DARE-19 Shows SGLT2 Inhibitor Potential for Multi-Organ Protection

Mikhail Kosiborod, MD

A clinical assessment review for an SGLT-2 inhibitor in treating patients hospitalized with COVID-19 raised the hypothesis that the popular cardiometabolic drug class may provide multi-organ protection for acute illness—just not significantly so for COVID-19.

In a presentation at The Metabolic Institute of America’s (TMIOA) 2021 Heart in Diabetes sessions in New York, NY, findings from the Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial were discussed in relation to the potential of the agent in acute care settings.

Led by DARE-19 trial author Mikhail Kosiborod, MD, Professor of Medicine at Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City School of Medicine, the presentation expanded on the data previously reported at the American College of Cardiology (ACC) 2021 Sessions earlier this year: dapagliflozin did not significantly reduce patient risk of composite all-cause death or new/worsened organ dysfunction in patients hospitalized with COVID-19, but it also did not indicate the need to discontinue dapagliflozin nor other SGLT-2 inhibitors in such patients.

Rather, Kosiborod explained, the agent was associated with statistically insignificant improvements in mortality and organ dysfunction risk versus placebo, all while being tolerable. He defended the prospect of SGLT-2 inhibitors benefitting multiple organ systems amid acute illness.

As Kosiborod explained, the severe forms of illness associated with SARS-CoV-2 infection includes processes that are prevalent in cardiovascular, diabetic, and renal diseases and are treated with SGLT-2 inhibitors: endothelial dysfunction, inflammation, vascular damage, and increased oxidative stress.

“As the pandemic was ongoing, one of the things that occurred to myself and several other people who ultimately led the DARE-19 trial was that we had a class of agents that we already knew could protect at least certain organs,” Kosiborod said.

There’s also “clearly a relationship” between obesity, insulin resistance, and susceptibility to worsened COVID-19 outcomes, Kosiborod noted—a pair of factors which SGLT2 inhibitors are indicated to help treat in patients with cardiometabolic disease.

The DARE-19 trial included patients hospitalized with confirmed or suspected SARS-CoV-2 infection for ≤4 days, with ≥94% oxygen saturation and 1 or more risk factors for severe disease such as hypertension, type 2 diabetes, atherosclerosis, heart failure, or chronic kidney disease. Kosiborod and colleagues observed a 30-day treatment period following screening and 1:1 randomization to either 10 mg daily dapagliflozin or placebo plus standard care; a 60-day observational follow-up was conducted after the last treatment dose.

From March to August 2020, the investigators observed a “precipitous,” 5-fold adjusted COVID-19 mortality rate decrease. However, as noted in discussions during and after the presentation, this rate may have been influenced by the advancement of standard COVID-19 therapy.

Hospitalized COVID-19 patients treated with dapagliflozin experienced 70 total composite endpoint events in 30 days (11.2%), versus 86 events (13.8%) in patients treated with placebo (hazard ratio [HR], 0.80; 95% CI, 0.58 - 1.10; P = .168). All-cause death was slightly more greatly reduced with dapagliflozin (HR, 0.77; 95% CI, 0.52 - 1.16).

Kosiborod additionally noted that primary composite endpoint prevention did not differ among patients with and without diabetes. What’s more, patients treated with dapagliflozin reported fewer severe adverse events (n = 65) than patients treated with placebo (n = 82).

This latter finding was of significant note to Kosiborod and colleagues, who were cognizant of kidney failure or injury risk in SGLT2 inhibitor-treated patients with comorbid diabetes or heart failure hospitalized with COVID-19. Just 2 cases of diabetic ketoacidosis were observed in treated patients.

“The safety overall looked very favorable, and dapagliflozin was also consistent in patients with type 2 diabetes,” Kosiborod said.

The trial author stressed that, though dapagliflozin did not achieve statistical significance for the composite primary endpoints of reduced organ failure or all-cause death in hospitalized, at-risk COVID-19 patients, the therapy was associated with numerically fewer patients to reach such an endpoint at 30 days—and with consistent success across varied patient disease backgrounds.

This, the first trial to evaluate the SGLT2 inhibitor drug class in patients with acute illness, at least supported the continued use of such therapy for cardiometabolic or renal benefit in patients with COVID-19—as long as patients are monitored.

It also fuels the prospect of more assessment into the drug class for acute illnesses. As Kosiborod concluded, there’s piqued interest in the ongoing RECOVERY trial, which is observing empagliflozin for the treatment of COVID-19.

“From the research implication standpoint, I think DARE-19 actually supports the hypothesis of SGLT2 inhibitors for multi-organ protection,” he said.