Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus
et al., medRxiv, doi:10.64898/2026.07.06.26357398, Jul 2026
Metformin for COVID-19
3rd treatment shown to reduce risk in
July 2020, now with p < 0.00000000001 from 113 studies.
Lower risk for mortality, ventilation, ICU, hospitalization, progression, recovery, and viral clearance.
No treatment is 100% effective. Protocols
combine treatments.
6,600+ studies for
220+ treatments. c19early.org
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Retrospective 53,332 adults with type 2 diabetes mellitus and COVID-19 in the U.S. National Clinical Cohort Collaborative (N3C), showing lower 12-month all-cause mortality and probable long COVID with metformin vs. DPP4 inhibitor (DPP4i) use during acute COVID-19.
Standard of Care (SOC) for COVID-19 in the study country,
the USA, is very poor with very low average efficacy for approved treatments1.
Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.
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risk of death, 39.0% lower, RR 0.61, p < 0.001, treatment 1,220 of 50,965 (2.4%), control 128 of 2,367 (5.4%), adjusted per study, day 365.
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risk of long COVID, 13.0% lower, RR 0.87, p < 0.001, treatment 8,444 of 50,965 (16.6%), control 464 of 2,367 (19.6%), NNT 33, adjusted per study, probable long COVID (model-based phenotype), day 365.
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risk of long COVID, 10.0% lower, RR 0.90, p = 0.48, treatment 635 of 50,965 (1.2%), control 37 of 2,367 (1.6%), adjusted per study, diagnosed long COVID (ICD-10 U09.9), day 365.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
Butzin-Dozier et al., 9 Jul 2026, retrospective, USA, preprint, 21 authors, study period 1 October, 2021 - 15 November, 2023.
Contact: zdozier@stanford.edu.
Abstract: It is made available under a CC-BY 4.0 International license . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) medRxiv preprint doi: https://doi.org/10.64898/2026.07.06.26357398; this version posted July 9, 2026. The copyright holder for this preprint
Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus
Zachary Butzin-Dozier 1 , Ph.D., Lin-Chiun Wang 2 , Yunwen Ji 2 , Ph.D., A. Jerrod Anzalone 3 , Ph.D., Oluwasolape Olawore 4 , Ryan Hafen 5 , Ph.D., Eric Hurwitz 4 , Ph.D., Manav Kumar 2 , Rena C. Patel 6 , M.D., Sc.D., Ariana Budhihartanto 2 , Mark van der Laan, Ph.D. 2 , John M. Colford, Jr. 2 , M.D., Ph.D., Alan E. Hubbard 2 , Ph.D., John B. Buse 4 , M.D, Ph.D., Steven Johnson 7 , Ph.D., Jane Reusch 8 , M.D., Lauren E. Chan 9 , Ph.D., Richard Moffitt 10 , Ph.D., Rachel Wong 10 *, M.D., Carolyn Bramante 7 *, M.D., on behalf of the National Clinical Cohort Collaborative (N3C) Consortium +
*Contributed equally to this manuscript
+ Members are listed at the end of the manuscript
1 Stanford University School of Medicine, Stanford, CA, USA
- 2 School of Public Health, University of California, Berkeley, Berkeley, CA USA
3 University of Nebraska Medical Center, Omaha, NE, USA
4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5 Purdue University, West Lafayette, IN, USA
6 University of Alabama at Birmingham, Birmingham, AL, USA
7 University of Minnesota, Minneapolis, MN, USA
8 University of Colorado, Anschutz, Aurora, CO, USA
9 University of Chicago, Chicago, IL, USA
10 Renaissance School of Medicine, Stony Brook University, New York, NY, USA
Correspondence :
Zachary Butzin-Dozier, PhD, MPH Stanford University School of Medicine 3145 Porter Drive Palo Alto, CA 94304 zdozier@stanford.edu +1 (302) 437-6262
It is made available under a CC-BY 4.0 International license . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) medRxiv preprint doi: https://doi.org/10.64898/2026.07.06.26357398; this version posted July 9, 2026. The copyright holder for this preprint
ABSTRACT
Background : Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19.
Methods : We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results : In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but..
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"abstract": "<jats:p>Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19.\nMethods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. \nResults: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. \nConclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.</jats:p>",
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