Abstract: Metformin use is associated with a decrease in risk of hospitalization and mortality in COVID-19 diabetic patients: a population-based study in Lombardy. Luisa Ojeda-Fernández PhD1, Andreana Foresta MSc1, Giulia Macaluso MSc1, Pierluca Colacioppo MSc1, Mauro Tettamanti MSc2, Antonella Zambon MSc3, Stefano Genovese MD4, Ida Fortino MSc5, Olivia Leoni MSc5, Maria Carla Roncaglioni MSc 1, Marta Baviera Pharm Dr1 1 Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 2 Laboratory of Geriatric Neuropsychiatry, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 3 Department of Statistics and Quantitative Methods, University of Milano Bicocca, Milano, Italy 4 Centro Cardiologico Monzino IRCCS, Milan, Italy 5 Unità Organizzativa Osservatorio Epidemiologico Regionale, Lombardy Region, Milan, Italy. Correspondence Dr. Luisa Ojeda Fernández Laboratory of Cardiovascular Prevention Department of Cardiovascular Medicine Istituto di Ricerche Farmacologiche Mario Negri IRCCS Via Mario Negri 2, 20156 Milan, Italy Tel: +39 0239014561 e-mail: luisa.ojeda@marionegri.it This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.14648 This article is protected by copyright. All rights reserved. ABSTRACT Aims. We compared the association of metformin use and COVID-19 outcomes in a cohort of 31,966 patients with diabetes in Lombardy. Methods. We used a COVID-19 linkable administrative regional database to select diabetic patients over 40 years old. They had at least two prescriptions of antidiabetic drugs in 2019 and a positive test for SARS-CoV-2 between 15 February 2020 and 15 March 2021. The association of metformin use and clinical outcomes was assessed by multivariable logistic regression analyses and after propensity score matching. Clinical outcomes were all-cause mortality, in-hospital mortality, hospitalization for COVID-19 and admission to an intensive care unit (ICU). Results. In multivariable models metformin use was associated with a significantly lower risk of total mortality (OR 0.70; 95% CI 0.66-0.75), in-hospital mortality (OR 0.68; 95% CI 0.63-0.73), hospitalization for COVID-19 (OR 0.86; 95% CI 0.81-0.91) and ICU admission (OR 0.81; 95% CI 0.69-0.94) compared with metformin non-users. Results were similar in propensity score analysis; metformin was associated with significantly lower risk of total mortality (OR 0.79; 95% CI, 0.730.86), in-hospital mortality (OR 0.74; 95% CI, 0.67-0.81) and ICU admission (OR 0.77; 95% CI, 0.63-0.95). Conclusions. In this large cohort, metformin use was associated with a protective effect in COVID19 clinical outcomes, suggesting that it might be a potentially useful drug to prevent severe COVID19 disease, although randomized clinical trials (RCT) are needed to confirm this. While awaiting the results of RCT, we suggest continuing prescribing metformin to diabetic patients with COVID-19. Keywords COVID-19, Diabetes Mellitus, Metformin, Outcomes This article is protected by copyright. All rights reserved.