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Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial
Caio A M Tavares1,2, Luciano C P Azevedo1, Álvaro Rea-Neto3,4,5
1Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil.
Importance:
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown.
Objective:
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.
Design, Setting, And Participants:
Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. 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, with follow-up through September 27, 2023.
Intervention:
Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.
Main Outcomes And Measures:
The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models.
Results:
Among 507 randomized participants (mean age, 63.9 [SD, 15] 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 (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group.
Conclusion And Relevance:
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.
Trial Registration:
ClinicalTrials.gov Identifier: NCT05558098.
Insights
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors like dapagliflozin did not improve outcomes in critically ill patients with organ dysfunction. Further research is needed as confidence intervals were wide, not excluding potential benefits or harms.
Area of Science:
- Critical Care Medicine
- Nephrology
- Cardiology
- Endocrinology
Background:
- Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are established treatments for type 2 diabetes, heart failure, and chronic kidney disease.
- The efficacy of SGLT-2 inhibitors in critically ill patients with acute organ dysfunction remains undetermined.
Purpose of the Study:
- To evaluate the impact of dapagliflozin, an SGLT-2 inhibitor, on clinical outcomes in critically ill patients experiencing acute organ dysfunction.
- To assess whether standard intensive care unit (ICU) care plus dapagliflozin improves patient outcomes compared to standard care alone.
Main Methods:
- A multicenter, randomized, open-label clinical trial involving 507 critically ill patients with at least one organ dysfunction (respiratory, cardiovascular, or kidney).
- Participants received either 10 mg of dapagliflozin plus standard ICU care or standard care alone for up to 14 days or until ICU discharge.
- The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay, analyzed using the win ratio method.
Main Results:
- The addition of dapagliflozin did not significantly improve the primary composite outcome, with a win ratio of 1.01 (95% CI, 0.90-1.13; P=.89).
- A secondary analysis showed a higher probability of benefit for dapagliflozin regarding the use of kidney replacement therapy (10.9% vs 15.1%).
- Confidence intervals for the primary outcome were wide, precluding definitive conclusions about potential benefits or harms.
Conclusions:
- Dapagliflozin, when added to standard care, did not demonstrate a significant improvement in clinical outcomes for critically ill patients with acute organ dysfunction.
- The wide confidence intervals indicate uncertainty regarding the true effect of dapagliflozin in this population.
- Further investigation is warranted to clarify the role and safety of SGLT-2 inhibitors in critical care settings.
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