麻豆果冻传媒影音

Adding an SGLT2 inhibitor to standard care did not improve clinical outcomes in critically ill patients with acute organ dysfunction, an open-label randomized trial involving intensive care units (ICUs) in Brazil found.

In the study of some 500 patients, the primary outcome -- a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and length of stay in the ICU through 28 days -- showed no difference for patients randomized to oral dapagliflozin (Farxiga) or standard care alone, with a win ratio of 1.01 (95% CI 0.90-1.13, P=0.89), reported Fernando Zampieri, MD, PhD, of the Hospital Israelita Albert Einstein in São Paulo, Brazil, and colleagues in .

Of the seven secondary endpoints, there was only a potential suggestion of benefit when it came to the initiation of kidney replacement therapy, according to findings of the DEFENDER trial, which were simultaneously presented at the meeting in Belfast, Ireland.

"Despite a neutral result for the primary endpoint, dapagliflozin use appeared safe in a population of critically ill patients with a hospital mortality rate of 35%," wrote Zampieri and co-authors. "More specifically, adverse events of interest that have been suggested to occur with dapagliflozin use, including bloodstream or urinary infections, were uncommon and occurred at similar rates in both groups, and no ketoacidosis event was reported during the trial."

Several agents in the class of SGLT2 inhibitors, including dapagliflozin, are approved for type 2 diabetes, heart failure, and/or chronic kidney disease (CKD), based on their ability to reduce the risk of cardiovascular death, heart failure hospitalizations, and CKD progression with long-term use.

But their potential benefit in critically ill patients with organ failure is unknown, the researchers explained.

"Experimental models that simulate acute ICU conditions reveal that SGLT2 inhibitors attenuate inflammation and provide protection against organ injury," noted Zampieri and colleagues. "In particular, nephroprotective effects of SGLT2 inhibitors may be of interest to those treating critically ill populations, given the high incidence of acute kidney injury in this population."

Furthermore, noted Hernando Gómez, MD, MPH, of the University of Pittsburgh, and Lennie P. G. Derde, MD, PhD, of the University of Utrecht in the Netherlands, "data from large randomized trials also suggest that long-term SGLT2 inhibition may reduce the incidence of acute organ dysfunction, raising the possibility of benefit in critically ill patients."

"Arguably, the organ dysfunction most likely to have been improved by SGLT2 inhibition therapy [in DEFENDER] would have been acute kidney injury," they noted in an . "However, this study enrolled patients at low risk of acute kidney injury."

Still, Gómez and Derde said, as no specific treatment can prevent or reverse acute organ dysfunction, along with "the indirect evidence supporting a role for SGLT2 inhibitors in modifying the course of organ injury and dysfunction, particularly in the kidney, and the evidence from DEFENDER that the therapy appeared safe, there will hopefully be further investigations into the role of these therapies in critical illness."

From November 2022 to August 2023, randomized 507 critically ill adults with acute organ dysfunction at 22 ICUs in Brazil to either standard care plus oral dapagliflozin (10 mg once daily) or standard care alone. Dapagliflozin was administered for 14 days or until discharge from the ICU.

Participants were excluded if they had organ dysfunction for more than 24 hours, end-stage kidney disease, type 1 diabetes, a history of diabetic ketoacidosis, a planned ICU admission for an elective surgery, or previously used an SGLT2 inhibitor.

Patients were otherwise an unselected and heterogeneous population, according to Zampieri and colleagues. They had a mean age of 64 years, 47% were women, and more than 70% were white. Patients were most commonly admitted to the ICU for infections (40%), followed by cardiovascular (32%), neurological (12-15%), or other reasons. About half met study entry criteria due to needing respiratory support, 42-48% had hypotension, and 40-43% had acute kidney injury.

Secondary outcomes (all through day 28) included hospital mortality (35.5% in the dapagliflozin group vs 34.4% among controls); initiation of kidney replacement therapy (10.9% vs 15.2%, respectively); along with days free of the ICU (median 18 vs 16.5 days), hospital (8.5 vs 2.5 days), mechanical ventilation (25 vs 23 days), kidney replacement therapy (29 vs 29 days), and vasopressors (26 vs 25 days).

Serious adverse events occurred in 46% of the dapagliflozin group and 48% of controls, the most common of which included infections and infestations (20% vs 22%, respectively), cardiac disorders (11% in each group), and kidney and urinary disorders (9% vs 13%).

Beyond the open-label design, other potential limitations included the heterogeneous population and the possibility of inadequate dapagliflozin absorption, the researchers said.

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