Is Metformin Use Associated with a More Favorable COVID-19 Course in People with Diabetes?
Giovanni Antonio Silverii, Carlo Fumagalli, Renzo Rozzini, Marta Milani, Edoardo Mannucci, Niccolò Marchionni
Journal of Clinical Medicine, doi:10.3390/jcm13071874
Background: Diabetes Mellitus (DM) has been associated with a higher Coronavirus disease-19 (COVID-19) mortality, both in hospitalized patients and in the general population. A possible beneficial effect of metformin on the prognosis of COVID-19 has been reported in some observational studies, whereas other studies disagree. Methods: To investigate the possible effect of metformin on COVID-19 in-hospital mortality, we performed a retrospective study that included all SARS-CoV-2-positive patients with DM who were admitted to two Italian hospitals. In order to adjust for possible confounders accounting for the observed reduction of mortality in metformin users, we adopted the COVID-19 Mortality Risk Score (COVID-19 MRS) as a covariate. Results: Out of the 524 included patients, 33.4% died. A binomial logistic regression showed that metformin use was associated with a significant reduction in case fatality , p = 0.039), with no significant effect on the need for ventilation ], p = 0.146). After adjusting for COVID-19 MRS, metformin did not retain a significant association with in-hospital mortality , p = 0.342]. Conclusions: A beneficial effect of metformin on COVID-19 was not proven after adjusting for confounding factors. The use of validated tools to stratify the risk for COVID-19 severe disease and death, such as COVID-19 MRS, may be useful to better explore the potential association of medications and comorbidities with COVID-19 prognosis.
Author Contributions: G.A.S. was involved in the design, data collection, analysis, and writing of the manuscript; C.F., M.M., and R.R. were involved in patient s enrollment and data collection; E.M. and N.M. were involved in the design, analysis, writing of the manuscript, and manuscript revision. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and agreed to the published version of the manuscript. Funding: No Funding was provided for this research. This research was performed as a part of the institutional activity of the units, with no specific funding. All expenses, including salaries of the investigators, were covered by public research funds assigned to the units.
Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and its protocol approved by the local Ethical Review Board (Comitato Area Vasta Centro, CARE-COVID19 AOU Careggi Protocol 00/08761 15 April 2020).
Informed Consent Statement: Each patient provided an informed oral consent which was recorded during the 1-month telephone interview. Conflicts of Interest: G.A. Silverii reports personal fees from Astra Zeneca, Eli Lilly, and Novo Nordisk outside the submitted work; E. Mannucci reports grants and personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Genentech, Molteni, Merck,..
References
Al-Kuraishy, Al-Gareeb, El Kholy, El-Khateeb, Alexiou et al., The potential therapeutic effect of metformin in type 2 diabetic patients with severe COVID-19, Eur. Rev. Med. Pharmacol. Sci,
doi:10.26355/eurrev_202312_34583Alraddadi, Watson, Almarashi, Abedi, Turkistani et al., Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Illness in Humans, Saudi Arabia, Emerg. Infect. Dis,
doi:10.3201/eid2201.151340Bedston, Almaghrabi, Patterson, Agrawal, Woolford et al., Risk of severe COVID-19 outcomes after autumn 2022 COVID-19 booster vaccinations: A pooled analysis of national prospective cohort studies involving 7.4 million adults in England, Northern Ireland, Scotland and Wales, Lancet Reg. Health-Eur,
doi:10.1016/j.lanepe.2023.100816Blüher, Fasshauer, Tönjes, Kratzsch, Schön et al., Association of Interleukin-6, C-reactive Protein, Interleukin-10 and Adiponectin Plasma Concentrations with Measures of Obesity, Insulin Sensitivity and Glucose Metabolism, Exp. Clin. Endocrinol. Diabetes,
doi:10.1055/s-2005-872851Bramante, Buse, Liebovitz, Nicklas, Puskarich et al., Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): A multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial, Lancet Infect. Dis,
doi:10.1016/S1473-3099(23)00299-2Bramante, Huling, Tignanelli, Buse, Liebovitz et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2201662Bramante, 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(20)30033-7Cariou, 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-xCasqueiro, Casqueiro, Alves, Infections in patients with diabetes mellitus: A review of pathogenesis, Indian J. Endocr. Metab,
doi:10.4103/2230-8210.94253Ceriello, De Nigris, Prattichizzo, Why is hyperglycaemia worsening COVID-19 and its prognosis?, Diabetes Obes. Metab,
doi:10.1111/dom.14098Chen, Fang, Chen, Rajaofera, Li et al., The efficacy and safety of remdesivir alone and in combination with other drugs for the treatment of COVID-19: A systematic review and meta-analysis, BMC Infect. Dis,
doi:10.1186/s12879-023-08525-0Diabetes, Professional, Committee; Elsayed, Aleppo, Bannuru et al., Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024, Diabetes Care,
doi:10.2337/dc24-S009Dicembrini, Silverii, Clerico, Fornengo, Gabutti et al., Influenza: Diabetes as a risk factor for severe related-outcomes and the effectiveness of vaccination in diabetic population. A meta-analysis of observational studies, Nutr. Metab. Cardiovasc. Dis,
doi:10.1016/j.numecd.2023.03.016El-Arabey, Abdalla, Metformin and COVID-19: A novel deal of an old drug, J. Med. Virol,
doi:10.1002/jmv.25958Fumagalli, Rozzini, Vannini, Coccia, Cesaroni et al., Clinical risk score to predict in-hospital mortality in COVID-19 patients: A retrospective cohort study, BMJ Open,
doi:10.1136/bmjopen-2020-040729Fumagalli, Zocchi, Tassetti, Silverii, Amato et al., Factors associated with persistence of symptoms 1 year after COVID-19: A longitudinal, prospective phone-based interview follow-up cohort study, Eur. J. Intern. Med,
doi:10.1016/j.ejim.2021.11.018Han, Ma, Sun, Zhang, Qu et al., Association Between Anti-diabetic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis, Arch. Med. Res,
doi:10.1016/j.arcmed.2021.08.002Horvath, Békeffy, Németh, Szelke, Fazekas-Pongor et al., The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic, Geroscience,
doi:10.1007/s11357-023-00931-1Huang, Guo, Liu, Taksa, Cheng et al., Changing impact of COVID-19 on life expectancy 2019-2023 and its decomposition: Findings from 27 countries, SSM-Popul. Health,
doi:10.1016/j.ssmph.2023.101568Jiang, 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.2020.108619Kelly, Tannahill, Murphy, Neill, Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages, J. Biol. Chem,
doi:10.1074/jbc.M115.662114Kerr, Bedston, Cezard, Sampri, Murphy et al., Undervaccination and severe COVID-19 outcomes: Meta-analysis of national cohort studies in England, Northern Ireland, Scotland, and Wales, Lancet,
doi:10.1016/S0140-6736(23)02467-4Khalifa, Al Ramahi, After the Hurricane: Anti-COVID-19 Drugs Development, Molecular Mechanisms of Action and Future Perspectives, IJMS,
doi:10.3390/ijms25020739Khunti, Knighton, Zaccardi, Bakhai, Barron et al., Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: A nationwide observational study in England, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(21)00050-4Lai, Chao, Hsueh, Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials, J. Microbiol. Immunol. Infect,
doi:10.1016/j.jmii.2021.05.011Lalau, 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.2020.101216Lalau, Kajbaf, Bennis, Hurtel-Lemaire, Belpaire et al., Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4, Diabetes Care,
doi:10.2337/dc17-2231Mannucci, Silverii, Monami, Saturation of critical care capacity and mortality in patients with the novel coronavirus (COVID-19) in Italy, Trends Anaesth. Crit. Care,
doi:10.1016/j.tacc.2020.05.002Mantovani, Byrne, Zheng, Targher, Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: A meta-analysis of observational studies, Nutr. Metab. Cardiovasc. Dis,
doi:10.1016/j.nu-mecd.2020.05.014Mcgurnaghan, Weir, Bishop, Kennedy, Blackbourn et al., Risks of and risk factors for COVID-19 disease in people with diabetes: A cohort study of the total population of Scotland, Lancet Diabetes Endocrinol,
doi:10.1016/S2213-8587(20)30405-8Menendez, Metformin and SARS-CoV-2: Mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19, Aging,
doi:10.18632/aging.103347Nag, Mandal, Mukherjee, Mukherjee, Kundu, DPP-4 Inhibitors as a savior for COVID-19 patients with diabetes, Future Virol,
doi:10.2217/fvl-2022-0112Novida, Soelistyo, Cahyani, Siagian, Hadi et al., Factors associated with disease severity of COVID-19 in patients with type 2 diabetes mellitus, Biomed. Rep,
doi:10.3892/br.2022.1590Pala, Pezzatini, Dicembrini, Ciani, Gelmini et al., Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells, Acta Diabetol,
doi:10.1007/s00592-010-0195-3Penlioglou, Papachristou, Papanas, COVID-19 and Diabetes Mellitus: May Old Anti-diabetic Agents Become the New Philosopher s Stone?, Diabetes Ther,
doi:10.1007/s13300-020-00830-0Postler, Peng, Bhatt, Ghosh, Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism, Sci. Rep,
doi:10.1038/s41598-021-97441-xPérez-Belmonte, Torres-Peña, López-Carmona, Ayala-Gutiérrez, Fuentes-Jiménez 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/s12916-020-01832-2Reis, Dos, Silva, Medeiros Silva, Thabane et al., Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial, Lancet Reg. Health-Am,
doi:10.1016/j.lana.2021.100142Schaller, Sharma, Dupee, Nguyen, Urueña et al., Ex vivo SARS-CoV-2 infection of human lung reveals heterogeneous host defense and therapeutic responses, JCI Insight,
doi:10.1172/jci.insight.148003Scoccimarro, Panichi, Ragghianti, Silverii, Mannucci et al., SARS-CoV-2 vaccine hesitancy in Italy: A survey on subjects with diabetes, Nutr. Metab. Cardiovasc. Dis,
doi:10.1016/j.numecd.2021.09.002Silverii, Monami, Cernigliaro, Vigneri, Guarnotta et al., Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily, Nutr. Metab. Cardiovasc. Dis,
doi:10.1016/j.numecd.2020.09.028Singh, Gupta, Ghosh, Misra, Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations, Diabetes Metab. Syndr. Clin. Res. Rev,
doi:10.1016/j.dsx.2020.04.004Singh, Khunti, Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review, Diabetes Res. Clin. Pract,
doi:10.1016/j.diabres.2020.108266Singh, Singh, Is metformin ahead in the race as a repurposed host-directed therapy for patients with diabetes and COVID-19?, Diabetes Res. Clin. Pract,
doi:10.1016/j.diabres.2020.108268Solerte, Addio, Trevisan, Lovati, Rossi et al., Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study, Diabetes Care,
doi:10.2337/dc20-1521Watson, Dhaliwal, Robertshaw, Verdin, Benterud et al., Consensus Recommendations for Sick Day Medication Guidance for People With Diabetes, Kidney, or Cardiovascular Disease: A Modified Delphi Process, Am. J. Kidney Dis,
doi:10.1053/j.ajkd.2022.10.012Williamson, Walker, Bhaskaran, Bacon, Bates et al., Factors associated with COVID-19-related death using OpenSAFELY, Nature,
doi:10.1038/s41586-020-2521-4Xin, Wei, Ji, Zheng, Gu et al., Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release, Sci. Rep,
doi:10.1038/srep36222Yang, Feng, Yuan, Yuan, Fu et al., Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS, Diabet. Med,
doi:10.1111/j.1464-5491.2006.01861.x
