Two Trials Show Paxlovid and Metformin May Prevent Long COVID — But Physicians Are Split

Two rigorous randomized, placebo-controlled trials — the first of their kind — suggest that common drugs taken during acute COVID-19 infection may prevent long COVID, Nature reported this week. A Paxlovid trial published in The Lancet Infectious Diseases found a roughly 40% reduction in long-COVID risk at three months: 26% of treated participants reported at least one long-COVID symptom versus 43% on placebo. The trial, led by Nina Langeland of the University of Bergen, involved 144 people with recent infections.

The Metformin Result

A separate 2,983-participant metformin trial, led by Carolyn Bramante of the University of Minnesota and published in Clinical Infectious Diseases, found the drug cut healthcare-provider-diagnosed long COVID at six months by about half — 0.7% versus 1.4% on placebo. Notably, the trial did not meet its primary endpoint of reducing self-reported COVID symptoms at six months; the doctor-diagnosed reduction was a secondary endpoint, which fuels part of the scientific debate.

Prevention, Not Cure

Physicians are split. Supporters including David Smith (UC San Diego) and Timothy Henrich (UCSF) say early viral-load reduction plausibly lowers post-infection symptoms and are prepared to discuss the drugs with patients. Skeptics such as Walid Gellad (University of Pittsburgh) and Jonathan Li (Brigham and Women's Hospital) question the 43% placebo rate in the Paxlovid trial versus ~8% in prior analyses, and note neither drug is FDA-approved for long-COVID prevention. The NIH's RECOVER-VITAL and RECOVER-ENERGIZE trials found both drugs fail to treat established long COVID — underscoring that the window is early infection, not chronic illness.