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. 2022 Nov 17;17(11):e0271574.
doi: 10.1371/journal.pone.0271574. eCollection 2022.

Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study

Carolyn T Bramante  1 , Steven G Johnson  2 , Victor Garcia  3 , Michael D Evans  4 , Jeremy Harper  5 , Kenneth J Wilkins  6 , Jared D Huling  7 , Hemalkumar Mehta  8 , Caleb Alexander  9 , Jena Tronieri  10 , Stephenie Hong  8 , Anna Kahkoska  11 , Joy Alamgir  12 , Farrukh Koraishy  13 , Katrina Hartman  1 , Kaifeng Yang  7 , Trine Abrahamsen  14 , Til Stürmer  15 , John B Buse  16 ; N3C core authors
Affiliations

Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study

Carolyn T Bramante et al. PLoS One. .

Abstract

Background: While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size.

Methods: Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome.

Results: 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control.

Conclusions: There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: TS owns stock in Novartis, Roche, and Novo Nordisk. T.J.A. is an employee of Novo Nordisk and reports personal fees and non-financial support from Novo Nordisk during the conduct of the study, as well as personal fees from Novo Nordisk outside the submitted work. J.A. is founder of ARIScience. J.B.B.’s contracted consulting fees and travel support for contracted activities are paid to the University of North Carolina by Adocia, AstraZeneca, Eli Lilly, Intarcia Therapeutics, MannKind, Novo Nordisk, Sanofi, Senseonics, and vTv Therapeutics; he reports grant support from AstraZeneca, Dexcom, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, NovaTarg, Novo Nordisk, Sanofi, Theracos, Tolerion, and vTv Therapeutics; he has received fees for consultation from Anji Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Cirius Therapeutics Inc, Eli Lilly, Fortress Biotech, Janssen, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Stability Health, and Zealand Pharma; he holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health; and he is supported by grants from the National Institutes of Health, Patient Centered Outcomes Research Institute, Juvenile Diabetes Research Foundation International and the American Diabetes Association. Dr. Bramante holds an FDA IND for investigation of metformin for early outpatient treatment of COVID-19, NCT04510194. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. This represents the number of patients included in the analysis after the inclusion and exclusion criteria were applied.
Fig 2
Fig 2. The x axis the standardized mean difference for continuous variables and difference in proportions for categorical variables for the 100 terms with the greatest imbalance after weighing.
The circles represent the balance before weighting and the squares represent the balance after weighing.
Fig 3
Fig 3. This represents the risk ratios and 95% confidence intervals for the overall cohort as well as for subgroups by gender and subgroups by BMI (<25kg/m2 and ≥ 25kg/m2).
The three panels on the left represent the metformin vs. DPP4i inhibitor comparison. The three panels on the right represent the metformin vs. SU comparison. The circles represent the raw comparison, and the squares represent the adjusted analysis. Within each panel, from top to bottom, the top result is risk of hospitalization; the 2nd result is risk of ventilation (including ECMO); the 3rd result is the risk of mortality; and the 4th comparison is the risk of a back pain, calculated as a negative control outcome. Abbreviations: MET = metformin; DPP4i = dipeptidyl peptidase 4 inhibitors; SU = sulfonylurea.
See this image and copyright information in PMC

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