METFORMIN did not significantly prevent 6-month COVID-19 symptoms but lowered clinician-diagnosed long COVID.
Metformin And Long COVID Prevention
Metformin did not meet the prespecified efficacy threshold for preventing post-acute sequelae of SARS-CoV-2 infection at 6 months in a large randomized trial of outpatient adults with mild to moderate COVID-19. However, the ACTIV-6 trial showed a reduction in clinician-diagnosed long COVID, offering a more nuanced signal for clinicians evaluating potential early interventions after acute infection.
The quadruple-blinded, randomized, placebo-controlled, decentralized platform trial enrolled 2,983 adults aged 30 years or older from 90 U.S. sites between September 2023 and May 2024. Participants had confirmed SARS-CoV-2 infection and at least 2 COVID-19 symptoms within 7 days of symptom onset. They were randomized to immediate-release metformin or placebo for 14 days.
Most participants reflected a contemporary outpatient population with prior immunity. Median age was 47 years, 63% were female, 47% identified as Hispanic or Latino, and 83% reported at least 1 prior COVID-19 infection or at least 2 SARS-CoV-2 vaccine doses.
Six-Month COVID-19 Symptoms Remained Low
At day 180, 79 participants, or 2.6%, reported symptoms they attributed to COVID-19, and no deaths occurred. Symptoms were reported by 33 participants in the metformin group and 46 in the placebo group. The adjusted risk of post-acute sequelae of SARS-CoV-2 was 0.8 percentage points lower with metformin, with a 95% credible interval of -2.2 to 0.6. The posterior probability of efficacy was 0.83, below the 0.975 threshold required to declare efficacy.
Symptom rates were also low at earlier follow-up points, with 3.2% reporting COVID-19 symptoms at day 90 and 3.4% at day 120. The low event rate may be clinically important when interpreting the results, particularly because many participants had prior vaccination, prior infection, or both.
Clinician-Diagnosed Long COVID Signal
Metformin showed a stronger signal for clinician-diagnosed long COVID. By day 180, 8 participants in the metformin group and 18 in the placebo group reported receiving a clinician diagnosis. Compared with placebo, metformin lowered the adjusted risk by 0.7 percentage points, with a posterior probability of efficacy of 0.96 and a risk ratio of 0.50.
Exploratory analyses suggested that participants without known prior infection may have been more likely to benefit, although these findings require caution. Safety findings were reassuring, with no episodes of lactic acidosis and 6 participant-reported hypoglycemia events, 2 with metformin and 4 with placebo.
Overall, ACTIV-6 suggests that metformin did not clearly prevent patient-reported COVID-19 symptoms at 6 months in a largely immune, low-risk outpatient population, but the reduction in clinician-diagnosed long COVID warrants continued attention.
Reference
Bramante CT et al. Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial. Clinical Infectious Diseases. 2026;doi:10.1093/cid/ciag335.
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