Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study

Abstract

Background While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. Methods Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. Results 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32–1.44), and mortality (RR 0.82, 0.41–1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28–0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33–0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. Conclusions There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.

Old drug, new tricks: the utility of metformin in infection and vaccination responses to influenza and SARS-CoV-2 in older adults

“…This study showed that metformin use in diabetics was associated with less severe COVID-19 compared with sulfonylurea use but not dipeptidyl-peptidase-4-inhibitors, two other common diabetes medications ( Bramante et al, 2022a ). More specifically, metformin use was associated with a lower risk of ventilation and mortality ( Bramante et al, 2022a ). Further studies also determined that diabetic metformin users who were hospitalized with COVID-19 had a shortened hospital stay duration, a lower rate of intubation, and decreased inflammatory markers compared to diabetics on other oral hypoglycemic medications ( Usman et al, 2022 ).…”

“…One study determined that metformin use was beneficial in preventing severe COVID-19 outcomes in subjects with prediabetes or polycystic ovary syndrome (PCOS, a condition that is commonly treated with metformin off-label) compared to control-matched participants ( Chan et al, 2022 ). Another retrospective study evaluated the associations between metformin use and COVID-19 outcomes in diabetics compared to diabetics on other therapeutically equivalent diabetes monotherapies ( Bramante et al, 2022a ). This study showed that metformin use in diabetics was associated with less severe COVID-19 compared with sulfonylurea use but not dipeptidyl-peptidase-4-inhibitors, two other common diabetes medications ( Bramante et al, 2022a ).…”

“…Another retrospective study evaluated the associations between metformin use and COVID-19 outcomes in diabetics compared to diabetics on other therapeutically equivalent diabetes monotherapies ( Bramante et al, 2022a ). This study showed that metformin use in diabetics was associated with less severe COVID-19 compared with sulfonylurea use but not dipeptidyl-peptidase-4-inhibitors, two other common diabetes medications ( Bramante et al, 2022a ). More specifically, metformin use was associated with a lower risk of ventilation and mortality ( Bramante et al, 2022a ).…”

Risk of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) Among Patients with Type 2 Diabetes Mellitus on Anti-Hyperglycemic Medications

“…Confounders were identified based on clinical assessment of variables associated with the exposures and the outcomes and follows selections used in previous comparisons of these antidiabetic drug classes. 24 Comorbidities and medications of interest were identified from patient records in the previous 12 months using ICD-10 codes and medication lists and were defined using translated OMOP concepts.…”

“… 25 , 26 Several observational analyses in patients with T2DM describe an association between prevalent metformin use and less severe COVID-19 compared to prevalent use of other therapeutic equivalents for T2DM. 24 , 27 However, few observational analyses have assessed PASC as an outcome when comparing metformin use at the time of SARS-CoV-2 infection in adults with T2DM.…”