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Dapagliflozin (Farxiga) didn't significantly help hospitalized COVID-19 patients in the phase III DARE-19 trial, but it did appear safe in that setting, which might have broader implications.

The SGLT2 inhibitor showed a nonsignificant 20% relative reduction in organ failure or death from any cause (11.2% vs 13.8%, P=0.168), reported Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute in Kansas City, Missouri, at the American College of Cardiology (ACC) virtual meeting.

The co-primary endpoint of recovery, driven by time to discharge, didn't show a significant advantage either (win ratio 1.09, 95% CI 0.97-1.22).

If the trial had been powered with 3,000 to 5,000 patients, the differences likely would have been statistically significant, Kosiborod told ACC attendees.

That effect, while not significant, was "compelling and certainly consistent with the treatment effect of SGLT2 inhibitors in trials of other diagnoses," noted James Januzzi Jr., MD, of Massachusetts General Hospital in Boston. He pointed out that an impact on the organ failure and death outcome might have undermined the recovery endpoint.

However, severe and fatal adverse events were actually numerically less common with dapagliflozin, as was acute kidney injury. Diabetic ketoacidosis (DKA) occurred in two patients in the dapagliflozin group, both with diabetes, but again without a significant difference compared with placebo.

What may be the most important finding was the safety of dapagliflozin in this acutely ill population, Januzzi said, "since it's become routine to stop SGLT2 inhibitors when patients are admitted to the hospital to avoid risk of ketoacidosis."

Some groups recommend stopping SGLT2 inhibitors (SGLT2i) for COVID-19 patients, even for patients with conditions like diabetes and heart failure where there has been a proven benefit, Kosiborod noted.

"The results of DARE-19 suggest that, with careful monitoring of ketoacidosis, these agents should be continued," Januzzi said.

The trial included 1,250 adults hospitalized with confirmed or strongly suspected COVID-19 who were randomized to 30 days of dapagliflozin (10 mg/day) or matching placebo. Patients were enrolled from seven countries, but the majority were in the U.S. and Mexico.

Dapagliflozin was continued for the full 30 days even if patients were discharged from the hospital. The trial almost exclusively enrolled patients from the general wards rather than those whose COVID-19 was already severe enough to require ICU care. However, Kosiborod noted that many patients did end up in the ICU after enrollment.

"DARE-19 raises a hypothesis that SGLT2i may afford organ protection in other types of acute illness," he said. "This should be evaluated in future trials."

This hypothesis is worth exploring in sepsis and other similar acute illness, Kosiborod added.

The rationale for trying dapagliflozin in COVID-19 is that the latter's damage mirrors some of the same as with metabolic syndrome and type 2 diabetes. SGLT2 inhibitors also make sense mechanistically as they reverse a lot of the processes adversely impacted by viruses like SARS-CoV-2 -- for example, improving endothelial function, reducing inflammation and insulin levels, and inhibiting glycolysis, Kosiborod previously noted.

There's definitely an opportunity to study the drug more broadly in acute illness, as the drug appears to act fairly quickly, commented Sanjeev Gulati, MD, of Sanger Heart & Vascular Institute in Charlotte, North Carolina.

Certainly for COVID-19 patients, these findings give confidence in not stopping the with good monitoring, including after discharge, he said.

"That's where it really helps all the providers, not only the cardiologists, but the people in the hospital taking care of those patients, whether it's pulmonary critical care taking care of the COVID patients and then the hospitalists -- even primary care in the 30 days after leaving the hospital -- to keep a closer eye for complications like DKA, but feeling confident so you can keep these patients on that medication," he said. "There's a lot of data to show that when you leave the hospital with heart failure and you are not on certain medications, that they [medications] don't get restarted or there are often delays in getting started."

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