Metformin Use in Relation to Clinical Outcomes and Hyperinflammatory Syndrome Among COVID-19 Patients With Type 2 Diabetes: A Propensity Score Analysis of a Territory-Wide Cohort
Carlos K H Wong, David T W Lui, Angel Y C Lui, Marshall C H Low, Ashley C Y Kwok, Kristy T K Lau, Ivan C H Au, Xi Xiong, Matthew S H Chung, Eric H Y Lau, Benjamin J Cowling
Frontiers in Endocrinology, doi:10.3389/fendo.2022.810914
This study was conducted in order to evaluate the association between metformin use and clinical outcomes in type 2 diabetes mellitus (T2DM) patients hospitalized with coronavirus disease 2019 . Methods: Patients with T2DM with confirmed diagnosis of COVID-19 and admitted between January 21, 2020, and January 31, 2021 in Hong Kong were identified in our cohort. Exposure was defined as metformin use within 90 days prior to admission until hospital discharge for COVID-19. Primary outcome was defined as clinical improvement of ≥1 point on the WHO Clinical Progression Scale (CPS). Other outcomes were hospital discharge, recovery, in-hospital death, acidosis, hyperinflammatory syndrome, length of hospitalization, and changes in WHO CPS score. Results: Metformin use was associated with greater odds of clinical improvement (OR = 2.74, p = 0.009), hospital discharge (OR = 2.26, p = 0.009), and recovery (OR = 2.54, p = 0.005), in addition to lower odds of hyperinflammatory syndrome (OR = 0.71, p = 0.021) and death (OR = 0.41, p = 0.010) than control. Patients on metformin treatment had a shorter hospital stay (−2.76 days, p = 0.017) than their control counterparts. The average WHO CPS scores were significantly lower in metformin users than non-users since day 15 (p < 0.001). However, metformin use was associated with higher odds of acidosis. Conclusions: Metformin use was associated with lower mortality and lower odds for hyperinflammatory syndrome. This provides additional insights into the potential mechanisms of the benefits of metformin use in T2DM patients with COVID-19.
ETHICS STATEMENT The study protocol was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster (Reference No. . Given the extraordinary nature of the COVID-19 pandemic, individual patient informed consent was not required for this retrospective cohort study using anonymized data.
AUTHOR CONTRIBUTIONS CW reviewed the literature, designed the statistical analysis, conducted the analyses, and wrote the manuscript. DL, AL, AK, ML, and KL reviewed the literature, contributed to the
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2022.
810914/full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Apicella, Campopiano, Mantuano, Mazoni, Coppelli et al., COVID-19 in People With Diabetes: Understanding the Reasons for Worse Outcomes, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(20)30238-2Barron, Bakhai, Kar, Weaver, Bradley et al., Associations of Type 1 and Type 2 Diabetes With COVID-19-Related Mortality in England: A Whole-Population Study, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(20)30272-2Bode, Garrett, Messler, Mcfarland, Crowe et al., Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States, J Diabetes Sci Tech,
doi:10.1177/1932296820924469Bornstein, Rubino, Khunti, Mingrone, Hopkins et al., Practical Recommendations for the Management of Diabetes in Patients With COVID-19, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(20)30152-2Bramante, Ingraham, Murray, Marmor, Hovertsen et al., Metformin and Risk of Mortality in Patients Hospitalised With COVID-19: A Retrospective Cohort Analysis, Lancet Healthy Longevity,
doi:10.1016/S2666-7568(20)30033-7Chen, 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/dc20-0660Cheng, 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.2020.08.013Gao, Liu, Zhong, Liu, Zhou et al., Risk of Metformin in Patients With Type 2 Diabetes With COVID-19: A Preliminary Retrospective Report,
doi:10.1111/cts.12897Hariyanto, Kurniawan, Metformin Use Is Associated With Reduced Mortality Rate From Coronavirus Disease 2019 (COVID-19) Infection, Obes Med,
doi:10.1016/j.obmed.2020.100290Ilyas, Wallis, Soilleux, Townsend, Zehnder et al., High Glucose Disrupts Oligosaccharide Recognition Function via Competitive Inhibition: A Potential Mechanism for Immune Dysregulation in Diabetes Mellitus, Immunobiology,
doi:10.1016/j.imbio.2010.06.002Katulanda, Dissanayake, Ranathunga, Ratnasamy, Wijewickrama et al., Prevention and Management of COVID-19
Kopec, Kowalski, Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship, J? Med Toxicol,
doi:10.1007/s13181-012-0278-3Koufakis, Maltese, Metallidis, Zebekakis, Kotsa, Looking Deeper Into the Findings of DARE-19: Failure or an Open Door to Future Success?, Pharmacol Res,
doi:10.1016/j.phrs.2021.105872Koufakis, Metallidis, Zebekakis, Ajjan, Kotsa, Sodium-Glucose Cotransporter 2 Inhibitors in the Era of COVID-19 Pandemic: Is the Benefit to Risk Ratio Still Favorable?, J Diabetes Sci Tech,
doi:10.1177/1932296820932155Koufakis, Pavlidis, Metallidis, Kotsa, Sodium-Glucose Co-Transporter 2 Inhibitors in COVID-19: Meeting at the Crossroads Between Heart, Diabetes and Infectious Diseases, Int J Clin Pharmacy,
doi:10.1007/s11096-021-01256-9Kow, Hasan, Mortality Risk With Preadmission Metformin Use in Patients With COVID-19 and Diabetes: A Meta-Analysis, J Med Virol,
doi:10.1002/jmv.26498Lalau, Arnouts, Sharif, Broe, Metformin and Other Antidiabetic Agents in Renal Failure Patients, Kidney Int,
doi:10.1038/ki.2014.19Lukito, Pranata, Henrina, Lim, Lawrensia et al., The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis, Diabetes Metab Syndrome: Clin Res Rev,
doi:10.1016/j.dsx.2020.11.006Lumbers, Delforce, Pringle, Smith, The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; the Need for Clinical Trials, Front Med,
doi:10.3389/fmed.2020.00248Luo, 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 Hygiene,
doi:10.4269/ajtmh.20-0375Mirabelli, Chiefari, Puccio, Foti, Brunetti, Potential Benefits and Harms of Novel Antidiabetic Drugs During COVID-19
Pal, Banerjee, Mukherjee, Bhogal, Kaur et al., Dipeptidyl Peptidase-4 Inhibitor Use and Mortality in COVID-19 Patients With Diabetes Mellitus: An Updated Systematic Review and Meta-Analysis, Ther Adv Endocrinol Metab,
doi:10.1177/2042018821996482Sardu, Onofrio, Balestrieri, Barbieri, Rizzo et al., Outcomes in Patients With Hyperglycemia Affected by COVID-19: Can We do More on Glycemic Control?, Diabetes Care,
doi:10.2337/dc20-0723Sharif-Askari, Sharif-Askari, Mdkhana, Heialy, Ratemi et al., Effect of Common Medications on the Expression of SARS-CoV-2 Entry Receptors in Liver Tissue, Arch Toxicol,
doi:10.1007/s00204-020-02869-1Suetrong, Walley, Lactic Acidosis in Sepsis: It's Not All Anaerobic: Implications for Diagnosis and Management, Chest,
doi:10.1378/chest.15-1703Tom, Mina, To Interpret the SARS-CoV-2 Test, Consider the Cycle Threshold Value, Clin Infect Dis,
doi:10.1093/cid/ciaa619Webb, Peltan, Jensen, Hoda, Hunter et al., Clinical Criteria for COVID-19-Associated Hyperinflammatory Syndrome: A Cohort Study, Lancet Rheumatol,
doi:10.1016/S2665-9913(20)30343-XWong, Lui, Lui, Kwok, Low et al., Use of DPP4i Reduced Odds of Clinical Deterioration and Hyperinflammatory Syndrome in COVID-19 Patients With Type 2 Diabetes: Propensity Score Analysis of a Territory-Wide Cohort in Hong Kong, Diabetes Metab,
doi:10.1016/j.diabet.2021.101307Xiao, Sakagami, Miwa, ACE2: The Key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?, Viruses,
doi:10.3390/v12050491Yang, Sun, Zhang, Zhang, The Effect of Metformin on Mortality and Severity in COVID-19 Patients With Diabetes Mellitus, Diabetes Res Clin Practice,
doi:10.1016/j.diabres.2021.108977Zhang, Dong, Martin, He, Gongol et al., AMP-Activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension, Am J Respir Crit Care Med,
doi:10.1164/rccm.201712-2570OCZhu, 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
