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

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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
The Lancet Diabetes & Endocrinology ( IF 44.0 ) Pub Date : 2021-07-21 , DOI: 10.1016/s2213-8587(21)00180-7
Mikhail N Kosiborod ₁ , Russell Esterline ₂ , Remo H M Furtado ₃ , Jan Oscarsson ₄ , Samvel B Gasparyan ₄ , Gary G Koch ₅ , Felipe Martinez ₆ , Omar Mukhtar ₇ , Subodh Verma ₈ , Vijay Chopra ₉ , Joan Buenconsejo ₂ , Anna Maria Langkilde ₄ , Philip Ambery ₄ , Fengming Tang ₁₀ , Kensey Gosch ₁₀ , Sheryl L Windsor ₁₀ , Emily E Akin ₁₁ , Ronaldo V P Soares ₁₂ , Diogo D F Moia ₁₂ , Matthew Aboudara ₁₃ , Conrado Roberto Hoffmann Filho ₁₄ , Audes D M Feitosa ₁₅ , Alberto Fonseca ₁₆ , Vishnu Garla ₁₇ , Robert A Gordon ₁₈ , Ali Javaheri ₁₉ , Cristiano P Jaeger ₂₀ , Paulo E Leaes ₂₁ , Michael Nassif ₁₀ , Michael Pursley ₂₂ , Fabio Serra Silveira ₂₃ , Weimar Kunz Sebba Barroso ₂₄ , José Roberto Lazcano Soto ₂₅ , Lilia Nigro Maia ₂₆ , Otavio Berwanger ₁₂

Affiliation

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.
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.

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.

中文翻译：

达格列净治疗因 COVID-19 住院的有心脏代谢危险因素的患者 (DARE-19)：一项随机、双盲、安慰剂对照的 3 期试验

背景

COVID-19 可导致多器官衰竭。Dapagliflozin 是一种 SGLT2 抑制剂，对心脏和肾脏具有显着的保护作用。我们的目的是了解这种药物是否可以通过影响急性疾病期间失调的过程来为 COVID-19 患者提供器官保护。

方法

DARE-19 是一项随机、双盲、安慰剂对照试验，对象是因 COVID-19 住院且至少有一个心脏代谢危险因素（即高血压、2 型糖尿病、动脉粥样硬化性心血管疾病、心力衰竭和慢性肾病）的患者). 筛选时病情危重的患者被排除在外。患者按 1:1 的比例随机分配至达格列净（每日口服 10 毫克）或匹配的安慰剂组，为期 30 天。在意向治疗人群中评估了双重主要结果：预防结果（出现新的或恶化的器官功能障碍或死亡的时间），以及恢复的分层复合结果（第 30 天临床状态的变化）。在接受至少一剂研究药物治疗的患者中，安全性结果包括严重不良事件、导致停药的不良事件和感兴趣的不良事件。

发现

2020 年 4 月 22 日至 2021 年 1 月 1 日期间，1250 名患者被随机分配，每组 625 名。预防的主要复合结局显示达格列净组 70 名患者 (11·2%) 和安慰剂组 86 名 (13·8%) 患者发生器官功能障碍或死亡（风险比 [HR] 0·80, 95%置信区间 0·58–1·10；p=0·17）。对于恢复这一主要结局，达格列净组 547 名 (87·5%) 患者和安慰剂组 532 名 (85·1%) 患者的临床状况有所改善，尽管这在统计学上并不显着（胜率 1·09、95 % 置信区间 0·97–1·22；p=0·14）。达格列净组有 41 例 (6·6%) 死亡，安慰剂组有 54 例 (8·6%) 死亡 (HR 0·77，95% CI 0·52–1·16)。613 名接受达格列净治疗的患者中有 65 名 (10·6%) 和接受安慰剂治疗的 616 名患者中有 82 名 (13·3%) 报告了严重不良事件。