DARE-19 Phase III trial did not reach statistical significance for primary endpoints, but showed numerically fewer events of new or worsened organ dysfunction or death in patients hospitalized with COVID-19

KANSAS CITY, Mo. - In April 2020, COVID-19 was just beginning to sweep across the United States. At that time, the mortality and complication rates for hospitalized patients were high, with more than 30% of those patients experiencing organ failure or dying.  It was under those circumstances, as the world attempted to grapple with the new virus, that the research team at Saint Luke’s Mid America Heart Institute hypothesized that a drug already used for treatment of other conditions (including Type 2 diabetes and heart failure) might be able to prevent organ failure and death in patients hospitalized with COVID-19.

As a result of that hypothesis, in March 22, 2020, Saint Luke's did something unprecedented for the health system.  In collaboration with AstraZeneca and George Clinical, Saint Luke's Mid America Heart Institute sponsored and launched DARE-19, the first global trial led by the organization. The trial's goal was to assess whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, can reduce the risk of complications and death due to COVID-19 in patients who also have cardiovascular (CV), metabolic or kidney risk factors.

"This was a tremendous undertaking for the health system, but one we felt was essential as a member of the global clinical community," said Dr. Mikhail Kosiborod, cardiologist at Saint Luke's Mid America Heart Institute, vice president for Research at Saint Luke’s Health System, and the study’s principal investigator. "We also knew if we were going to take on this challenge, it was critical we design the trial with a high level of scientific rigor.  I am proud to say DARE-19 reflected that rigor, and we proved that it is possible to produce high quality evidence in the middle of the pandemic.”

DARE-19 tested a hypothesis whether dapagliflozin, a medication that is already used for management of chronic conditions such as Type 2 diabetes, heart failure and kidney disease, can prevent organ failure or death, and improve recovery in patients with cardiometabolic risk factors that are hospitalized with COVID-19. Cardiac, kidney and metabolic comorbidities have been associated with poor outcomes and death in patients hospitalized with COVID-19.

“We knew that SGLT2 inhibitors provide organ protection in patients with cardiometabolic risk factors, such as heart failure, Type 2 diabetes and chronic kidney disease, and we hypothesized that these agents may also benefit patients at high risk for complications that are acutely hospitalized with COVID-19,” Kosiborod said.

The international, multi-center, double-blind, placebo-controlled trial enrolled 1250 patients in less than nine months.  The very first patient enrolled was at Saint Luke's Hospital, which ended up being the leading recruiting site in the United States. Investigators and study teams at 95 sites across seven countries contributed to the effort. Patients received either dapagliflozin or placebo for 30 days, and neither the patient, nor the research team or treating clinicians knew the treatment assignment.

At 30 days, the number of patients that developed organ failure or died was numerically lower among those that received dapagliflozin versus placebo, 11.2% versus 13.8%, respectively, but this difference was not statistically significant. The findings were similar for individual components of organ failure or death outcome, including respiratory, cardiac, kidney failure or death from any cause. There was no difference between the groups in recovery, which was driven mostly by time to hospital discharge.

“Our results generate a hypothesis that dapagliflozin may offer organ protection in patients hospitalized with COVID-19, but we were not able to prove this beyond a reasonable doubt because the rates of organ failure and death declined rapidly during the study period due to improvements in the standard of care, making it harder to reach statistical certainty”.

"However, these results are important, will inform clinical science and should be further investigated in future trials," Kosiborod said.

Of importance, dapagliflozin was well tolerated in this acutely ill patient population, the highest risk group ever tested with SGLT2 inhibitors. There were numerically fewer serious adverse events in patients receiving dapagliflozin versus placebo. Two non-severe cases of diabetic ketoacidosis were observed in the trial, both in the dapagliflozin group and in patients with history of Type 2 diabetes.

"One of the critical questions in the DARE-19 trial was to evaluate the safety of dapagliflozin in patients hospitalized with Covid-19. This medication has been proven to have significant benefits and be well tolerated in patients with Type 2 diabetes, heart failure, and chronic kidney disease under more stable conditions, but had not yet been tested as extensively in a setting of acute illness, such as Covid-19" said Kosiborod.

"The most important clinically actionable information gained from DARE-19 is that dapagliflozin was well-tolerated in patients hospitalized with COVID-19 and cardiometabolic risk factors. Given the proven benefits of dapagliflozin in patients with Type 2 diabetes, heart failure and chronic kidney disease, our results do not support discontinuation of SGLT2 inhibitors in individuals that have established indications when they are hospitalized with Covid-19, as long as patients are monitored."

Detailed results from the DARE-19 trial were presented on Sunday, May 16, at the American College of Cardiology's 70th Annual Scientific Session.

DARE-19

DARE-19 was an international, randomized, double-blind, placebo-controlled, investigator-sponsored Phase III trial in 1,250 patients evaluating the efficacy and safety of dapagliflozin in addition to background local standard of care therapy in adults who are hospitalized with COVID-19 at the time of trial enrolment. Patients enrolled in DARE-19 also had a medical history of hypertension, type-2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure (HF) or chronic kidney disease (CKD) Stages 3-4 and received dapagliflozin or placebo for 30 days.^1,2

The trial was led by Saint Luke’s Mid America Heart Institute in close collaboration with AstraZeneca and George Clinical.

Saint Luke's Mid America Heart Institute

Saint Luke's Mid America Heart Institute is a member of Saint Luke's Health System, which consists of 16 area hospitals and campuses and several primary and specialty care practices, and provides a range of inpatient, outpatient, and home care services. Founded as a faith-based, not-for-profit organization, our mission includes a commitment to the highest levels of excellence in health care and the advancement of medical research and education. The health system is an aligned organization in which the physicians and hospitals assume responsibility for enhancing the physical, mental, and spiritual health of people in the metropolitan Kansas City area and the surrounding region.