Long COVID affects millions worldwide, causing persistent symptoms months after initial COVID-19 infection1 . Recent research suggests that metformin, a common diabetes medication, may significantly reduce the risk of developing Long COVID, especially in people with overweight or obesity2 . This finding opens new possibilities for preventing the long-term effects of COVID-19 in vulnerable populations3 .
Metformin Reduces Long COVID Risk
The COVID-OUT trial, a large randomized phase 3 study, found that metformin reduced the incidence of Long COVID by about 41% compared to placebo, with a cumulative incidence of 6.3% in the metformin group versus 10.4% in the placebo group by day 3004 . This trial enrolled 1,125 adults aged 30 to 85 years with overweight or obesity, who were treated within seven days of symptom onset4 . Participants were randomly assigned to receive metformin, ivermectin, fluvoxamine, or placebo for 14 days4 . Notably, starting metformin within three days of symptom onset was associated with a greater than 60% reduction in Long COVID risk compared to later initiation5 .
A recent UK population-based retrospective cohort study confirmed these findings in a real-world setting. Among 624,308 adults with overweight or obesity, those who initiated metformin within 90 days of COVID-19 diagnosis had a 64% lower risk of developing Long COVID over one year compared to those who did not use metformin (hazard ratio 0.36) 3. This reduction translated to an absolute risk difference of about 12.6%, meaning roughly eight patients would need to be treated with metformin to prevent one case of Long COVID3 . The protective effect was consistent across subgroups defined by age, sex, BMI category, diabetes status, and dominant viral variants3 .
Additional evidence from electronic health record data also supports metformin’s association with a lower risk of Long COVID or death in adults with type 2 diabetes, showing a 13% to 21% reduction compared to other diabetes medications6 . These findings suggest that metformin’s benefits extend beyond glycemic control and may apply to a broad population at risk for Long COVID.
Key points on metformin’s effect on Long COVID risk include:
- Metformin reduced Long COVID incidence by approximately 41% in a randomized trial4 .
- Early initiation (within 3 days of symptoms) enhanced the protective effect, reducing risk by over 60% 5.
- Real-world data showed a 64% reduction in Long COVID risk among overweight or obese adults starting metformin within 90 days post-infection3 .
- Benefits were consistent across age, sex, BMI, diabetes status, and viral variant subgroups3 .
- Metformin users with type 2 diabetes had lower Long COVID or death rates compared to those on other diabetes drugs6 .
How Metformin Affects COVID Outcomes
Metformin’s potential to reduce Long COVID risk is thought to arise from several biological mechanisms beyond its primary role in diabetes management. It lowers glucose production in the liver and has anti-inflammatory effects, which may help mitigate the prolonged inflammatory state associated with COVID-197 .
One key pathway involves metformin’s inhibition of the mammalian target of rapamycin (mTOR), a cellular pathway important for viral replication. By restricting mTOR activity, metformin may act like an antiviral agent, reducing viral persistence and thus lowering the risk of Long COVID8 .
Metformin also reduces oxidative stress on cells and dampens inflammatory mediator release, which could protect against tissue damage and chronic symptoms seen in Long COVID7 . Supporting this, viral load analysis from the COVID-OUT trial showed that metformin reduced SARS-CoV-2 viral load by approximately 3.6-fold compared to placebo8 9. This reduction in viral load likely contributes to the observed decreases in hospitalization and Long COVID incidence9 .
Additional mechanisms proposed include:
- Activation of AMP-activated protein kinase (AMPK), which may interfere with viral entry and replication2 .
- Modulation of angiotensin-converting enzyme 2 (ACE2) phosphorylation, potentially hindering viral adhesion2 .
- Attenuation of dipeptidyl peptidase 4 activity, reducing viral entry and inflammatory marker expression10 .
These multifaceted actions position metformin as a promising agent to reduce both acute and long-term COVID-19 complications.
Summary of metformin’s mechanisms relevant to COVID-19:
- Reduces hepatic glucose production and systemic inflammation7 .
- Inhibits mTOR pathway, limiting viral replication and persistence8 .
- Lowers oxidative stress and inflammatory mediator release7 .
- Decreases SARS-CoV-2 viral load and viral rebound8 9.
- Modulates cellular pathways affecting viral entry and immune response10 2.
People with long COVID frequently require continued medical treatment or are unable to work for 6 months or longer. Although disease prevention is a public health challenge, taking the next steps to implement metformin as a COVID-19 treatment to prevent long COVID is an urgent public health need5 .
Long COVID Treatment Implications
The evidence that metformin reduces Long COVID risk has important implications for treatment and prevention strategies. Metformin is widely available, inexpensive, and generally safe, with few side effects, making it an attractive option for early outpatient COVID-19 treatment5 3. A 30-day supply of metformin 500 mg tablets costs approximately $13, enhancing its accessibility5 .
However, further research is needed to confirm these findings in broader populations, including people with normal BMI, younger individuals, and those with prior SARS-CoV-2 infections5 3. The COVID-OUT trial excluded adults under 30 and those with normal BMI, so generalizability remains uncertain4 3. Additionally, the optimal timing and duration of metformin treatment for Long COVID prevention require clarification5 .
Among the volunteers in this randomized trial, there was a more than 41% reduction of long COVID among those receiving metformin and a 58% reduction in hospitalization by 28 days. This new study explains why this occurred. Metformin reduced the amount of SARS-CoV-2 virus present, which likely accounts for why this $1 medication reduced hospitalizations and long COVID.
— Carolyn T. Bramante, MD, MPH9
Current clinical guidelines do not yet reflect metformin’s potential role in Long COVID prevention, partly due to limited awareness and the need for more definitive trials11 . The National Institutes of Health (NIH) RECOVER initiative and other research programs are actively investigating metformin’s effects on Long COVID and related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 11.
Key considerations for metformin use in Long COVID prevention:
- Metformin is safe, well-tolerated, and inexpensive5 3.
- Early initiation (within days of symptom onset) may maximize benefit5 .
- More randomized controlled trials are needed to confirm efficacy and define treatment protocols10 3.
- Current guidelines do not yet recommend metformin for Long COVID prevention11 .
- Ongoing research aims to clarify mechanisms and long-term outcomes11 .
