Metformin Use Is Associated with Decreased Mortality in COVID-19 Patients with Diabetes: Evidence from Retrospective Studies and Biological Mechanism

Background and Aims: The coronavirus disease 2019 (COVID-19) increases hyperinflammatory state, leading to acute lung damage, hyperglycemia, vascular endothelial damage, and a higher mortality rate. Metformin is a first-line treatment for type 2 diabetes and is known to have anti-inflammatory and immunosuppressive effects. Previous studies have shown that metformin use is associated with decreased risk of mortality among patients with COVID-19; however, the results are still inconclusive. This study investigated the association between metformin and the risk of mortality among diabetes patients with COVID-19. Methods: Data were collected from online databases such as PubMed, EMBASE, Scopus, and Web of Science, and reference from the most relevant articles. The search and collection of relevant articles was carried out between 1 February 2020, and 20 June 2021. Two independent reviewers extracted information from selected studies. The random-effects model was used to estimate risk ratios (RRs), with a 95% confidence interval. Results: A total of 16 studies met all inclusion criteria. Diabetes patients given metformin had a significantly reduced risk of mortality (RR, 0.65; 95% CI: 0.54-0.80, p < 0.001, heterogeneity I-2 = 75.88, Q = 62.20, and tau(2) = 0.06, p < 0.001) compared with those who were not given metformin. Subgroup analyses showed that the beneficial effect of metformin was higher in the patients from North America (RR, 0.43; 95% CI: 0.26-0.72, p = 0.001, heterogeneity I-2 = 85.57, Q = 34.65, tau(2) = 0.31) than in patients from Europe (RR, 0.67; 95% CI: 0.47-0.94, p = 0.02, heterogeneity I-2 = 82.69, Q = 23.11, tau(2) = 0.10) and Asia (RR, 0.90; 95% CI: 0.43-1.86, p = 0.78, heterogeneity I-2 = 64.12, Q = 11.15, tau(2) = 0.40). Conclusions: This meta-analysis shows evidence that supports the theory that the use of metformin is associated with a decreased risk of mortality among diabetes patients with COVID-19. Randomized control trials with a higher number of participants are warranted to assess the effectiveness of metformin for reducing the mortality of COVID-19 patients.