Large clinical trials and real-world data point to a familiar diabetes drug as a simple, safe way to reduce the long-term toll of COVID-19 when given early in infection.
Study: Preventing Long COVID With Metformin. Image credit: Jack_the_sparow/Shutterstock.com
Authors of an editorial commentary in Clinical Infectious Diseases reviewed evidence from randomized trials and real-world analyses to evaluate why metformin should be offered to adults with COVID-19 to prevent long COVID.
The commentary argues that clinical and observational data together support the safety and efficacy of the common diabetes medicine metformin in reducing the risk of long coronavirus disease 2019 (COVID-19) following infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus.
Long COVID symptoms and risks
COVID-19 is an infectious disease caused by the SARS-CoV-2 virus that emerged in 2019 and led to a global pandemic. While most people recovered from the acute infection within a few weeks, a significant proportion developed long COVID, also known as post-COVID-19 condition, a complex syndrome characterized by persistent symptoms that can last months or even years after the initial infection.
Common manifestations of long COVID include fatigue, shortness of breath, chest pain, and cognitive impairment, often referred to as “brain fog”. Long COVID covers a wide range of other symptoms that can substantially impact quality of life and functional capacity, sometimes limiting a person’s ability to work or carry out daily activities.
Researchers have consistently focused on understanding the symptoms of long COVID, its underlying mechanisms, and preventive measures.
Diabetes medicine and antiviral effect
Scientists have examined various approaches, including the use of diabetes medication to prevent long COVID symptoms. Although using a diabetes medication for a viral infection may seem counterintuitive, it has a solid rationale. Biguanides, the drug class to which metformin belongs, were originally explored for the treatment of viruses and malaria. However, around 1940, their use declined after lactic acidosis was observed with phenformin and buformin.
Metformin, a widely used diabetes medication, has shown antiviral properties in laboratory studies since the 2000s due to its effects on immune function and cellular metabolism. When COVID-19 emerged, early research, including observational studies, computer modeling, and laboratory experiments, suggested metformin might be effective against SARS-CoV-2. These findings, combined with metformin's low cost, widespread availability, excellent safety profile, and lack of need for monitoring during short-term use, made it an ideal candidate for clinical trials in outpatients with acute COVID-19.
Clinical trials indicate the safety and efficacy of metformin in reducing long COVID risks
In July 2021, the COVID-OUT trial was conducted to assess whether early treatment prevented long COVID. At that time, it wasn't clear which symptoms counted as long COVID or how severe they needed to be. Symptom-based measures couldn't be verified in medical records, so a verifiable outcome was needed.
To capture how doctors actually diagnose long COVID, researchers asked participants, “Have you been told by a medical provider that you have long COVID?” This allowed the authors to obtain medical records and confirm diagnoses. These diagnoses were provided by community doctors who weren’t involved in the study.
The COVID-OUT trial found that metformin reduced the risk of long COVID by 41 % over 10 months. Notably, a 63 % reduction was observed among participants who started metformin within three days of symptom onset, highlighting the importance of early treatment during acute infection.
A small randomized trial found that metformin reduced COVID-19 viral load by 93.2 %, compared to 78.3 % with placebo. The virus became undetectable in 3.3 days with metformin, compared with 5.6 days with placebo. COVID-OUT also showed that metformin reduced viral load, supporting a potential biological mechanism for reducing long COVID risk.
To evaluate whether these findings extended to broader populations, researchers conducted a second large randomized trial called ACTIV-6. This separate confirmatory study was designed to test metformin in a more diverse population. While COVID-OUT focused on people with a BMI of 25 or higher and excluded those with prior COVID-19 infection, ACTIV-6 expanded eligibility to include participants with normal BMI and those with prior COVID-19 infection. This design enabled researchers to evaluate metformin’s safety and effectiveness in a broader range of patients who might benefit from the treatment.
ACTIV-6 used the same dose as COVID-OUT, 500 mg, starting with a low dose and gradually increasing over 14 days, 36 doses total. Metformin didn’t cause significant stomach problems or safety concerns in either trial. Low blood sugar was rare and actually less common with metformin than placebo. ACTIV-6 measured symptom severity at 6 months and asked participants if they’d been diagnosed with long COVID. The trial estimated a 50 % lower risk of clinician-diagnosed long COVID, although the uncertainty interval was wide, supporting but not definitively proving the COVID-OUT findings.
Conclusions
Together, two large, well-designed randomized controlled trials suggest that metformin taken during acute COVID-19 infection can reduce the risk of clinician-diagnosed long COVID, with risk reductions of approximately 40 % in COVID-OUT and around 50 % in ACTIV-6. The authors note that these findings are further supported by electronic health record-based “target trial emulation” analyses that aim to mimic randomized trials using real-world healthcare data.
It must be noted that long COVID was a secondary outcome in both trials, and estimates, particularly from ACTIV-6, carry statistical uncertainty. However, the trials evaluated metformin in diverse populations, including people with and without prior immunity, across different BMI ranges, and during the Omicron era, and the results were directionally consistent across multiple analytical approaches, strengthening confidence in the overall signal.
Considering safety and efficacy, along with metformin's low cost, wide availability, good tolerability, and lack of interactions with other COVID-19 treatments, the authors argue it should be offered to outpatients with acute COVID-19 as a preventive option. If adopted broadly, this approach could meaningfully reduce the ongoing burden of long COVID on individuals, healthcare systems, and society.
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