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Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.

Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: mkosiborod@saint-lukes.org. Late-stage Development, CVRM, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA. Academic Research Organization-Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Instituto do Coracao do Hospital das Clinicas da FMUSP, Sao Paulo, Brazil. Late-stage Development, CVRM, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. National University of Córdoba, Córdoba, Argentina. Experimental Medicine and Immunotherapeutics Division, Department of Medicine, University of Cambridge, Cambridge, UK. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, ON, Canada; Department of Surgery and Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Max Super Speciality Hospital, New Delhi, India. Saint Luke's Mid America Heart Institute, Kansas City, MO, USA. George Clinical Inc, Overland Park, KS, USA. Academic Research Organization-Hospital Israelita Albert Einstein, Sao Paulo, Brazil. Division of Pulmonary and Critical Care, Saint Luke's Health System, Kansas City, MO, USA. Hospital Regional Hans Dieter Schmidt, Joinville, Brazil. PROCAPE, Recife, Brazil. Hospital Coracao do Brasil, Brasília, Brazil. Department of Endocrinology, Diabetes and Metabolism, Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Clinical and Translational Research, Jackson, MI, USA. North Shore University Health System, Evanston, IL, USA. Washington University School of Medicine, St Louis, MO, USA. Hospital Mãe de Deus, Porto Alegre, Brazil. Irmandade Da Santa Casa de Misericórdia de Porto Alegre, Brazil. Heart Group of the Eastern Shore, Fairhope, AL, USA. Centro de Pesquisa Clínica do Coração, Aracaju, Brazil. Liga de Hipertensão Arterial -Universidade Federal de Goiás, Brazil; HCAMP-Secretaria Estadual de Saúde, Goiás, Brazil. Instituto de Investigaciones Aplicadas a la Neurociencia AC, Durango City, Mexico. Centro Integrado de Pesquisas, Hospital de Base, São José do Rio Preto, Brazil.

The lancet. Diabetes & endocrinology. 2021;(9):586-594
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Abstract

BACKGROUND COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. METHODS DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593. FINDINGS Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58-1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97-1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52-1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. INTERPRETATION In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. FUNDING AstraZeneca.

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