Metformin on the Presence of COVID-19 Symptoms 6 Months after Infection: The ACTIV-6 Randomized Clinical Trial.

Publication date: Jun 04, 2026

We conducted a quadruple-blinded, randomized, placebo-controlled trial of metformin for treating acute SARS-CoV-2 infection to prevent long COVID symptoms in low-risk adults. The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 2983 outpatient adults ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms were included within 7 days of symptom onset from 90 sites. Participants were randomized to metformin or placebo for 14 days. Post-acute sequelae of SARS-CoV-2 or death (PASCD) was ascertained by asking whether participants had symptoms they attributed to COVID-19 on day 180. Secondary outcomes included clinician-diagnosed long COVID. The median age was 47 years (interquartile range 38-57); 63% were female; 47% Hispanic/Latino; 83% reported ≥1 prior COVID-19 infections or ≥2 SARS-CoV-2 vaccines. There were no deaths. Overall, 96 (3. 2%) reported COVID-19 symptoms on day 90, 101 (3. 4%) on day 120, and 79 (2. 6%) on day 180. The adjusted risk of symptoms on day 180 was 0. 8 percentage points lower with metformin (95% credible interval [CrI] -2. 2 to 0. 6) with a posterior probability of efficacy [PPE] for preventing symptoms of 0. 83, risk ratio 0. 79 (95% CrI 0. 474 to 1. 230). Compared with placebo, the risk of clinician-diagnosed long COVID was 0. 7 percentage points lower with metformin (95% CrI -1. 5 to 0. 1); PPE 0. 96; risk ratio 0. 495 (95% CrI 0. 155 to 0. 995). In low-risk adults, most with prior immunity, metformin did not exceed the efficacy threshold of 0. 975 for PASC. Metformin reduced the risk of clinician-diagnosed long COVID.

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