurniawan, Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection, Obes Med,
doi:10.1016/j.obmed.2020.100290Heckman-Stoddard, Decensi, Sahasrabuddhe, Ford, Repurposing metformin for the prevention of cancer and cancer recurrence, Diabetologia,
doi:10.1007/s00125-017-4372-6Kheirollahi, Wasnick, Biasin, Vazquez-Armendariz, Chu et al., Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis, Nat Commun,
doi:10.1038/s41467-019-10839-0Lalau, Al-Salameh, Hadjadj, ACE inhibitors, angiotensin converting enzyme inhibitors, Diabetes & Metabolism
Lalau, Al-Salameh, Hadjadj, None, Diabetes & Metabolism
Liang, Ding, Li, Wang, Kan et al., 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 Lond Engl,
doi:10.1186/s13054-019-2346-4Luo, 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.20-0375Malik, Mehdi, Ali, Patel, Basharat et al., Is metformin poised for a second career as an antimicrobial?, Diabetes Metab Res Rev,
doi:10.1002/dmrr.2975Mao, Li, Propensity score weighting methods for dichotomous treatments; R package version
Marcucci, Romeo, Caserta, Rumio, Lefoulon, Context-dependent pharmacological effects of metformin on the immune system, Trends Pharmacol Sci,
doi:10.1016/j.tips.2020.01.003Maruthur, Tseng, Hutfless, Wilson, Suarez-Cuervo et al., Diabetes Medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis, Ann Intern Med,
doi:10.7326/M15-2650Menendez, Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19, Aging,
doi:10.18632/aging.103347Mra, mineralocorticoid-receptor antagonist (i.e. spironolactone and eplerenone)
Pe ´rez-Belmonte, Torres-Pen ˜a, Lo ´pez-Carmona, Ayala-Gutie ´rrez, Fuentes-Jime ´nez 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/s12916-020-01832-2Robert, Fendri, Hary, Lacroix, Andre ´jak et al., Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects, Diabetes Metab,
doi:10.1016/s1262-3636(07)70037-xRotermund, Machetanz, Fitzgerald, The therapeutic potential of metformin in neurodegenerative diseases, Front Endocrinol,
doi:10.3389/fendo.2018.00400Roussel, Travert, Pasquet, Wilson, Smith et al., Metformin use and mortality among patients with diabetes and atherothrombosis, Arch Intern Med,
doi:10.1001/archinternmed.2010.409Scheen, Marre, Thivolet, Prognostic factors in patients with diabetes hospitalized for COVID-19: findings from the CORONADO study and other recent reports, Diabetes Metab,
doi:10.1016/j.diabet.2020.05.008Singh, Singh, Is metformin ahead in the race as a repurposed hostdirected therapy for patients with diabetes and COVID-19?, Diabetes Res Clin Pract,
doi:10.1016/j.diabres.2020.108268Wiernsperger, Metformin as a cellular protector; a synoptic view of modern evidences, J Nephropharmacology
Williamson, Walker, Bhaskaran, Bacon, Bates et al., Factors associated with COVID-19-related death using OpenSAFELY, Nature,
doi:10.1038/s41586-020-2521-4Zhu, She, Cheng, Qin, Zhang et al., Association of Blood Glucose control and outcomes in patients with Covid-19 and pre-existing type 2 diabetes, Cell Metab,
doi:10.1016/j.cmet.2020.04.021
