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

  1. Zhiyuan Ma
  2. Mahesh Krishnamurthy

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Abstract

Aims

Coronavirus disease 2019 (COVID-19) is a new pandemic that the entire world is facing since December of 2019. Increasing evidence has shown that metformin is linked to favorable outcomes in patients with COVID-19. The aim of this study was to address whether outpatient or inpatient metformin therapy offers low in-hospital mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19.

Methods

We searched studies published in PubMed, Embase, Google Scholar and Cochrane Library up to October 1, 2021. Raw event data extracted from individual study were pooled using the Mantel-Haenszel approach. Odds ratio (OR) or hazard ratio (HR) adjusted for covariates that potentially confound the association using multivariable regression or propensity score matching was pooled by the inverse-variance method. Random effect models were applied for meta-analysis due to variation among studies.

Results

Nineteen retrospective observational studies were selected. The pooled unadjusted OR for outpatient metformin therapy and in-hospital mortality was 0.54 (95% CI, 0.42-0.68), whereas the pooled OR adjusted with multivariable regression or propensity score matching was 0.72 (95% CI, 0.47-1.12). The pooled unadjusted OR for inpatient metformin therapy and in-hospital mortality was 0.19 (95% CI, 0.10-0.36), whereas the pooled adjusted HR was 1.10 (95% CI, 0.38-3.15).

Conclusions

Our results suggest that there is a significant reduction of in-hospital mortality with metformin therapy in patients with type 2 diabetes mellitus hospitalized for COVID-19 in the unadjusted analysis, but this mortality benefit does not retain after adjustments for confounding bias.

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  1. ScreenIT

    SciScore for 10.1101/2022.04.03.22273353: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Strategy of literature search for meta-analysis: A systemic literature search of studies published in English was performed in PubMed, Embase, Google Scholar and Cochrane Library up to October 1, 2021 using the key words ‘metformin or biguanides’, ‘SARS-CoV2 or COVID-19’ and ‘mortality’.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Several limitations are present in our study. First, owing to lack of randomized clinical trials, all studies included for analysis were retrospective studies. Although efforts were made to balance and control for potential confounding factors by multiple variable adjustments and propensity score matching, due to the inherent nature of retrospective observational studies, residual confounders are likely to exist and could not be balanced. Therefore, even meta-analysis of studies with adjusted ORs o HRs could be misleading. Second, the size of the retrospective studies that were included in the meta-analysis varied considerably, resulting in moderate-to-high heterogeneity. Third, there were few studies investigating inpatient metformin use and in-hospital mortality. More studies are needed to perform a robust meta-analysis for inpatient metformin therapy and in-hospital mortality in patient with diabetes hospitalized for COVD-19. In conclusion, our findings demonstrate that there is 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, but this mortality benefit does not retain after adjustments for confounding bias. Therefore, further randomized clinical trials are needed to provide clinical evidence regarding metformin therapy and in-hospital mortality in patient with diabetes hospitalized for COVD-19.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.04.03.22273353v1 on medRxiv