Association Between Metformin Use and Mortality Among Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19 Infection
Abstract*Visual Abstracts prepared by Dr. Francis Xavier Mislang
Introduction. Metformin has known mechanistic benefits on COVID-19 infection due to its anti-inflammatory effects and its action on the ACE2 receptor. However, some physicians are reluctant to use it in hypoxemic patients due to potential lactic acidosis. The primary purpose of the study was to determine whether metformin use is associated with survival. We also wanted to determine whether there is a difference in outcomes in subcategories of metformin use, whether at home, in-hospital, or mixed home/in-hospital use.
Objectives. This study aimed to determine an association between metformin use and mortality among patients with type 2 diabetes mellitus hospitalized for COVID-19 infection.
Methodology. This was a cross-sectional analysis of data acquired from the COVID-19 database of two tertiary hospitals in Cebu from March 1, 2020, to September 30, 2020. Hospitalized adult Filipino patients with type 2 diabetes mellitus who tested positive for COVID-19 via RT-PCR were included and categorized as either metformin users or metformin non-users.
Results. We included 355 patients with type 2 diabetes mellitus in the study, 186 (52.4%) were metformin users. They were further categorized into home metformin users (n=109,30.7%), in-hospital metformin users (n=40,11.3%), and mixed home/in-hospital metformin users (n=37,10.4%). Metformin use was associated with a lower risk for mortality compared to non-users (p=0.001; OR=0.424). In-hospital and mixed home/in-hospital metformin users were associated with lower mortality odds than non-users (p=0.002; OR=0.103 and p=0.005; OR 0.173, respectively). The lower risk for mortality was noted in metformin, regardless of dosage, from 500 mg to 2 g daily (p=0.002). Daily dose between ≥1000 mg to <2000 mg was associated with the greatest benefit on mortality (p<0.001; OR=0.252). The survival distributions between metformin users and non-users were statistically different, showing inequality in survival (χ2=5.67, p=0.017).
Conclusion. Metformin was associated with a lower risk for mortality in persons with type 2 diabetes mellitus hospitalized for COVID-19 disease compared to non-users. Use of metformin in-hospital, and mixed home/in-hospital metformin use, was also associated with decreased risk for mortality. The greatest benefit seen was in those taking a daily dose of ≥1000 mg to <2000 mg.
World Health Organization. COVID-19 situation reports. WHO Director-General’s opening remarks at the media briefing on COVID-19. March 2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.
Worldometer COVID-19 data. Coronavirus cases. Worldometer. September 28, 2021. https://www.worldometers.info/coronavirus/.
Worldometer COVID-19 data. Reported cases and deaths by country or territory. Worldometer. September 28, 2021. https://www.worldometers.info/coronavirus/#countries.
Zhou P, Yang XL, Wang XG, et.al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270–3. https://pubmed.ncbi.nlm.nih.gov/32015507. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095418. https://doi.org/10.1038/s41586-020-2012-7.
Zou X, Chen K, Zou JW, Han PY, Hao J, Han Z. The single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to Wuhan 2019-nCoV infection. Front Med. 2020; 14(2):185–92. https://pubmed.ncbi.nlm.nih.gov/32170560. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7088738. https://doi.org/10.1007/s11684-020-0754-0.
Hoffman M, Weber-Kleine H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8. https://pubmed.ncbi.nlm.nih.gov/32142651. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102627. https://doi.org/10.1016/j.cell.2020.02.052.
Hojyo S, Uchida M, Tanaka K, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020;40:37. https://pubmed.ncbi.nlm.nih.gov/33014208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527296. https://doi.org/10.1186/s41232-020-00146-3.
Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-5. https://pubmed.ncbi.nlm.nih.gov/32173574. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194638. https;//doi.org/10.1016/j.ijid.2020.03.017.
Bajgain KT, Badal S, Bajgain BB, Santana MJ. Prevalence of comorbidities among individuals with COVID-19: A rapid review of current literature. Am J Infect Control. 2021;49(2):238-46. https://pubmed.ncbi.nlm.nih.gov/32659414. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351042. https://doi.org/10.1016/j.ajic.2020.06.213.
Shi Q, Zhang X, Jiang F, et al. Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: A two-center, retrospective study. Diabetes Care. 2020;43(7):1382-91. https://pubmed.ncbi.nlm.nih.gov/32409504. https://doi.rog/10.2337/dc20-0598.
Targher G, Mantovani A, Wang XB, et al. Patients with diabetes are at higher risk for severe illness from COVID-19. Diabetes Metab. 2020;46(4):335-37. https://pubmed.ncbi.nlm.nih.gov/32416321. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255326. https://doi.org/10.1016/j.diabet.2020.05.001.
Kumar A, Arora A, Sharma P, et.al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020;14(4):535–45. https://pubmed.ncbi.nlm.nih.gov/32408118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200339. https://doi.org/10.1016/j.dsx.2020.04.044.
Shang J, Wang Q, Zhang H, et.al. The relationship between diabetes mellitus and COVID-19 prognosis: A retrospective cohort study in Wuhan, China. Am J Med. 2021;134(1):e6-14. https://pubmed.ncbi.nlm.nih.gov/32653423. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350644. https://doi.org/10.1016/j.amjmed.2020.05.033.
Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: A descriptive study. Lancet Infect Dis. 2013;13(9):752-61. https://pubmed.ncbi.nlm.nih.gov/23891402. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185445. https://doi.org/10.1016/S1473-3099(13)70204-4.
Alqahtani FY, Aleanizy FS, Ali El Hadi Mohamed R, et al. Prevalence of comorbidities in cases of Middle East respiratory syndrome coronavirus: A retrospective study. Epidemiol Infect. 2018;147:1-5. https://pubmed.ncbi.nlm.nih.gov/30394248. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518603. https://doi.org/10.1017/S0950268818002923.
Chan J, Ng C, Chan Y, et al. Short-term outcome and risk factors for adverse clinical outcomes in adults with severe respiratory syndrome (SARS). Thorax. 2003;58(8):686-9. https://pubmed.ncbi.nlm.nih.gov/12885985. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746764. https://doi.org/10.1136/thorax.58.8.686.
Raz I. Guideline approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(Suppl 2): S139-44. https://pubmed.ncbi.nlm.nih.gov/23882038. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3920774. https://doi.org/10.2337/dcS13-2035.
Hyun B, Shin S, Lee A, et al. Metformin down-regulates TNF-alpha secretion via suppression of scavenger receptors in macrophages. Immune Netw. 2013;13(4):123–32. https://pubmed.ncbi.nlm.nih.gov/24009539. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759709. https://doi.org/10.4110/in.2013.13.4.123.
Cameron AR, Morrison VL, Levin D, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–65. https://pubmed.ncbi.nlm.nih.gov/27418629. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990459. https://doi.org/10.1161/CIRCRESAHA.116.308445.
Cheng X, Liu YM, Li H, et al. Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and preexisting type 2 diabetes. Cell Metab. 2020;32(4):537-47. https://pubmed.ncbi.nlm.nih.gov/32861268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439986. https://doi.org/10.1016/j.cmet.2020.08.013.
Silvestre J, Carvalho S, Mendes V, et.al. Metformin-induced lactic acidosis: A case series. J Med Case Rep. 2007;1:126. https://pubmed.ncbi.nlm.nih.gov/17974034. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169248. https://doi.org/10.1186/1752-1947-1-126.
Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr. 2020;14(3):211-2. https://pubmed.ncbi.nlm.nih.gov/32172175. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102582. https://doi.org/10.1016/j.dsx.2020.03.002.
Bornstein SR, Rubino F, Khunti K, et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020;8(6):546-50. https://pubmed.ncbi.nlm.nih.gov/32334646. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180013. https://doi.org/10.1016/S2213-8587(20)30152-2.
Lalau JD, Al-Salameh A, Hadjadj S, et al. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalized for COVID-19. Diabetes Metab. 2020;47(5):101216. https://pubmed.ncbi.nlm.nih.gov/33309936. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832745. https://doi.org/10.1016/j.diabet.2020.101216.
Bode B, Garrett V, Messler J, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol. 2020;14(4):813-21. https://pubmed.ncbi.nlm.nih.gov/32389027. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673150. https://doi.org/10.1177/1932296820924469.
Maiese K. The mechanistic target of Rapamycin (mTOR): Novel considerations as an antiviral treatment. Curr Neurovasc Res. 2020;17(3):332-7. https://pubmed.ncbi.nlm.nih.gov/32334502. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541431. https://doi.org/10.2174/1567202617666200425205122.
Liu J, Li X, Lu Q, et al. AMPK: A balancer of the renin-angiotensin system. Biosci Rep. 2019;39(9): BSR20181994. https://pubmed.ncbi.nlm.nih.gov/31413168. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722492. https://doi.org/10.1042/BSR20181994.
Plattner F, Bibb JA. Elsevier. Serine and Threonine Phosphorylation. In Basic Neurochemistry; 2012. https://doi.org/10.1016/B978-0-12-374947-5.00025-0
Dalan R. Metformin, neutrophils, and COVID-19 infection. Diabetes Res Clin Pract. 2020;164:108230. https://pubmed.ncbi.nlm.nih.gov/32446796. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242188. https://doi.org/10.1016/j.diabres.2020.108230.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65. https://pubmed.ncbi.nlm.nih.gov/9742977.
Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36(5):1304–11. https://pubmed.ncbi.nlm.nih.gov/2323009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631843. https://doi.org/10.2337/dc12-0719.
Bramante CT, Ingraham NE, Murray TA, et al. Metformin and risk of mortality in patients hospitalized with COVID-19: A retrospective cohort analysis. Lancet Healthy Longev. 2021;2(1): e34-41. https://pubmed.ncbi.nlm.nih.gov/33521772. https://www.ncbi.nlm.nih.gov/pmc/articles/MC7832552. https://doi.org/10.1016/S2666-7568(20)30033-7.
Luo P, Qiu L, Liu Y, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am J Trop Med Hyg. 2020;103(1):69-72. https://pubmed.ncbi.nlm.nih.gov/32446312. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356425. https://doi.org/10.4269/ajtmh.20-0375.
Crouse A, Grimes T, Li P, Might M, Ovalle F, Shalev A. Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. medRxiv. 2020;2020.07.29.20164020. https://pubmed.ncbi.nlm.nih.gov/32766607. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402067. https://doi.org/10.1101/2020.07.29.20164020.
Lally MA, Tsoukas P, Halladay CW, O’Neill E, Gravenstein S, Rudolph JL. Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV2. J AM Med Dir Assoc. 2021;22(1):193-8. https://pubmed.ncbi.nlm.nih.gov/33232684. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586924. https://doi.org/10.1016/j.jamda.2020.10.031.
Cariou B, Hadjadj S, Wargny M, et al. Phenotypic characteristics and prognosis of in-patients with COVID-19 and diabetes: The CORONADO study. Diabetologia. 2020;63(8):1500-15. https://pubmed.ncbi.nlm.nih.gov/32472191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256180. https://doi.org/10.1007/s00125-020-05180-x.
Wargny M, Potier L, Gourdy P, et al. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: Updated results from the nationwide CORONADO study. Diabetologia. 2021;64(4):778-94. https://pubmed.ncbi.nlm.nih.gov/33599800. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890396. https://doi.org/10.1007/s00125-020-05351-w.
Copyright (c) 2021 Angeli Nicole Ong, Ceryl Cindy Tan, Maria Teresa Cañete, Bryan Albert Lim, Jeremyjones Robles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Journal of the ASEAN Federation of Endocrine Societies is licensed under a Creative Commons Attribution-NonCommercial 4.0 International. (full license at this link: http://creativecommons.org/licenses/by-nc/3.0/legalcode).
To obtain permission to translate/reproduce or download articles or use images FOR COMMERCIAL REUSE/BUSINESS PURPOSES from the Journal of the ASEAN Federation of Endocrine Societies, kindly fill in the Permission Request for Use of Copyrighted Material and return as PDF file to firstname.lastname@example.org or email@example.com.
A written agreement shall be emailed to the requester should permission be granted.