Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis

Abstract

Importance/Background: The coronavirus disease (COVID-19) pandemic is a critical public health issue. Evidence has shown that metformin favorably influences COVID-19 outcomes. This study aimed to assess the benefits and risks of metformin in COVID-19 patients.Methods: We searched the PubMed, Embase, Cochrane Library, and Chinese Biomedical Literature Database from inception to February 18, 2021. Observational studies assessing the association between metformin use and the outcomes of COVID-19 patients were included. The primary outcome was mortality, and the secondary outcomes included intubation, deterioration, and hospitalization. Random-effects weighted models were used to pool the specific effect sizes. Subgroup analyses were conducted by stratifying the meta-analysis by region, diabetic status, the adoption of multivariate model, age, risk of bias, and timing for adding metformin.Results: We identified 28 studies with 2,910,462 participants. Meta-analysis of 19 studies showed that metformin is associated with 34% lower COVID-19 mortality [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.56–0.78; I2 = 67.9%] and 27% lower hospitalization rate (pooled OR, 0.73; 95% CI, 0.53–1.00; I2 = 16.8%). However, we did not identify any subgroup effects. The meta-analysis did not identify statistically significant association between metformin and intubation and deterioration of COVID-19 (OR, 0.94; 95% CI, 0.77–1.16; I2 = 0.0% for intubation and OR, 2.04; 95% CI, 0.65–6.34; I2 = 79.4% for deterioration of COVID-19), respectively.Conclusions: Metformin use among COVID-19 patients was associated with a reduced risk of mortality and hospitalization. Our findings suggest a relative benefit for metformin use in nursing home and hospitalized COVID-19 patients. However, randomized controlled trials are warranted to confirm the association between metformin use and COVID-19 outcomes.Study Registration: The study was registered on the PROSPERO on Feb 23, 2021 (CRD42021238722).

Does Metformin Decrease Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysis

“…We also used extractable raw data instead of pre-calculated ORs or HRs to determine the pooled OR for the unadjusted analysis. We found that there was a significant reduction of in-hospital mortality with outpatient or inpatient metformin therapy in patients with type 2 diabetes mellitus hospitalized for COVID-19 in the unadjusted analysis, which is in line with previous meta-analyses [39–41]. Furthermore, evidence obtained from observational studies is an of great importance source for clinical practice where randomized clinical trials are unavailable or infeasible [42].…”

“…To further compare and integrate the results of different studies and to increase statistical power, we set out to perform a meta-analysis. Prior to this meta-analysis, several meta-analyses [39][40][41] of the association between metformin therapy and severity and mortality were published, but they have issues. First, metformin therapy was not differentiated between outpatient and inpatient use, as oral hypoglycemic medications including metformin are usually held during hospitalization.…”

Integrative analysis of viral entry networks and clinical outcomes identifies a protective role for spironolactone in severe COVID-19

“…Of the drugs meeting centrality significance, only three medications had a sufficient treatment cohort size for PSM analysis: carvedilol, quetiapine, and spironolactone (Figure 4B). Additionally, we included metformin as a positive control, as it has demonstrated a significant negative association with COVID-19 severity in clinical studies (9,(34)(35)(36).…”

“…Heterogeneity in expression patterns of accessory entry factors, which facilitate viral adhesion, cleavage events, and membrane fusion, is a chief determinant of viral susceptibility in terms of both tissue types and patient subgroups (6,7). Consequently, drug interactions with such host factors can promote or inhibit viral entry in vitro and have in some cases demonstrated clinical efficacy in large-scale studies (8)(9)(10). With the emergence of SARS-CoV-2 variants with significant genome-wide mutational load, such as the BA.2 and XE strains, therapeutics and vaccines targeting viral proteins of early strains have shown reduced efficacy in recent outbreaks (11)(12)(13).…”

Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

“…There are many studies investigating MTF and COVID-19, and in particular mortality from this disease; the studies point to a beneficial (lowering) effect on mortality, but most did not report results by sex/gender of MTF users [ 119 , 120 , 121 , 122 ]. A large-scale study of mortality attributed to COVID-19 vis-à-vis MTF therapy [ 123 ] used anonymized data of patients with T2DM and/or obesity from a healthcare provider in the USA.…”