Multicenter, randomized, open-label, clinical trial

N= 507

To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction

Dapagliflozin group (n= 248)

Control group (n= 259)

Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023

Presence of organ dysfunction criteria for more than 24 hours, end-stage kidney disease undergoing maintenance dialysis, prior use of dapagliflozin or other SGLT-2 inhibitor, known type 1 diabetes, a history of diabetic ketoacidosis, and planned ICU admission following elective surgery

Participants were randomized to 10 mg of dapagliflozin plus standard care or to standard care alone for up to 14 days or until ICU discharge. Dapagliflozin was administered orally or enterally if necessary. Adherence was assessed daily for 14 days.

November 22, 2022, to August 30, 2023, with follow-up through September 27, 2023

Primary: Hierarchical composite of hospital mortality, initiation of kidney replacement therapy (KRT), and ICU length of stay through 28 days

Secondary: Individual components of the hierarchical outcome, duration of organ support–free days, ICU, and hospital stay

Serious adverse events were similar between groups. Adverse events of special interest included urinary tract infections (1.6% vs 1.2%), hypoglycemia (0.8% vs 0%), and bloodstream infections (0.4% vs 1.5%). No cases of ketoacidosis were reported.

The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.

The study was well-designed with a large sample size and multicenter approach, enhancing its generalizability. However, the open-label design may introduce bias, and the heterogeneous population may dilute potential effects in specific subgroups. The lack of blinding and absence of biological response data are notable limitations.

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

Randomised, double-blind, placebo-controlled, phase 3 trial

N=1250

To evaluate the efficacy and safety of dapagliflozin in providing organ protection in patients with COVID-19 who have cardiometabolic risk factors

Dapagliflozin (n=625)

Placebo (n=625)

Hospitalised with laboratory confirmed or clinically suspected SARS-CoV-2 infection, oxygen saturation of 94% or greater on supplemental oxygen, chest radiography findings consistent with COVID-19 pneumonia, and at least one cardiometabolic risk factor: hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease

Patients were randomly assigned to receive dapagliflozin 10 mg daily or placebo for 30 days. Monitoring included daily assessments of vital signs, laboratory tests, and organ dysfunction. If mechanical ventilation was necessary, medication was administered via feeding tube

April 22, 2020 to January 1, 2021

Primary: Prevention of new or worsened organ dysfunction or death, recovery (change in clinical status by day 30)

Secondary: Composite kidney outcome, death from any cause, total number of days alive and free from mechanical ventilation, time to hospital discharge

Total (N=1250)

p-value

Serious adverse events were reported in 65 (10.6%) of patients treated with dapagliflozin and in 82 (13.3%) of patients given the placebo. Diabetic ketoacidosis was reported in two patients in the dapagliflozin group

In patients with cardiometabolic risk factors 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.

The study was well-designed as a multicentre, randomised, double-blind, placebo-controlled trial, which is a strength. However, the lower-than-anticipated event rates due to improvements in standard care may have limited the ability to detect statistically significant differences. Additionally, the study's findings may not be generalisable to all populations due to specific eligibility criteria and the modest proportion of patients receiving remdesivir and systemic corticosteroids.