Metformin and Covid-19: a systematic review of systematic reviews with meta-analysis

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Fabio Petrelli
Iolanda Grappasonni
Cuc Thi Thu Nguyen
Marina Tesauro
Paola Pantanetti
Sonila Xhafa
Giovanni Cangelosi


Metformin, COVID-19, Type II diabetes (DM2), Systematic Review



Introduction: the COVID-19 infection, caused by severe Coronavirus 2 syndrome (Sars-Cov-2), immediately appeared to be the most tragic global pandemic event of the twentieth century. Right from the start of the pandemic, diabetic patients treated with metformin experienced a reduction in mortality and complications from COVID-19 compared to those with different treatments or no treatment.

Objective The main objective of the study was to observe the effects of metformin in hospitalized subjects infected with COVID-19. Specifically, the outcomes of hospitalization in Intensive Care Units or death were examined.

Materials and Methods A specific research PICOS was developed and the Pubmed, Embase and Scopus databases were consulted down to April 30, 2022. To estimate the extent of the metformin effect and risk of severity in SARS-CoV-2 infection, the Odd Ratio (OR) with 95% Confidence Interval (CI) published by the authors of the selected systematic reviews was used.

Results from five systematic reviews 36 studies were selected. The final meta-analysis showed that thanks to treatment with metformin, DM2 patients affected by COVID-19 had protection against risk of disease severity, complications (ES 0.80; 95% CI) and mortality (ES 0.69; 95% CI).

Conclusions More in-depth studies on the use of metformin, compared to other molecules, may be required to understand the real protective potential of the drug against negative outcomes caused by COVID-19 infection in DM2 patients.


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1.World Health Organization (WHO). Coronavirus. Available online at: health topics/coronavirus [Last accessed: 2022 November 1]
2.Covid-19 Coronavirus Pandemic COVID-19 Coronavirus Pandemic. Available online at: https://www. [Last Accessed: 2022 April 5]
3.American Diabetes Association. Glycemic targets. Diabetes Care. 2017. Jan; 40 (Supplement 1): S48-S56. Available on line on: doi: 10.2337/dc17-S009 [Last Accessed: 2022 April 19]
4.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 Jul-Aug;14(4):535-545. doi: 10.1016/j.dsx.2020.04.044.
5.Puig-Domingo M, Marazuela M, Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine 2020; 68 (1): 2–5. doi: 10.1007/s12020-020-02294-5
6.Saha S, Rami HAR, Sujata S. Diabetes prevalence and mortality in COVID-19 patients: a systematic review, meta-analysis, and meta-regression. J Diabetes Metab Disord. 2021 Mar 31;20(1):939-950. doi: 10.1007/s40200-021-00779-2
7.Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38(1):140–149. doi: 10.2337/dc14-2441
8.Hariyanto TI, Kurniawan A. Metformin Use is Associated With Reduced Mortality Rate From Coronavirus Disease 2019 (COVID-19) Infection. Obes Med 2020; 19:100290. doi: 10.1016/j.obmed.2020.100290
9.Moher D, Liberati A, Tetzlaff J, et al, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151:264-9, W64. doi: 10.7326/0003-4819-151-4-200908180-00135
10.Page MJ, Mckenzie JE, Bossuyt PM, et al, The PRISMA 2020 statement: an update guideline for reporting systematic reviews, BMJ 2021; 372: n71. doi: 10.1136/bmj.n71
11.Critical Appraisal Skills Programme (CASP) part of Oxford Centre for Triple Value Healthcare Ltd. Available on: [Last accessed: 2022 November 1]
12.Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statics in Medicine. 2002;21 (11): 1539-58. doi: 10.1002/sim.1186
13.Lukito AA, Pranata R, Henrina J, et al. The effect of metformin consumption on mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis. Diabetes Metab Syndr. 2020 Nov-Dec;14(6):2177-2183. doi: 10.1016/j.dsx.2020.11.006
14.Oscanoa TJ, Amado J, Vidal X, et al. Metformin therapy, severity and mortality of SARS-CoV-2 infection: a meta-analysis. Clinical Diabetology 2021; 10(4): 317-329. doi: 10.5603/DK. a2021.0035
15.Kan C, Zhang Y, Han F, et al. Mortality Risk of Antidiabetic Agents for Type 2 Diabetes With COVID-19: A Systematic Review and Meta-Analysis. Front. Endocrinol. Sept 2021; 12:708494. doi: 10.3389/fendo.2021.708494
16.Li Y, Yang X, Yan P, et al. Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front. Med. 8:704666. doi: 10.3389/fmed.2021.704666
17.Yang W, Sun X, Zhang J, et al. The effect of Metformin on Mortality and Severity in COVID-19 patients with Diabetes Mellitus. Diabetes Res Clin Pract. 2021 Aug;178:108977. doi: 10.1016/j.diabres.2021.108977
18.Abu-Jamous B, Anisimovich A, Baxter J, et al. Associations of comorbidities and medications with COVID- 19 outcome: a retrospective analysis of real-world evidence data. 2020. doi: 10.1101/2020.08.20.20174169
19.Cariou B, Hadjadj S, Wargny M, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63: 1500e15. doi: 10.1007/s00125-020-05180-x
20.Bramante CT, Ingraham NE, Murray TA, et al. Observational study of metformin and risk of mortality in patients hospitalized with covid-19. MedRxiv Prepr Serv Heal Sci 2020. doi: 10.1101/2020.06.19.20135095. 2020.06.19.20135095
21.Bramante CT, Ingraham N, Murray T, et al. Metformin and risk of mortality in patients hospitalised with COVID19: a retrospective cohort analysis. The Lancet Healthy Longevity. 2021; 2(1): e34–e41. doi: 10.1016/s2666-7568(20)30033-7
22.Bramante CT, Tignanelli CJ, Dutta N, et al. Non-alcoholic fatty liver disease (NAFLD) and risk of hospitalization for COVID-19. medRxiv [Preprint]. 2020. doi: 10.1101/2020.09.01.201 85850
23.Chen Y, Yang D, Cheng B, et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020; 43:1399e407. doi: 10.2337/dc20-0660
24.Crouse A, Grimes T, Li P, et al. Metformin use IS associated with reduced mortality IN a diverse population with COVID-19 and diabetes. MedRxiv Prepr Serv Heal Sci 2020. doi: 10.1101/ 2020.07.29.20164020
25.Kim MK, Jeon JH, Kim SW, et al. The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea. Diabetes Metab J. 2020; 44:602e13. doi: 10.4093/dmj.2020.0146
26.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; 103:69e72. doi: 10.4269/ajtmh.20-0375
27.Philipose Z, Smati N, Wong CSJ, Aspey K, Mendall M. Obesity, old age, and frailty are the true risk factors for COVID-19 mortality and not chronic disease or ethnicity. MedRxi. 2020. doi: 10.1101/2020.08.12.20156257
28.Cheng X, Liu YM, 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. 2020 Oct 6;32(4):537-547.e3. doi: 10.1016/j.cmet.2020.08.013
29.Mirani M, Favacchio G, Carrone F, et al. Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a Case series from an Academic Hospital in Lombardy, Italy. Diabetes Care. 2020; 43(12): 3042–3049. doi: 10.2337/dc20-1340
30.Jiang N, Chen Z, Yin X, 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. 2020; 173:108619. doi: 10.1016/j.diabres.2020.108619
31.Gao Y, Liu T, Zhong W, et al. Risk of metformin in patients with type 2 diabetes with COVID-19: a preliminary retrospective report. Clin Transl Sci. 2020; 13(6): 1055–1059. doi: 10.1111/cts.12897
32.Lally MA, Tsoukas P, Halladay CW, et al. Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV-2. J Am Med Dir Assoc. 2021; 22(1): 193–198. doi: 10.1016/j.jamda.2020.10.031
33.Pérez-Belmonte LM, Torres-Peña JD, López-Carmona MD, 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. 2020; 18(1): 359. doi: 10.1186/s12916-020-01832-2
34.Wang B, Van Oekelen O, Mouhieddine TH et al. A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward. J Hematol Oncol. 2020; 13(1): 94. doi: 10.1186/s13045-020-00934-x
35.Wang J, Cooper JM, Gokhale K, et al. Association of metformin with susceptibility to COVID-19 in people with type 2 diabetes. J Clin Endocrinol Metab. 2021; 106: dgab067. doi: 10.1210/clinem/dgab067
36.Yan H, Valdes AM, Vijay A, et al. Role of drugs used for chronic disease management on susceptibility and severity of COVID-19: a large case-control study. medRxiv. 2020. doi: 10.1101/2020.04.24.20077875
37.Hippisley-Cox J, Young D, Coupland C, et al. Risk of severe COVID-19 disease with ACE inhibitors and angiotensin recep- tor blockers: cohort study including 8.3 million people. Heart. 2020; 106(19): 1503–1511. doi: 10.1136/heartjnl-2020-317393
38.Shestakova MV, Vikulova OK, Isakov M, et al. Diabetes and COV- ID-19: analysis of the clinical outcomes according to the data of the russian diabetes registry. Probl Endokrinol (Mosk). 2020; 66(1): 35–46. doi: 10.14341/probl12458
39.Sourij H, Aziz F, Bräuer A, et al. COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission. Diabetes Obes Metab. 2021; 23(2): 589–598. doi: 10.1111/dom.14256
40.Li J, Wei Q, Li WX, et al. Metformin use in diabetes prior to hospitalization: effects on mortality in covid-19. Endocr Pract. 2020; 26(10): 1166–1172. doi: 10.4158/EP-2020-0466
41.Do JY, Kim SW, Park JW, et al. Is there an association between metform- in use and clinical outcomes in diabetes patients with COVID-19? Diabetes Metab. 2020 [Epub ahead of print]: 101208. doi: 10.1016/j.diabet.2020.10.006
42.Liu Z, Bai Xi, Han X, et al. The association of diabetes and the prognosis of COVID-19 patients: A retrospective study. Diabetes Res Clin Pract. 2020; 169: 108386. doi: 10.1016/j.dia- bres.2020.108386
43.Nafakhi H, Alareedh M, Al-Buthabhak K, et al. Predictors of adverse in-hospital outcome and recovery in patients with diabetes mellitus and COVID-19 pneumonia in Iraq. Diabetes Metab Syndr. 2021; 15(1): 33–38. doi: 10.1016/j.dsx.2020.12.014
44.Goodall JW, Reed TAN, Ardissino M, et al. Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study. Epidemiol Infect. 2020; 148: e251. doi: 10.1017/S0950268820002472
45.Lalau JD, Al-Salameh A, Hadjadj S, et al. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19. Diabetes Metab. 2020 [Epub ahead of print]; 47(5): 101216. doi: 10.1016/j.diabet.2020.101216
46.Orioli L, Servais T, Belkhir L, et al. Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: A retrospective study from an academic center in Belgium. Diabetes Metab Syndr. 2021; 15(1): 149–157. doi: 10.1016/j. dsx.2020.12.020
47.Cernigliaro A, Allotta AV, Scondotto S. Can diabetes and its related hypoglycemic drug treatment be considered risk factors for health outcomes in COVID-19 patients? The results of a study in the population residing in Sicily Region (Southern Italy). Epidemiol Prev. 2020; 44(5-6 Suppl 2): 315–322. doi: 10.19191/EP20.5-6. S2.132
48.Ramos-Rincón JM, Pérez-Belmonte LM, Carrasco-Sánchez FJ, et al. Association between prior cardiometabolic therapy and in-hospital mortality in very old patients with type 2 diabetes mellitus hospitalized due to COVID-19. A nationwide observational study in Spain. Research Square. doi: 10.21203/
49.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; 64:778–94. doi: 10.1007/s00125-020-05351-w
50.Mirsoleymani S, Nekooghadam SM, Marzaleh MA, et al. Assessment of risk factors for severe coronavirus disease 2019 among Iranian patients. Iran Red Crescent Med J. 2020; 22: e72. doi: 10.32592/ircmj.2020.22.9.72
51.Khunti K, Knighton P, Zaccardi F, 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. 2021; 9:293–303. doi: 10.1016/S2213-8587(21)00050-4
52.Ghany R, Palacio A, Dawkins E, et al. Metformin is associated with lower hospitalizations, mortality and severe coronavirus infection among elderly medicare minority patients in 8 states in USA. Diabetes Metab Syndr. 2021;15(2):513–8
53.Oh TK, Song IA. Metformin use and risk of COVID-19 among patients with type II diabetes mellitus: an NHIS-COVID-19 database cohort study. Acta Diabetol 2021;58(6):771–8
54.Soliman A, Nair AR, Al Masalamani MS, et al. Prevalence, clinical manifestations, and biochemical data of type 2 diabetes mellitus versus nondiabetic symptomatic patients with COVID-19: A comparative study. Acta Biomed 2020; 91 (3): e2020010. doi: 10.23750/abm.v91i3.10214
55.Altınbilek E, Öztürk D, Atasoy C, et al. Analysis of the Patients Who Admitted To A Turkish Emergency Department During COVID-19 Pandemic. Acta Biomed 2020; 91 (4): e2020201. doi: 10.23750/abm.v91i4.10227
56.Bas NB, Metin S, Sevinç SA, et al. The Effect of Diabetes Mellitus on Mortality in Patients Hospitalized Intensive Care Unit in Covid-19 Pandemic. Acta Biomed 2022; 93 (3): e2022068. doi: 10.23750/abm.v93i3.11880
57.Petrelli F, Cangelosi G, Nittari G, et al. Chronic Care Model in Italy: a narrative review of the literature. Primary Health Care Research & Development 2021; 22(e32): 1–7. doi: 10.1017/S1463423621000268
58.Petrelli F, Cangelosi G, Scuri S, et al. Conoscenze alimentari in pazienti afferenti ad un centro di diabetologia. Acta Biomed 2020; 91 (Supplement 3): S160-S164 doi: 10.23750/abm.v91i3-S.9418
59.Petrelli F, Cangelosi G, Scuri S, et al. Diabetes and technology: A pilot study on the management of patients with insulin pumps during the COVID-19 pandemic. Diabetes Res Clin Pract. 2020 Nov;169:108481. doi: 10.1016/j.diabres.2020.108481
60.Scuri S, Tesauri M, Petrelli F, et al. Use of an online platform to evaluate the impact of social distancing measures on psycho-physical well-being in the COVID-19 Era. Int. J. Environ. Res. Public Health 2022; 19: 6805. doi: 10.3390/ijerph19116805
61.Natalucci V, Villarini M, Emili R, et al. Special Attention to Physical Activity in Breast Cancer Patients during the First Wave of COVID-19 Pandemic in Italy: The DianaWeb Cohort. J. Pers. Med. 2021; 11: 381. doi: 10.3390/jpm11050381
62.Cangelosi G, Grappasonni I, Pantanetti P, et al. Nurse Case Manager Lifestyle Medicine (NCMLM) in the Type Two Diabetes patient concerning post COVID-19 Pandemic management: Integrated-Scoping literature review. Ann Ig. 2022 Nov-Dec;34(6):585-602. doi: 10.7416/ai.2022.2500
63.D’Alleva A, Leigheb F, Rinaldi C, et al. Achieving quadruple aim goals through clinical networks: A systematic review. Journal of Healthcare Quality Research. 2019; 34(1): 29-39. doi: 10.1016/j.jhqr.2018.10.010
64.Acito M, Bartolini D, Ceccarini MR, et al. Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020. Dec;69:105001. doi: 10.1016/j.tiv.2020. 105001
65.Pantanetti P, Cangelosi G, Ambrosio G. Potential role of incretins in diabetes and COVID‑19 infection: a hypothesis worth exploring. Intern Emerg Med. 2020 Aug;15(5):779-782. doi: 10.1007/s11739-020-02389-x
66.De Sanctis V, Soliman A, Tzoulis P, et al. The use of oral glucose-lowering agents (GLAs) in β-thalassemia patients with diabetes: Pre-liminary data from a retrospective study of ICET-A Network. Acta Biomed 2022; 93 (2): e2022162. doi:10.23750/abm.v93i2.12056

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