Metformin Halves Long COVID Risk in Landmark ACTIV-6 Randomized Trial
New evidence from the large-scale ACTIV-6 (NCT04885530) randomized clinical trial, published in Clinical Infectious Diseases on June 4, 2026, demonstrates that the common and inexpensive diabetes medication metformin can significantly reduce the risk of developing long-term chronic symptoms following a COVID-19 infection. The trial revealed a 50% relative reduction in clinician-diagnosed long COVID—formally known as post-acute sequelae of SARS-CoV-2 (PASC)—at six months when metformin was started within seven days of acute symptom onset.
The ACTIV-6 trial evaluated nearly 3,000 outpatient adults aged 30 and older with mild-to-moderate COVID-19 across 90 sites in the United States. Crucially, 83% of the participants had prior immunity from vaccination, previous infection, or both, making the findings highly representative of contemporary population immunity. Participants received a 14-day pragmatic regimen of immediate-release metformin or a placebo:
- Day 1: 500 mg once daily
- Days 2–5: 500 mg twice daily
- Days 6–14: 1500 mg daily (500 mg in the morning, 1000 mg in the evening)
While the trial’s primary endpoint—the total prevention of all self-reported symptoms at Day 180—did not meet the strict threshold for statistical significance, the clinical benefit was stark for formal medical diagnoses. Clinician-diagnosed long COVID occurred in just 0.56% of the metformin group compared to 1.17% of the placebo group by the six-month mark. These results replicate and confirm findings from the earlier COVID-OUT (NCT04510194) trial, which also demonstrated a similar 40% to 50% relative risk reduction.
Mechanistically, researchers believe metformin's protective effect is host-directed. It is hypothesized that SARS-CoV-2 activates the mammalian target of rapamycin complex 1 (mTORC1) in the gut, damaging the epithelial barrier and fueling systemic inflammation. Metformin is believed to inhibit mTORC1 signaling while promoting beneficial gut bacteria that produce short-chain fatty acids (SCFAs), thereby preserving gut integrity and lowering systemic viral replication. No safety signals for lactic acidosis or significant hypoglycemia were detected, even among non-diabetic participants.
"This trial provides additional evidence that treating acute infection with this intervention that acts on metabolic health can reduce the likelihood of developing long COVID. The finding is particularly important because metformin is inexpensive, globally available, and has decades of clinical use supporting its safety." — Dr. Carolyn Bramante, MD, MPH, Assistant Professor at the University of Minnesota Medical School, in a University of Minnesota / EurekAlert Press Release