R3 Seminar Recap: Understanding metformin use and Long COVID and ME/CFS following COVID-19 infection: Insights from two studies

Drawing from both large-scale electronic health record (EHR) networks and RECOVER’s adult observational study, these studies illustrate critical links among COVID-19, persistent post-viral conditions, and potential prevention strategies involving available pharmaceutical drugs. While metformin’s exact mechanisms are still being explored by researchers, evidence supporting its use during acute COVID-19 infection continues to grow.

Drs. Bramante and Johnson led an EHR study analyzing data from the National COVID Cohort Collaborative (N3C) and the National Patient-Centered Clinical Research Network (PCORnet). Their study focused on adults with type 2 diabetes. They compared Long COVID outcomes between individuals already taking metformin and those using other diabetes medications, a type of study design known as “prevalent user, active comparator.” In other words, the researchers aimed to evaluate the association between pre-existing metformin use and the risk of developing Long COVID. Results showed a consistent trend: individuals on metformin were less likely to develop Long COVID compared to those not taking the drug. These findings aligned with earlier clinical trial data, including a randomized controlled study conducted by Dr. Bramante and the University of Minnesota’s COVID-OUT Study Team, which reduced Long COVID incidence by 31% through early metformin treatment.

Dr. Bramante noted that many clinicians remain unaware of metformin’s potential role beyond diabetes management. Although prescribing metformin off-label for COVID-19 prevention is legally permissible, this guidance is not yet reflected in most COVID-19 treatment guidelines—some of which are based on earlier clinical trials with less definitive results.

Dr. Vernon presented research findings from the RECOVER adult observational study examining risk of developing ME/CFS following a COVID-19 infection. ME/CFS is a chronic, disabling illness that includes symptoms such as severe fatigue; tiredness that gets much worse after physical, mental, or emotional activity; sleep that is not deep or restful; trouble remembering, learning new things, concentrating, or making decisions; and dizziness or other problems resulting from standing upright. Using the 2015 ME/CFS clinical diagnostic criteria from the National Academy of Medicine (formerly the Institute of Medicine), Dr. Vernon and her team found that:

• Approximately 1 in 20 people who had COVID-19 met the criteria for ME/CFS 6 months after infection.
• The estimated number of US adults with ME/CFS is over 15 million, compared with an estimate of about 3 million adults who had ME/CFS before the COVID-19 pandemic.
• Risk for ME/CFS was significantly higher among those who had a SARS-CoV-2 infection compared to individuals who did not have an infection in the study.
• ME/CFS cases were concentrated within the subgroups of Long COVID patients who displayed the greatest number of observable symptoms.

Dr. Vernon emphasized that medical teams must consider ME/CFS among the various diagnosable conditions that often follow COVID-19. RECOVER’s robust biosample collection and longitudinal studies provide an unprecedented opportunity to study how ME/CFS affects the body’s normal functioning. These resources also may provide the opportunity to develop diagnostic biomarkers for the condition, or indicators of ME/CFS that clinical laboratory tests can identify and that reliably pinpoint the presence of the condition.

To find recordings and transcripts of more R3 seminars, visit the RECOVER YouTube channel and the R3 webpage.