Dapagliflozin fails to improve outcomes in critically ill patients with acute organ dysfunction: DEFENDER Trial findings

The multicenter, open-label, randomized clinical trial that included 507 participants with at least one acute organ dysfunction (kidney injury, respiratory, hypotension) revealed that dapagliflozin, in addition to standard care for individuals with critical illness and acute organ dysfunction failed to improve outcomes.

"The use of 10 mg of dapagliflozin for up to 14 days did not significantly reduce the combined outcome of initiation of kidney replacement therapy, hospital mortality, and ICU length of stay, assessed by the win ratio method (win ratio, 1.01, not significant) through 28 days after randomization," the researchers reported. The findings were published online in the Journal of the American Medical Association (JAMA).

SGLT-2 inhibitors improve outcomes in patients with heart failure, type 2 diabetes, and chronic kidney disease. Still, their effect on the outcomes of critically ill patients with organ failure is unknown. Considering this, Caio A. M. Tavares, Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil, and colleagues aimed to determine whether dapagliflozin addition to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction.

For this purpose, the researchers conducted a multicenter, randomized, open-label, clinical trial at 22 ICUs in Brazil. It enrolled participants with unplanned ICU admission and presenting with at least one organ dysfunction (kidney, cardiovascular, or respiratory) between 2022 and 2023.

Participants were randomized to dapagliflozin 10 mg (intervention, n = 248) plus standard care or standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.

The primary outcome was a hierarchical composite of initiation of kidney replacement therapy, hospital mortality, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes were the individual components of the hierarchical outcome, duration of organ support–free days, hospital stay, and ICU assessed using Bayesian regression models.

The following were the key findings of the study:

• Among 507 randomized participants (mean age, 63.9 years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day.
• The win ratio for dapagliflozin for the primary outcome was 1.01.
• Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding kidney replacement therapy use among 10.9% of patients in the dapagliflozin group vs 15.1% in the control group.

"Dapagliflozin added 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 harms or benefits for dapagliflozin," the researchers concluded.

Reference:

Tavares CAM, Azevedo LCP, Rea-Neto Á, et al. Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial. JAMA. Published online June 14, 2024. doi:10.1001/jama.2024.10510