Dapagliflozin Misses Early Mark in COVID-19, but Kosiborod Sees Reasons for More Study

Dapagliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor with indications in type 2 diabetes (T2D), heart failure, and most recently chronic kidney disease (CKD), did not significantly reduce the risk of death or organ failure or hasten recovery in patients who were hospitalized with COVID-19 during the early months of the pandemic, according to results presented today during the American College of Cardiology's 70th Scientific Session.

But since the study, called DARE-19, enrolled only 1250 patients, it’s too soon to declare this experiment over. Today's presentation covered the first 30 days after patients began taking dapagliflozin, and the numbers favored the SGLT2 inhibitor over placebo. Lead investigator Mikhail N. Kosiborod, MD, of Saint Luke’s MidAmerica Heart Institute, said that his team is still waiting to see how things look for patients after 90 days.

A study that misses its mark would not typically generate this much interest, especially after trial sponsor AstraZeneca announced last month that results fell short of statistical significance. But with SGTL2 inhibitors gaining indications in heart failure and CKD, along with their original T2D approvals—conditions that put patients in danger when they get COVID-19—many suspect this weekend’s results will not be the last word.

Since Kosiborod is one of the world’s leading experts on SGLT2 inhibitors, it’s likely the curiosity will continue as the 90-day data mature. For one primary end point, 11.2% of patients treated with dapagliflozin experienced organ failure or death after 30 days (70 events) compared with 13.8% of those treated with placebo (86 events); the HR was 0.80 (95% CI, 0.58-1.10, P = .168). Among patients in the dapagliflozin group, 6.6% died compared with 8.6% in the placebo group.

Of great importance, the study showed that dapagliflozin is safe for patients who have COVID-19 and should not be discontinued, something that was hotly debated when the pandemic began.

“Our findings show that dapagliflozin is well tolerated in patients hospitalized with COVID-19, with no new safety issues being observed,” Kosiborod said. “This should have implications for clinical practice given that our results do not support discontinuation of SGLT2 inhibitors in this setting, as long as patients are monitored.”

From Earlier Trials, New Questions

The DARE-19 trial is the first phase 3 study to examine whether this SGLT2 inhibitor, which has proven effective for multiple chronic conditions, might be similarly useful in an acute setting.

“We realized very early in the course of the pandemic, that patients that have cardiometabolic comorbidities like type 2 diabetes, for example, heart failure, respiratory cardiovascular disease, chronic kidney disease, are also the patients that are the highest risk of developing complications, or even dying from COVID-19 [if] they're infected,” Kosiborod said in an interview with The American Journal of Managed Care®. “And we knew once the pandemic started about a year ago that if you are admitted to a hospital, if you are sick enough to be in the hospital with COVID-19 and you have one of these risk factors, your outcomes tend to be much worse than if you don't have to be hospitalize—or even if you're hospitalized, but don't have those risk factors.”

Drawing on knowledge gained from earlier trials involving SGLT2 inhibitors, Kosiborod explained, “There are mechanistic data that suggest that some of the key pathophysiologic processes that are dysregulated in the setting of COVID-19 are also the same processes that SGLT2 inhibitors might have a favorable impact on.”

“Our study opens the door to asking additional questions,” he said. “The idea for DARE-19 was quite unorthodox when we started—everyone was concentrating on antivirals and anti-inflammatory drugs—so it is fascinating to hypothesize that SGLT2 inhibitors may provide organ protection in acute illness. This should inform future clinical science and hopefully lead to further investigations.”

Designing DARE-19

The study team randomized 1250 patients at 95 sites in the United States, Brazil, Mexico, Argentina, India, Canada, and the United Kingdom between April 2020 and January 2021. Patients, who also had risk factors that included high blood pressure, diabetes, atherosclerotic vascular disease, heart failure, or CKD were randomized 1:1 to 10 mg of dapagliflozin or placebo once a day. Patients began taking the drug as soon as possible and no later than 4 days following admission to the hospital for 30 days—including after discharge. Patients, doctors, and study personnel were all unaware who was taking dapagliflozin and who was taking placebo.

The study had 2 primary end points:

• Prevention: this measured the time to the first major clinical event, including (1) respiratory, defined as invasive or noninvasive mechanical ventilation; (2) cardiovascular, defined as pressor, inotropes, new or worsened heart failure, sustained ventricular tachycardia/ventricular fibrillation, resuscitated cardiac arrest; (3) kidney, defined as doubling of creatinine or initiation of dialysis; and (4) death from any cause.
• Recovery: this hierarchical composite ranked each patient using the order of (1) death, (2) organ failure, (3) clinical status if still hospitalized after 30 days, and (4) time to discharge before day 30, which ended up being the leading driver of the end point.

Kosiborod said that although the results did not reach statistical significance, all were directionally favorable to dapagliflozin. This points to the need for further study, he said.

“Our study generates a hypothesis that dapagliflozin may offer organ protection in acutely ill patients who are hospitalized with COVID-19, but we were not able to prove this beyond a reasonable doubt because patient outcomes rapidly improved during the study period, making it much harder to accrue enough events and reach statistical certainty,” Kosiborod said.

Because the standard of care was rapidly evolving from the start of the pandemic through the summer of 2020, the share of hospitalized patients who died dropped from 25% in April to 5% by August of 2020, which likely affected the results. Thus, the second primary end point of recovery ended up being very similar between the 2 groups of patients.

The composite kidney end point had a numerical difference on par with the overall primary end point (events in 10.4% of the placebo group vs 7.7% of the dapagliflozin group). This comes as acute kidney injury (AKI) has emerged as a particularly serious problem during COVID-19, not only among at-risk patients but even among previously healthy patients, according to the National Kidney Foundation. AKI is a distinctly different condition from CKD and can leave patients at risk for chronic kidney failure.

There were numerically fewer serious adverse events in patients receiving dapagliflozin vs placebo, Two nonsevere cases of diabetic ketoacidosis were seen in the dapagliflozin group, both in patients with a prior history of T2D.

During today's late-breaking session, discussant Jim Januzzi, MD, of Massachusetts General Hospital praised Kosiborod's team for getting an international trial up at running in the pandemic's early chaotic weeks. He asked how many patients would need to be enrolled for the DARE-19 study team to have a clearer picture of whether dapagliflozin offers the organ protection they hypothesized; Kosiborod said at least 3000, and preferably 5000.

"A study size of 5000 sounds large," Januzzi responded, "but yesterday, globally, there were 836,000 cases of COVID-19, which comes down to approximately 580 per minute. So, it is certainly reasonable to expect that a study of that size would be feasible."

Maggie L. Shaw contributed to this report.