Metformin Shows Promise in Reducing Long COVID Risk: A Breakthrough in Outpatient Treatment


The COVID-19 pandemic has had a profound impact on global health, economy, and society. While significant efforts have been made to develop vaccines and therapeutics, the prevention and treatment of long COVID, a condition characterized by persistent symptoms following acute COVID-19 infection, have posed challenges.

However, a recent investigator-initiated clinical trial has shed light on a potential breakthrough in the outpatient treatment of COVID-19 using metformin. This article will explore the findings of the trial and its implications for managing long COVID.

The Study: Investigating the Efficacy of Metformin

The trial, a decentralised, multicentre, randomised, quadruple-blind, placebo-controlled, phase 3 study, aimed to evaluate the effectiveness of metformin in reducing the risk of long COVID among outpatient individuals with COVID-19.

The results were remarkable, indicating a 41.3% reduction in the risk of long COVID by day 300 in the metformin group compared to the placebo group. The cumulative incidence of long COVID was estimated to be 6.3% in the metformin group and 10.6% in the placebo group.

Furthermore, the study demonstrated that metformin also reduced the risk of severe COVID-19 outcomes, such as emergency department visits, hospitalizations, and death, by 42.3% by day 14. Participants who received metformin were also less likely to be hospitalized by day 28 compared to those who received the placebo. In contrast, the trial found no significant reduction in the risk of long COVID with the use of ivermectin and fluvoxamine, consistent with their lack of efficacy in reducing severe COVID-19 outcomes.

Understanding Long COVID and its Implications

Long COVID refers to the persistence or development of new symptoms that last for at least two months with no other explanation, occurring three months after the initial SARS-CoV-2 infection. This trial’s findings suggest that long COVID can affect individuals who did not experience severe COVID-19 symptoms. It highlights the need for effective outpatient treatments to prevent the progression to long COVID.

The exact pathophysiology of long COVID is still unknown, but it is believed to be multifactorial, involving the inflammatory response during acute infection and persistent viral replication. Metformin, a medication commonly used to treat diabetes, has shown promise in inhibiting viral replication and suppressing the translation of SARS-CoV-2 viral proteins. The drug’s antiviral properties, coupled with its actions against oxidative stress and inflammation, make it a potential candidate for mitigating long COVID symptoms.

Safety and Considerations

The trial demonstrated the safety of metformin in adults without diabetes, addressing concerns about lactic acidosis that arose from studies on other biguanides. Large-scale studies have consistently shown no increased risk of lactic acidosis in metformin users compared to non-users. Moreover, metformin has been deemed safe for individuals with kidney disease, including those with lower glomerular filtration rates.

The low risk of hypoglycemia associated with metformin usage, even in individuals without diabetes, further supports its safety profile. Extensive studies have validated its safety in various populations, including children, pregnant women, and those who are lactating.

Future Directions and Considerations

While the trial’s findings offer hope for preventing and treating long COVID, further research is needed to validate and expand upon these results. Future studies should explore the efficacy of metformin when administered during emergency department visits or hospitalizations for COVID-19, as well as in individuals already experiencing long COVID symptoms.

Additionally, investigations into the effectiveness of metformin in conjunction with other treatments and its impact on vaccinated individuals and those with previous SARS-CoV-2 infections are necessary. As the COVID-19 pandemic evolves, it is crucial to conduct prospective, interventional trials to assess the incidence of long COVID in diverse populations.


The investigator-initiated trial on outpatient treatment for COVID-19 using metformin has unveiled a potential breakthrough in managing long COVID. The study demonstrated that metformin significantly reduced the risk of long COVID by 41.3% and severe COVID-19 outcomes by 42.3% within the initial 14 days of treatment. In contrast, other drugs, such as ivermectin and fluvoxamine, did not show similar efficacy.

Metformin’s safety profile, wide availability, and low cost make it a promising option for addressing the long-term health, mental health, and economic implications of long COVID. However, further research is needed to consolidate these findings, explore its efficacy in different populations, and assess its potential synergy with other treatments.

As the world grapples with the consequences of the COVID-19 pandemic, metformin offers hope for reducing the burden of long COVID and improving the lives of millions affected by this debilitating condition.


Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo.


Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe.


Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

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