Large-scale clinical trials and real-world data point to familiar diabetes drugs as an easy and safe way to reduce long-term harm from COVID-19 when given early in the infection.
study: Metformin prevents long-lasting coronavirus. Image credit: Jack_the_sparrow/Shutterstock.com
Editorial Commentary Author clinical infections We reviewed evidence from randomized trials and real-world analyzes to assess why adult patients with COVID-19 should be offered metformin to prevent long-term COVID-19 infection.
This commentary asserts that both clinical and observational data support safety and security. efficacy of Common diabetes drug metformin reduces risk of long-term coronavirus infection in 2019COVID-19 (new coronavirus infection)) After severe acute respiratory syndrome coronavirus-2 infection (SARS-CoV-2) virus.
Symptoms and risks of long-term coronavirus
COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which emerged in 2019 and caused a global pandemic. Although most people recovered from acute infection within weeks, a significant proportion developed prolonged COVID-19 infection, also known as post-COVID-19 syndrome, a complex syndrome characterized by persistent symptoms lasting months or even years after initial infection.
Common symptoms of long-term coronavirus infection include fatigue, shortness of breath, chest pain, and cognitive impairment, often referred to as “brain fog.” Long-term COVID-19 infections cover a wide range of other symptoms that can significantly impact quality of life and functional ability, and in some cases limit a person’s ability to work and carry out daily activities.
Researchers have consistently focused on understanding the long-lasting coronavirus symptoms, underlying mechanisms, and preventive measures.
Diabetic drugs and antiviral effects
Scientists are considering various approaches, including the use of diabetes drugs, to prevent long-term coronavirus symptoms. Although it may seem counterintuitive to use antidiabetic drugs for viral infections, there is solid evidence for this. Biguanides, the drug class to which metformin belongs, were originally studied for the treatment of viruses and malaria. However, around 1940, lactic acidosis was observed with phenformin and buformin, so its use declined.
Metformin, a widely used antidiabetic drug, has shown antiviral properties in clinical 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 that metformin may be effective against SARS-CoV-2. These findings, combined with metformin’s low cost, wide 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 infection.
Clinical trial shows metformin is safe and effective in reducing long-term risk of coronavirus infection
In July 2021, the COVID-OUT trial was conducted to assess whether early treatment can prevent long-term COVID-19 infection. At that time, it was not clear which symptoms would count as a period of COVID-19 infection and how severe they needed to be. Symptom-based measures cannot be verified with medical records, so verifiable results were needed.
To understand how doctors actually diagnose long-term coronavirus, researchers asked participants, “Have you ever been told you have long-term coronavirus by a health care provider?” This allowed the authors to obtain medical records and confirm the diagnosis. These diagnoses were provided by local physicians not involved in the study.
The COVID-OUT trial found that metformin reduced the risk of long-term COVID-19 infection by 41% over 10 months. Of note, a 63% reduction was observed in participants who started metformin within 3 days of symptom onset, highlighting the importance of early treatment in acute infections.
Small randomized trial finds metformin reduces COVID-19 viral load The increase was 93.2% compared to 78.3% with placebo. Metformin made the virus undetectable in 3.3 days, compared to 5.6 days for placebo. COVID-OUT also showed that metformin reduces viral load, supporting a potential biological mechanism to reduce long-term COVID-19 risk.
To assess whether these findings extend to a broader population, researchers conducted a second large randomized trial called ACTIV-6. This separate confirmatory study was designed to test metformin in a more diverse population. COVID-OUT has focused on people with symptoms such as: BMI While ACTIV-6 targeted participants 25 years of age or older and excluded those who had previously been infected with COVID-19, ACTIV-6 expanded eligibility to include participants with a normal BMI and those who had previously been infected with COVID-19. This design allowed researchers to assess the safety and efficacy of metformin in a wider range of patients who could benefit from treatment.
ACTIV-6 used the same dose of 500 mg as COVID-OUT, starting with a low dose and increasing gradually over 14 days, for a total of 36 doses. In neither trial, metformin did not cause significant gastric problems or safety concerns. Hypoglycemia was rare and was actually less frequent with metformin than with placebo. ACTIV-6 measured symptom severity at six months and asked participants whether they had been diagnosed with long-term COVID-19 infection. The trial estimates a 50% lower risk of long-term coronavirus diagnosed by clinicians, supporting but not conclusively proving the findings for COVID-19, despite a wide range of uncertainties.
conclusion
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-term COVID-19 infection, with approximately 40% risk reduction in COVID-OUT and approximately 50% risk reduction in ACTIV-6. The authors note that these findings are further supported by electronic medical record-based “targeted trial emulation” analyzes that aim to mimic randomized trials using real-world medical data.
It should be noted that in both trials, prolonged COVID-19 infection was a secondary outcome, and the estimates, especially from ACTIV-6, are subject to statistical uncertainty. However, this trial evaluated metformin in a variety of populations, including those with and without prior immunity, across different BMI ranges, and in the Omicron era, and the results were directionally consistent across multiple analytical approaches, increasing confidence in the overall signal.
The authors argue that given metformin’s low cost, widespread availability, good tolerability, and lack of interaction with other COVID-19 treatments, as well as its safety and efficacy, it should be offered to outpatients with acute COVID-19 as a prophylactic option. If widely adopted, this approach has the potential to meaningfully reduce the ongoing burden of long-term COVID-19 infections on individuals, health systems, and society.