American Diabetes Association
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Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium–Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes

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Version 3 2021-06-25, 14:48
Version 2 2021-06-25, 14:48
Version 1 2021-06-16, 19:42
posted on 2021-06-25, 14:48 authored by Anna R. Kahkoska, Trine Julie Abrahamsen, G. Caleb Alexander, Tellen D. Bennett, Christopher G. Chute, Melissa A. Haendel, Klara R. Klein, Hemalkumar Mehta, Joshua D. Miller, Richard A. Moffitt, Til Stürmer, Kajsa Kvist, John B. Buse, N3C Consortium
Objective: To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose-linked cotransporter 2 inhibitors (SGLT2i) use, compared to premorbid dipeptidyl peptidase-4 inhibitor (DPP4i) use, with severity of outcomes in the setting of COVID-19 infection.

Research Design and Methods: We analyzed observational data from SARS-CoV-2-positive adults in the National COVID Cohort Collaborative, a multicenter, longitudinal U.S. cohort (January 2018–February 2021) with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period, and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics.

Results: The study included 12,446 individuals (53.4% female, 62.5% White, mean±SD age 58.6±13.1 years). The 60-day mortality was 3.11% (387/12,446), with 2.06% (138/6,692) for GLP1-RA use, 2.32% (85/3,665) for SGLT2i use, and 5.67% (199/3,511) for DPP4i use. Both GLP1-RA and SGLT2i use was associated with lower 60-day mortality compared to DPP4i use (OR (95% confidence intervals (95%CI)): 0.54 (0.37–0.80) and 0.66 (0.50–0.86), respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations.

Conclusions: Among SARS-CoV-2-positive adults, premorbid GLP1-RA and SGLT2i use, compared to DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.


A.R.K. is supported by the National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health under Award Number F30DK113728. J.B.B. effort was supported by grants from the National Institutes of Health’s National Center for Advancing Translational Sciences (UL1TR002489) and National Institute of Diabetes and Digestive and Kidney Disease (P30DK124723). T.S. receives investigator-initiated research funding and support as Principal Investigator (R01 AG056479) from the National Institute on Aging (NIA), and as Co-Investigator (R01 HL118255, R01MD011680), National Institutes of Health (NIH). T.D.B. receives research funding from NIH/NICHD and NIH/NCATS. This work was supported, in part, by NCATS UL1 TR002535 and NCATS UL1 TR002535 03S2. The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave and supported by NCATS U24 TR002306. This research was possible because of the patients whose information is included within the data and the organizations (see and scientists who have contributed to the on-going development of this community resource (19). N3C is supported by the following grant sources: Carilion Clinic (UL1TR003015-02S2: Provision of Clinical Data to Support a Nationwide COVID-19 Cohort Collaborative); George Washington Children's Research Institute (UL1TR001876: Clinical and Translational Science Institute at Children's National); Duke University (UL1TR002553: Duke CTSA); Johns Hopkins University (UL1TR003098: Johns Hopkins Institute for Clinical and Translational Research); Mayo Clinic Rochester (UL1TR002377: Mayo Clinic Center for Clinical and Translational Science); Medical University of South Carolina (UL1TR001450: South Carolina Clinical & Translational Research Institute SCTR); Penn State Health Milton S. Hershey Medical Center (UL1TR002014: Penn State Clinical and Translational Science Institute); Rush University M