Background
The effect of metformin on reducing symptom duration among low-risk, outpatient adults with mild to moderate coronavirus disease 2019 (COVID-19) has not been studied. Our objective was to test metformin compared to placebo for symptom resolution during acute infection with SARS-CoV-2.
Methods
The ACTIV-6 platform clinical trial evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023 and May 1, 2024, 3,214 participants were enrolled at 110 US sites to evaluate metformin. Participants were age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days. Participants were randomized to receive 14 days of metformin (titrated to 1,500mg daily) or placebo. The primary outcome was time to sustained recovery (3 consecutive days without COVID-19 symptoms) within 28 days of receiving study drug. Secondary outcomes included healthcare utilization (clinic visit, emergency department visit, hospitalization or death). Safety events of special interest included hypoglycemia and lactic acidosis.
Results
Among randomized participants who received study drug, the median age was 47 years (IQR 38-58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.4% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1,443 participants who received metformin and 1,548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR], 0.96 [95% credible interval, 0.89-1.03; P(efficacy) = 0.11]). The median time to sustained recovery was 9 days (95% CI 9 to 10) in the metformin group and 10 days (95% CI 9-10) in the placebo group. No deaths were reported; 111 participants reported a clinic visit, emergency department visit, or hospitalization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81, 1.75; P(efficacy)=0.135). There were no episodes of lactic acidosis, and 5 participants in each group reported that they had hypoglycemia. Prespecified analyses support hypotheses about early initiation and use with current variants.
Conclusions
Metformin was not shown to shorten the time to symptom resolution in adults with mild to moderate COVID-19; the median days to symptom resolution was numerically but not significantly lower for metformin than placebo. Emergency department visits and hospitalizations were too infrequent to draw conclusions. This was the first phase 3 trial to randomize adults without chronic disease or disease risk to metformin, and there were no safety concerns.