Prevalent Metformin Use in Adults with Diabetes and the Incidence of Long Covid: An EHR-based Cohort Study from the RECOVER Program

Objective: Studies show metformin use before and during SARS-CoV-2 infection reduces severe COVID-19 and post-acute sequelae of SARS-CoV-2 (PASC) in adults. Our objective was to describe the incidence of PASC and possible associations with prevalent metformin use in adults with T2DM. Research Design and Methods: This is a retrospective cohort analysis using N3C and PCORNet EHR databases with an active comparator design that examined metformin-exposed individuals vs non-metformin individuals on other diabetes medications. T2DM was defined by HbA1C>=6.5 or T2DM EHR diagnosis code. The outcome was death or PASC within 6 months, defined by EHR code or computable phenotype. Results: In the N3C, the hazard ratio (HR) for death or PASC-U09.9 was 0.79 (95% CI 0.71-0.88, p<0.001); and for death or PASC-N3C was 0.85 (95% CI 0.78-0.92, p<0.001). In PCORnet, the HR for death or PASC-U09.9 was 0.87 (95% CI 0.66-1.14, p= 0.08); and for death or PASC-PCORnet was 1.04 (95% CI 0.97-1.11, p=0.58). Incident PASC by diagnosis code was 1.6% metformin vs 2.0% comparator in the N3C; 2.1% metformin vs 2.5% comparator in PCORnet. By computable phenotype, incidence was 4.8% metformin and 5.2% comparator in the N3C; 24.7% metformin vs 26.1% comparator in PCORnet. Conclusions: Prevalent metformin use is associated with a slightly lower incidence of death or PASC after SARS-CoV-2 infection. PASC incidence by computable phenotype is higher than by EHR code, especially in PCORnet. These data are consistent with other observational analyses showing prevalent metformin is associated with favorable outcomes after SARS-CoV-2 infection in adults with T2DM.