Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID-19: Design and rationale for the DARE-19 study

Abstract

Aims: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19.

Materials and methods: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed.

Conclusions: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.

Keywords: SGLT2 inhibitor; clinical trial; dapagliflozin; phase III study; randomized trial.

FIGURE 1

Primary action of dapagliflozin is on the SGLT2s expressed on the proximal tubules of the nephrons of the kidney. SGLT2 inhibition results in an immediate adaptive response to minimize loss of water and sodium. Loss of glucose is balanced by increased endogenous glucose production. ⁴¹ , ⁴⁵ The new homeostasis may be responsible for the favourable effects of dapagliflozin on the cardiovascular, renal and immune functions. The effects on glucose control, including insulin demand, endothelial function, oxidative stress, oxygen delivery capacity, congestion and inflammation ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ⁴² , ⁴³ are probably most important to protect from worsening of organ function in hospitalized patients with COVID‐19 and medical history with risk factors, including hypertension, T2D, HF, CKD and obesity. CKD, chronic kidney disease; HF, heart failure; SGLT2i, sodium‐glucose cotransporter 2 inhibitor; T2D, type 2 diabetes

FIGURE 2

Study flow chart

FIGURE 3

Primary endpoints and components. A, First primary endpoint is a composite of new/worsened organ dysfunction during the index hospitalization or death from any cause at any time during the 30‐day treatment period. New/worsened organ dysfunction is defined as at least one of the following: respiratory decompensation requiring initiation of mechanical ventilation (includes invasive or non‐invasive ventilation, continuous positive airway pressure or bilevel positive airway pressure), and/or initiation of ECMO; new or worsening congestive heart failure (HF); requirement for vasopressor therapy and/or inotropic or mechanical circulatory support; ventricular tachycardia or fibrillation lasting at least 30 s and/or associated with haemodynamic instability or pulseless electrical activity, or resuscitated cardiac arrest; doubling of serum creatinine or initiation of renal replacement therapy. Congestive HF defined as at least one of the following: initiation of new intravenous therapy for HF; reinstitution of previous intravenous therapy for HF; increase in current intravenous therapy for HF. This is based on modification of a previous definition of in‐hospital worsening HF. B, Second primary endpoint is the hierarchical composite outcome measure (by increasing severity): 1. Death from any cause through day 30; 2. New/worsened organ dysfunction (as defined above); 3. Clinical status at day 30 for patients still hospitalized and without any worsening organ dysfunction (hospitalized, on high flow oxygen devices; hospitalized, requiring supplemental oxygen; hospitalized, not requiring supplemental oxygen); 4. Hospital discharge before day 30 and alive at day 30