Metformin on Time to Sustained Recovery in Adults with COVID-19: The ACTIV-6 Randomized Clinical Trial
Authors: Bramante Carolyn T. , Stewart Thomas G. , Boulware David R. , McCarthy Matthew W. , Gao Yue , Rothman Russell L. , Mourad Ahmad , Thicklin Florence , Cohen Jonathan B. , Garcia del Sol Idania T. , Ruiz-Unger Juan , Shah Nirav S. , Mehta Manisha , Cardona Orlando Quintero , Scott Jake , Ginde Adit A. , Castro Mario , Jayaweera Dushyantha , Sulkowski Mark , Gentile Nina , McTigue Kathleen , Felker G. Michael , Collins Sean , Dunsmore Sarah E. , Adam Stacey J. , Lindsell Christopher J. , Hernandez Adrian F. , Naggie Susanna ,   the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators
Published: January 2025

Importance

The effect of metformin on reducing symptom duration among outpatient adults with coronavirus disease 2019 (COVID-19) has not been studied.

Objective

Assess metformin compared with placebo for symptom resolution during acute infection with SARS-CoV-2.

Design, Setting, and Participants

The ACTIV-6 platform evaluated repurposed medications for mild to moderate COVID-19. Between September 19, 2023, and May 1, 2024, 2991 participants age ≥30 years with confirmed SARS-CoV-2 infection and ≥2 COVID-19 symptoms for ≤7 days, were included at 90 US sites.

Interventions

Participants were randomized to receive metformin (titrated to 1500 mg daily) or placebo for 14 days.

Main Outcomes and Measures

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 time to hospitalization or death; time to healthcare utilization (clinic visit, emergency department visit, hospitalization, or death). Safety events of special interest were hypoglycemia and lactic acidosis.

Results

Among 2991 participants who were randomized and received study drug, the median age was 47 years (IQR 38–58); 63.4% were female, 46.5% identified as Hispanic/Latino, and 68.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 1443 participants who received metformin and 1548 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [aHR] 0.96; 95% credible interval [CrI] 0.89–1.03; P(efficacy)=0.11). For participants enrolled during current variants, the aHR was 1.19 (95% CrI 1.05–1.34). The median time to sustained recovery was 9 days (95% confidence interval [CI] 9–10) for metformin and 10 days (95% CI 9–10) for placebo. No deaths were reported; 111 participants reported healthcare utilization: 58 in the metformin group and 53 in the placebo group (HR 1.24; 95% CrI 0.81–1.75; P(efficacy)=0.135). Seven participants who received metformin and 3 who received placebo experienced a serious adverse event over 180 days. Five participants in each group reported having hypoglycemia.

Conclusions and Relevance

In this randomized controlled trial, 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. Safety was not a limitation in the study population.

Trial Registration

ClinicalTrials.gov(NCT04885530).