Metformin at the Time of COVID‐19 Infection and Risk of Long COVID: A Target Trial Emulation Study

Our objective was to evaluate metformin prescribed at the time of SARS-CoV-2 infection on the risk of developing Long COVID (LC) in electronic health record data. We conducted a new user analysis of metformin prescribed within 6 days of documented infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) versus experimental control: prescription for fluvoxamine, fluticasone, ivermectin, or montelukast. INCLUSION CRITERIA: a clinic visit in the 0-6 months and the 6-12 months before infection. EXCLUSION CRITERIA: metformin or control within 12 months. PRIMARY OUTCOME: LC or death (LC/D), to address death as a competing risk, among patients prescribed drug within Days 0-6 of infection. LC was defined by diagnosis code or computable phenotype. We used entropy balancing to estimate the average treatment effect with a weighted log-linear model. After weighting, there were 248 in the metformin and control groups; the average age was 53 (16); 16% were Black; and 16% were Hispanic. In the primary analysis, 10/248 (4.0%) in the metformin group developed LC/D versus 21/248 (8.5%) in the control group, adjusted risk ratio (aRR) 0.47 (95% CI 0.25-0.89, p = 0.02). For prescriptions on Days 0-1 relative to infection, aRR was 0.39 (95% CI 0.12-1.24); for prescriptions on Days 0-14, the aRR was 0.75 (95% CI 0.52-1.08). In this observational analysis, metformin prescribed within a week of documented SARS-CoV-2 infection was associated with a 53% lower risk of LC over 6 months than comparator medications. With the aRR of 0.47 (95% CI 0.25-0.89), any risk reduction between 75% and 11% is highly compatible with our data. This analysis of electronic health record diagnoses is important for the reproducibility of clinical trial results that ascertained the same outcome but via participant-report.