Peer-reviewed / Randomised Controlled Trial / People
Peer-reviewed / Randomised Controlled Trial / People
The Lancet Infectious Diseases: Taking a common diabetes medication after testing positive for SARS-CoV-2 reduces risk of developing long COVID by 40%, study finds
- US study of 1,126 overweight and obese people finds 6.3% of participants who took metformin, a medication commonly used to control blood sugar in people with type 2 diabetes, within three days of testing positive for SARS-CoV-2 reported a long COVID diagnosis within 10 months, compared to 10.4% of those who received a placebo.
- This is the first published randomised control trial to suggest medication taken during the acute phase of COVID-19 may be able to reduce the risk of long COVID.
- Authors caution that the trial did not look at the effect of metformin on those who already had a long COVID diagnosis so it cannot draw any conclusions about metformin as a treatment for long COVID. They suggest further trials of metformin on those with lower BMI and previous SARS-CoV-2 infection.
Taking a two-week course of metformin, a safe and affordable diabetes medication after testing positive for SARS-CoV-2 leads to 40% fewer long COVID diagnoses over the following 10 months, compared to individuals taking a placebo, finds a new study published in The Lancet Infectious Diseases journal.
The long-term symptoms some people experience after SARS-CoV-2 infection, known as long COVID, are an emerging chronic illness potentially affecting millions of people around the world. Currently there are no proven treatments or ways to prevent long COVID, other than reducing the risk of infection in the first place.
This is the first phase 3 randomised controlled trial of a treatment for patients in the community that shows a medication can reduce the risk of long COVID when taken after testing positive for SARS-CoV-2.
“Long COVID is a significant public health emergency that may have lasting physical health, mental health, and economic impacts, especially in socioeconomically marginalised groups. There is an urgent need to find potential treatments and ways to prevent this disease. Our study showed that metformin, a medication that is safe, low-cost, and widely available, substantially reduces the risk of being diagnosed with long COVID if taken when first infected with the coronavirus. This trial does not indicate whether metformin would be effective as a treatment for those who already have long COVID,” says first author Dr Carolyn Bramante, University of Minnesota Medical School, USA. 
Participants in the trial were not hospitalised, were at a higher risk of severe COVID-19 (overweight or obesity), over the age of 30, and had tested positive for SARS-CoV-2 within the last three days but had no known previous SARS-CoV-2 infection. Trial recruitment was open from December 2020 to January 2022 with 1,126 patients given either metformin or an identical placebo pill after testing positive for SARS-CoV-2 during that time. Participants were followed up for 10 months with data gathered by self-report questionnaire every 30 days.
Metformin prevented over 40% of cases of long COVID in the trial with 6.3% (35/564) of participants given metformin reporting a long COVID diagnosis within 10 months of follow up, compared to 10.4% (58/562) of those receiving an identical placebo.
These findings reflect previously published results from this trial which found metformin prevented over 40% of emergency department visits, hospitalisations, and deaths due to COVID within two weeks of starting the treatment, compared to a placebo .
Other arms of the trial looked at ivermectin and fluvoxamine and found that neither prevented long COVID.
“Previous studies have found that metformin stops the SARS-CoV-2 virus from replicating in the lab [3,4], which is consistent with predictions from our mathematical modelling of viral replication, so that might be what is causing the reduction in both severe COVID-19 and Long COVID diagnoses seen in this trial,” says co-author David Odde, University of Minnesota biomedical engineer.
The authors acknowledge some limitations to the study, including that the trial excluded those with a BMI under 25 and those younger than 30 years, and therefore it is unknown if these findings could be generalised to those populations. They also caution that when the long COVID assessment was added to the trial, little was known about the best assessment tool for long COVID occurrence in clinical trial participants, however they believe the use of a long COVID diagnosis from a medical provider, as well as the long duration of follow-up, would address some of the issues around the changing nature of this disease definition.
Writing in a Linked Comment, Dr Jeremy Faust, Harvard Medical School, USA, who was not involved in this research, said: “If confirmed, the findings from the study by Bramante and colleagues are profound and potentially landmark […] this is the first high-quality evidence from a randomised controlled trial to show that the incidence of long COVID can be reduced by a medical intervention, metformin—an inexpensive treatment with which clinicians have ample experience.”
NOTES TO EDITORS
This study was funded by Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation. See the Article for a full list of author affiliations.
 Quote direct from author and cannot be found in the text of the Article.
 Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for COVID-19. The New England journal of medicine 2022; 387(7): 599-610.
 Parthasarathy H, Tandel D, Siddiqui AH, Harshan KH. Metformin suppresses SARS-CoV-2 in cell culture. Virus Res. 2022 Nov 20;323:199010.
 Schaller et al., JCI Insight, 2021 and Gordon et al., Nature, 2020
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The Lancet Infectious Diseases
Method of Research
Randomized controlled/clinical trial
Subject of Research
Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 tria
Article Publication Date
CTB was supported by grants (KL2TR002492 and UL1TR002494) from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and by a grant (K23 DK124654–01-A1) from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. JBB was supported by grants (UL1TR002489 and UM1TR004406) from NCATS and reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by Dexcom, NovaTarg, Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, CeQur, Cirius Therapeutics, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, Valo, and Zealand Pharma; and stock or stock options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health. JMN was supported by a grant (K23HL133604) from the National Heart, Lung, and Blood Institute of the NIH. DJO was supported by the Institute for Engineering in Medicine, University of Minnesota Office of Academic and Clinical Affairs COVID-19 Rapid Response Grant, the Earl E Bakken Professorship for Engineering in Medicine, and by grants (U54 CA210190 and P01 CA254849) from the National Cancer Institute of the NIH. TAM was supported in part by the Medtronic Faculty Fellowship. DML receives funding from NIH RECOVER (OT2HL161847). LKS was supported by NIH grants (18X107CF6 and 18X107CF5) through a contract with Leidos Biomedical and by grants from the National Heart, Lung, and Blood Institute of the NIH (T32HL129956), and the NIH (R01LM012982 and R21LM012744). MAP receives grants from the Bill & Melinda Gates Foundation (INV-017069), Minnesota Partnership for Biotechnology and Medical Genomics (00086722), and the National Heart, Lung, and Blood Institute of the NIH (OT2HL156812); and consulting fees from Opticyte and Cytovale. All other authors declare no competing interests.