Findings from a growing body of randomized trials and real-world analyses show that starting metformin during acute SARS-CoV-2 infection is safe and significantly reduces the risk of developing long COVID.
As the global health community continues to grapple with the long-term consequences of SARS-CoV-2 infection, preventing post–COVID-19 condition—commonly known as long COVID—has become a clinical priority. New evidence from randomized trials and target trial emulations suggests that an unlikely candidate, metformin, may offer a practical and effective strategy to reduce this risk when started early in acute infection.
Chaichana and colleagues recently conducted a sequential trial emulation to assess whether initiating metformin after SARS-CoV-2 infection lowers the risk of long COVID. Their findings closely align with results from randomized clinical trials, providing important validation across study designs. Together with data from earlier trials, these data strengthen the case for offering metformin to nonhospitalized adults with acute COVID-19 to prevent long-term sequelae.
At first glance, repurposing a chronic diabetes medication for an acute viral illness may seem counterintuitive. However, metformin’s history reveals a broader pharmacologic profile. Early work on biguanides in the early 20th century explored antiviral and antimalarial applications. Although phenformin and buformin were eventually abandoned due to lactic acidosis risk, metformin emerged as a safer alternative and became widely used for type 2 diabetes. Over time, findings from studies demonstrated its anti-inflammatory and immunometabolic effects, along with reassuring safety data showing no increased risk of lactic acidosis when used appropriately.
Interest in metformin as an antiviral agent reemerged in the 2000s, driven by findings from in vitro studies showing host-directed antiviral activity. When SARS-CoV-2 emerged in 2020, results from observational studies, computational modeling, and laboratory experiments further supported its potential role in acute COVID-19 treatment. Given its low cost, global availability, tolerability, and lack of need for laboratory monitoring during short-term use, metformin was well suited for clinical testing.
The COVID-OUT randomized trial was a pivotal step. In mid-2021, investigators amended the protocol to include long-term outcomes, recognizing the urgent need to understand postacute sequelae. Because long COVID definitions were still evolving, the trial used a pragmatic outcome: whether participants had been told by a medical provider that they had long COVID. This approach allowed diagnoses to be verified in medical records and reflected real-world clinical practice.
Findings from 2 randomized clinical trials and multiple target trial emulations show that early metformin use reduces the risk of long COVID by approximately 40% to 50%.
The largest benefit was observed when metformin was started within 3 days of symptom onset.
Metformin is inexpensive, widely available, and well tolerated, and it has no major drug-drug interactions with current COVID-19 therapies.
Over 10 months of follow-up, participants randomly assigned to metformin had a 41% lower risk of long COVID compared with placebo. Importantly, this benefit applied to the full study population. A larger risk reduction—63%—was observed among participants who started metformin within 3 days of symptom onset, highlighting the importance of early treatment.
Mechanistic data support these clinical findings. In a randomized trial, metformin significantly reduced SARS-CoV-2 viral load and shortened the time to viral clearance compared with placebo. Similar antiviral effects were observed within the COVID-OUT trial itself, suggesting a biologically plausible pathway linking early viral suppression to reduced long-term complications.
The ACTIV-6 trial findings provided critical confirmation in a broader population, including individuals with normal body mass index and prior SARS-CoV-2 infection. Using the same dosing regimen as COVID-OUT, ACTIV-6 results found that metformin again reduced the risk of long COVID, with no significant safety concerns. Gastrointestinal adverse effects were mild, and hypoglycemia was rare and comparable to that experienced with placebo.
Together, findings from these trials—conducted during the Omicron era and among participants with varying levels of prior immunity—demonstrate consistent benefit across populations. Although clinician-diagnosed long COVID was a secondary outcome, such outcomes are routinely used to inform treatment guidelines, particularly when supported by findings from multiple randomized studies and real-world validation.
In sum, findings from 2 large placebo-controlled trials, supported by target trial emulations, show that starting metformin during acute SARS-CoV-2 infection is safe and meaningfully lowers the risk of long COVID. Adding metformin to clinical guidelines for nonhospitalized adults could accelerate uptake of an accessible intervention, with the potential to reduce the long-term burden of COVID-19.
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