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

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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.

Original languageEnglish (US)
Article numbere0271574
JournalPloS one
Issue number11 November
StatePublished - Nov 2022

Bibliographical note

Funding Information:
The analyses described in this publication were conducted with data or tools accessed through the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) N3C Data Enclave (https://covid.cd2h. org) and N3C Attribution & Publication Policy v 1.2-2020-08-25b supported by NCATS U24 TR002306 and NCATS grants KL2TR002492 (CB) and UL1TR002494 (UMN, CB and SJ) and UL1TR002489 (UNC, JB); and and the National Institute of Digestive, Diabetes, and Kidney diseases K23DK124654 (CB), and K23DK116935 (JT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. TS receives investigator-initiated research funding and support as Principal Investigator (R01 AG056479) from the National Institute on Aging (NIA), and as Co-Investigator (R01 HL118255, R01MD011680), National Institutes of Health (NIH). He also receives salary support as Director of Comparative Effectiveness Research (CER), NC TraCS Institute, UNC Clinical and Translational Science Award (UL1TR002489), the Center for Pharmacoepidemiology (current members: GlaxoSmithKline, UCB BioSciences, Takeda, AbbVie, Boehringer Ingelheim), from pharmaceutical companies (Novo Nordisk), and from a generous contribution from Dr. Nancy A. Dreyer to the Department of Epidemiology, University of North Carolina at Chapel Hill. Dr. Stürmer does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, and Novo Nordisk. Consortial Authors: Melissa A. Haendel, PhD; Christopher G. Chute, MD, Dr.P.H, M.P.H. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/datatransfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource [25].

Publisher Copyright:
Copyright: © 2022 Bramante et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Adult
  • Child
  • Male
  • Humans
  • Middle Aged
  • Aged
  • Female
  • Diabetes Mellitus, Type 2/complications
  • Hypoglycemic Agents/therapeutic use
  • Retrospective Studies
  • COVID-19/drug therapy
  • RNA, Viral/therapeutic use
  • SARS-CoV-2
  • Treatment Outcome
  • Sulfonylurea Compounds/therapeutic use
  • Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
  • Metformin/therapeutic use
  • Cohort Studies

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


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