Evidence map›Paper›PMID 38690892›Full record

Trial reportClinical infectious diseases : an official publication of the Infectious Diseases Society of America2024

Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19.

Carolyn T Bramante, Kenneth B Beckman, Tanvi Mehta, Amy B Karger, David J Odde, Christopher J Tignanelli, John B Buse, Darrell M Johnson, Ray H B Watson, Jerry J Daniel and 27 more

Registry-linked trialOpen access · bronzeAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04510194 (COVID-OUT), which is not on this map. Cited by 32 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed, 1 pooled it
15.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04510194 phase3completednot on this map

COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19)

TypeinterventionalSponsorUniversity of MinnesotaRan2021 to 2022Enrolled1,323ConditionsCovid19, SARS-CoV InfectionArmsMetformin, Placebo, Fluvoxamine, Ivermectin
3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Trial
  4. Review
  5. Article
  6. Review
  7. Article
  8. Article
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  11. Article
  12. Effect of Metformin on the Risk of Post-COVID-19 Condition Among Individuals With Overweight or Obese: A Population-based Retrospective Cohort Study.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026
    Article
  13. Preventing Long COVID With Metformin.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026
    Article
  14. Review
  15. Bridging Gaps in Long COVID Therapy: A Review.Current medicinal chemistry · 2026
    Review
  16. Review
  17. Review
  18. Review
  19. Article
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors at 11 institutions in 1 country.

Carolyn T BramanteGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.ORCID 0000-0001-5858-2080
Kenneth B BeckmanGenomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
Tanvi MehtaDivision of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Amy B KargerDepartment of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
David J OddeDepartment of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
Christopher J TignanelliDepartment of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
John B BuseDepartment of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Darrell M JohnsonGenomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
Ray H B WatsonGenomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
Jerry J DanielGenomics Center, University of Minnesota, Minneapolis, Minnesota, USA.
David M LiebovitzGeneral Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Jacinda M NicklasGeneral Internal Medicine, University of Colorado, School of Medicine, Aurora, Colorado, USA.
Ken CohenUnitedHealth Group, Optum Labs, Minnetonka, Minnesota, USA.
Michael A PuskarichEmergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA.
Hrishikesh K BelaniDepartment of Medicine, Olive View-University of California, Los Angeles, California, USA.
Lianne K SiegelDivision of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Nichole R KlattDepartment of Surgery, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
Blake AndersonAtlanta Veterans Affairs Medical Center, Atlanta, Georgia, USA.
Katrina M HartmanGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Via RaoGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Aubrey A HagenGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Barkha PatelGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Sarah L FennoGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Nandini AvulaGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Neha V ReddyGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Spencer M EricksonGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Regina D FrictonGeneral Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Samuel LeeGeneral Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Gwendolyn GriffithsGeneral Internal Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Matthew F PullenDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Jennifer L ThompsonDepartment of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nancy E SherwoodDivision of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Thomas A MurrayDivision of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
Michael R RoseDepartment of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
David R BoulwareDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Jared D HulingDivision of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
COVID-OUT Study Team
University of Minnesota · USNorthwestern University · USUniversity of Minnesota Medical Center · USEmory University · USHennepin County Medical Center · USOptum (United States) · USUniversity of California, Los Angeles · USUniversity of Colorado Denver · USUniversity of North Carolina at Chapel Hill · USVanderbilt University Medical Center · USJohns Hopkins University · US

Funding

ACTIV Integration of Host-targeting Therapies for COVID-19 Administrative Coordinating CenterOT2HL156812 · NHLBI · RESEARCH TRIANGLE INSTITUTE · PI NOLEN, TRACY L, THOMAS, SONIA M · 2020 to 2024
$1270.7M
OTA-21-015A Post-Acute Sequelae of SARS-CoV-2 Infection Initiative: NYU Langone Health Clinical Science Core, Data Resource Core, and PASC Biorepository CoreOT2HL161847 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI GROSS, RACHEL SHARON, HORWITZ, LEORA · 2021 to 2025
$651.0M
Re-Entry Supplement: Investigation of Oral Microbial Enzymes for the Detection and Treatment of Periodontal DiseaseUL1TR002489 · NCATS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BUSE, JOHN BERNARD, SHAHEEN, NICHOLAS J · 2018 to 2022
$48.6M
University of Minnesota Clinical and Translational Science Institute (UMN CTSI)UL1TR002494 · NCATS · UNIVERSITY OF MINNESOTA · PI BLAZAR, BRUCE R, WEISDORF, DANIEL J · 2018 to 2022
$34.9M
Project 2: Cell Migration in Mechanically Complex MicroenvironmentsU54CA210190 · NCI · UNIVERSITY OF MINNESOTA · PI LARGAESPADA, DAVID ANDREW · 2016 to 2020
$10.0M
Project 3P01CA254849 · NCI · UNIVERSITY OF MINNESOTA · PI PROVENZANO, PAOLO · 2021 to 2025
$9.4M
Institutional Career Development CoreKL2TR002492 · NCATS · UNIVERSITY OF MINNESOTA · PI INGBAR, DAVID H · 2018 to 2022
$6.3M
Statistical Methods and Software for Multivariate Meta-analysisR01LM012982 · NLM · UNIVERSITY OF MINNESOTA · PI LIN, LIFENG, SIEGEL, LIANNE · 2019 to 2022
$1.3M
Training in Biostatistics for Heart, Lung and Blood Disease ResearchT32HL129956 · NHLBI · UNIVERSITY OF MINNESOTA · PI NEATON, JAMES DENNIS · 2016 to 2020
$1.1M
Self-weighing for Weight Management in Adolescents with ObesityK23DK124654 · NIDDK · UNIVERSITY OF MINNESOTA · PI BRAMANTE, CAROLYN T · 2021 to 2024
$801k
Iterative development and pilot testing of a mobile health intervention to increase postpartum weight loss in women at increased risk for cardiometabolic diseaseK23HL133604 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI NICKLAS, JACINDA MAWSON · 2016 to 2019
$769k
Identifying Areas to Improve ICU Outcomes through Provider VariationK23HL166783 · NHLBI · UNIVERSITY OF MINNESOTA · PI Nicholas E Ingraham · 2023 to 2026
$645k
Apotex PharmacyEdenbridge PharmacyEducation and Research InstituteFast GrantsInstitute for Engineering in MedicineLeidos BiomedicalMinnesota Partnership for Biotechnology and Medical Genomics 00086722Minnesota's Rainwater Foundation GrantNational Cancer Institute of the NIHNational Heart, Lung, and Blood Institute of the NIH OT2HL156812National Heart, Lung, and Blood Institute of the NIH T32HL129956NCATS NIH HHS KL2 TR002492NCATS NIH HHS UL1 TR002489NCATS NIH HHS UL1 TR002494NCI NIH HHS P01 CA254849NCI NIH HHS U54 CA210190NHLBI NIH HHS K23 HL133604NHLBI NIH HHS K23 HL166783NHLBI NIH HHS OT2 HL156812NHLBI NIH HHS OT2 HL161847NHLBI NIH HHS T32 HL129956NIDDK NIH HHS K23 DK124654NIH HHS K23 DK124654-01-A1NIH RECOVER OT2HL161847NLM NIH HHS R01 LM012982NLM NIH HHS R21 LM012744Olive View-Parsemus FoundationRainwater Charitable FoundationSubaward of the UniversityUnitedHealth Group Foundation KL2TR002492
6 · The paper itself

Abstract

backgroundMetformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%.

methodsCOVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction.

resultsThe mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo.

conclusionsIn this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Indexed as

Antiviral AgentsCOVID-19COVID-19 Drug TreatmentMetforminSARS-CoV-2Viral LoadAdultAgedDouble-Blind MethodFemaleFluvoxamineHumansIvermectinMaleMiddle AgedAntiviral AgentsFluvoxamineIvermectinMetforminlong COVIDmetforminmTORoutpatient COVID-19 treatmentviral load

Identifiers

PMID38690892
PMCPMC11327787
OpenAlexW4396600997

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.