Metformin use before COVID-19 vaccination and the risks of COVID-19 incidence, medical utilization, and all-cause mortality in patients with type 2 diabetes mellitus
Fu-Shun Yen, Shiow-Ing Wang, Shih-Yi Lin, James Cheng-Chung Wei
Diabetes Research and Clinical Practice, doi:10.1016/j.diabres.2023.110692
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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Authors' contribution FSY: study concept and design, drafting of the manuscript, critical revision of the manuscript for important intellectual content. SIW: data acquisition, analysis, and interpretation; statistical analysis and drafting of the manuscript. SYL: study concept and design, data interpretation, critical revision of the manuscript for important intellectual content. JCCW: critical revision of the manuscript for important intellectual content, technical and material support, and study supervision.
Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/•••.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
Bornstein, 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
Bramante, Huling, Tignanelli, Buse, Liebovitz et al., Randomized trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2201662
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(20)30033-7
Cameron, Morrison, Levin, Mohan, Forteath et al., Anti-inflammatory effects of metformin irrespective of diabetes status, Circ Res,
doi:10.1161/CIRCRESAHA.116.308445
Diaz, Romero, Vazquez, Lechner, Blomberg et al., Metformin improves in vivo and in vitro B cell function in individuals with obesity and type-2 diabetes, Vaccine,
doi:10.1016/j.vaccine.2017.03.078
Dispinseri, Lampasona, Secchi, Bazzigaluppi, Negri, Robust neutralizing antibodies to SARS-CoV-2 develop and persist in subjects with diabetes and COVID-19 pneumonia, J Clin Endocrinol Metab,
doi:10.1210/clinem/dgab055
Draznin, Aroda, Bakris, Benson, Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes-2022, Diabetes Care,
doi:10.2337/dc22-S004
Edwards, Baric, Saphire, Ulmer, Stopping pandemics before they start: lessons learned from SARS-CoV-2, Science,
doi:10.1126/science.abn1900
Kifle, Woldeyohanis, Demeke, A review on protective roles and potential mechanisms of metformin in diabetic patients diagnosed with COVID-19, Metabol Open,
doi:10.1016/j.metop.2021.100137
Kritas, Ronconi, Caraffa, Gallenga, Ross et al., Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy, J Biol Regul Homeost Agents,
doi:10.23812/20-Editorial-Kritas
Lampasona, Secchi, Scavini, Bazzigaluppi, Brigatti et al., Antibody response to multiple antigens of SARS-CoV-2 in patients with diabetes: an observational cohort study, Diabetologia,
doi:10.1007/s00125-020-05284-4
Li, Wang, Kan, Wang, 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,
doi:10.1186/s13054-019-2346-4
Li, Yang, Yan, Sun, Zeng et al., Metformin in patients with COVID-19: a systematic review and meta-analysis, Front Med (Lausanne),
doi:10.3389/fmed.2021.704666
Lim, Bae, Kwon, Nauck, COVID-19 and diabetes mellitus: from pathophysiology to clinical management, Nat Rev Endocrinol,
doi:10.1038/s41574-020-00435-4
Mannick, Giudice, Lattanzi, Valiante, Praestgaard et al., mTOR inhibition improves immune function in the elderly, Sci Transl Med,
doi:10.1126/scitranslmed.3009892
Marfella, Onofrio, Sardu, Scisciola, Maggi et al., Does poor glycaemic control affect the immunogenicity of the COVID-19 vaccination in patients with type 2 diabetes: the CAVEAT study, Diabetes Obes Metab,
doi:10.1111/dom.14547
Mbara, Mato, Driver, Nzuza, Mkhombo et al., Metformin turns 62 in pharmacotherapy: emergence of non-glycaemic effects and potential novel therapeutic applications, Eur J Pharmacol,
doi:10.1016/j.ejphar.2021.173934
Pal, Bhadada, Misra, COVID-19 vaccination in patients with diabetes mellitus: current concepts, uncertainties and challenges, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2021.02.026
Polack, Thomas, Kitchin, Absalon, Gurtman et al., Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine, N Engl J Med,
doi:10.1056/NEJMoa2034577
Wang, Wang, Wang, Wei, Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks, EClinicalMedicine,
doi:10.1016/j.eclinm.2022.101619
Watson, Barnsley, Toor, Hogan, Winskill et al., Global impact of the first year of COVID-19 vaccination: a mathematical modelling study, Lancet Infect Dis,
doi:10.1016/S1473-3099(22)00320-6
Yen, Wei, Shih, Hsu, Hsu et al., Metformin use before influenza vaccination may lower the risks of influenza and related complications, Vaccines (Basel),
doi:10.3390/vaccines10101752
Yen, Wei, Yip, Hsu, Hwu, Metformin use and the risks of herpes zoster and postherpetic neuralgia in patients with type 2 diabetes, J Med Virol,
doi:10.1002/jmv.28278
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