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

ABSTRACT

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.