DARE-19: No significant decrease in major events; dapagliflozin well tolerated in COVID-19
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The SGLT2 inhibitor dapagliflozin did not significantly reduce risk for organ failure or death or improve recovery among adults hospitalized with COVID-19 vs. placebo, though data showed lower event numbers among treated patients.
Main results from the DARE-19 trial were presented at the American College of Cardiology Scientific Session, on the heels of topline data announced in April.
Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute, professor of medicine at the University of Missouri-Kansas City School of Medicine, said the ever-evolving dynamics of the COVID-19 pandemic made it challenging to accrue a large number of events in DARE-19, as the standard of care for hospitalized patients rapidly improved and fewer hospitalized patients experienced organ failure or death.
“There are things we learned relatively early after the pandemic started; one was that patients with cardiometabolic risk factors like HF, diabetes, kidney disease, were at the highest risk for being hospitalized with COVID-19,” Kosiborod told Healio. “Once hospitalized, they were at the highest risk for organ failure complications. The attention, initially, was directed toward anti-inflammatory and antiviral drugs, but we had this class of medicines, SGLT2 inhibitors, which already demonstrated organ protection in the very population at highest risk for COVID-19 complications, granted under more stable chronic disease conditions. The idea behind DARE-19 was straightforward: Is it possible that this agent can also provide benefit in acute illness?”
Main results
DARE-19 randomized 1,250 adults hospitalized with COVID-19 and at least one risk factor for COVID-19 complications, such as hypertension, type 2 diabetes, HF, chronic kidney disease and/or atherosclerotic CVD, recruited from 95 sites in the U.S., Brazil, Mexico, Argentina, India, Canada and the U.K. Researchers randomly assigned patients dapagliflozin 10 mg (Farxiga, AstraZeneca; n = 625; mean age, 61 years; 42% women; 50% with type 2 diabetes) or matching placebo (n = 625; mean age, 62 years; 44% women; 52% with type 2 diabetes) for 30 days. Treatment was initiated no more than 4 days after hospital admission and continued even if patients were discharged. Patients with type 1 diabetes or prior diabetic ketoacidosis were excluded.
The trial was initiated in April 2020, shortly after COVID-19 was declared a global pandemic, and the last patient was enrolled in January 2021.
Dual primary endpoints were time to new or worsened organ dysfunction, or death and the hierarchical composite of clinical recovery.
As Healio previously reported, the trial did not achieve statistical significance for the primary endpoint of prevention measuring organ dysfunction or all-cause mortality, and the primary endpoint of recovery measuring a change in clinical status — from early recovery to death — at 30 days.
At 30 days, organ failure or death occurred in 11.2% of patients treated with dapagliflozin vs. 13.8% of patients treated with placebo (HR = 0.8; 95% CI, 0.58-1.1; P = .168).
Fewer patients receiving dapagliflozin died compared with those assigned placebo (6.6% vs. 8.6%, respectively); however, this number did not reach statistical significance (HR = 0.77; 95% CI, 0.52-1.16). Similarly, results numerically favored dapagliflozin for every component of organ failure or death, including respiratory, CV, renal failure or death from any cause.
The second primary endpoint of recovery, driven mostly by time to hospital discharge, was similar between patients taking dapagliflozin and placebo.
Dapagliflozin was well-tolerated, with no new safety issues identified. There were fewer serious adverse events in the dapagliflozin group vs. placebo (65 vs. 82).
COVID-19 ‘not stable disease’
Rapid improvements in the standard of care for patients hospitalized with COVID-19 between spring and summer of 2020 — and the resulting improvement in outcomes — resulted in substantial declines in the number of patients with organ failure or death. That, in turn, complicated trialists ability to assess study endpoints, as a large number of events are needed for statistical certainty.
“When we designed the trial, rates for organ failure and death were extremely high,” Kosiborod said in an interview. “At that time, in March and April 2020, more than 30% of those patients [hospitalized with COVID-19] were heading for organ failure or death. By August 2020, that number was about 10%. Mortality in the U.S. fell from about 25% in April 2020 to about 5% in August. You are dealing with a disease rapidly shifting in many different ways. This is what makes it so different from doing trials in diabetes and heart disease. COVID-19 is not a stable disease. It keeps changing.”
The results, while not statistically significant, should be taken in context with the number of events and the realities of a trial conducted during a public health emergency, he said.
“If you look at the numbers, numerically fewer patients in the dapagliflozin group had organ failure or death events and every component of that endpoint was numerically lower in the dapagliflozin group compared with placebo,” Kosiborod said. “What we can say is that the trial raises the hypothesis that SGLT2 inhibitors may provide organ protection, but we didn’t prove this hypothesis with statistical certainty.”
Treatment implications
DARE-19 is the first large randomized controlled trial evaluating an SGLT2 inhibitor in adults hospitalized with COVID-19. Given a lack of data prior to COVID-19, there were concerns about the safety of using SGLT2 inhibitors in the setting of COVID-19, due to potential risk for acute kidney injury and diabetic ketoacidosis.
“This fueled recommendations from some groups to stop SGLT2 inhibitors in patients with COVID-19, even if they had conditions in which this class has been proven to produce substantial benefits, such as type 2 diabetes and HF,” Kosiborod said during a presentation.
Kosiborod said the safety data from DARE-19 showed that dapagliflozin was well tolerated, with no new safety issues identified. The results of DARE-19, therefore, do not support discontinuation of SGLT2 inhibitor therapy in the setting of COVID-19, as long as patients are monitored, he told Healio. The study raises the hypothesis that SGLT2 inhibitors may afford organ protection in other types of acute illness, which should be evaluated in future studies, he said.
Discussing the study design of DARE-19 at the virtual Heart in Diabetes conference in August 2020, Kosiborod said SGLT2 inhibitors could potentially target key mechanisms activated in COVID-19, increasing lipolysis, reducing glycolysis, inflammation and oxidative stress, and improving endothelial function to reduce organ damage.
Perspective
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Gregg C. Fonarow, MD, FACC, FAHA, FHFSA
SGLT2 inhibitors have been demonstrated to have potent CV and renal protective effects in diabetes, HF and chronic kidney disease; however, use of dapagliflozin in patients hospitalized with COVID-19 did not significantly reduce the risk for organ failure or death compared with placebo. In addition, there was not a significant improvement in recovery in this patient population.
These data do not support the routine use of SGLT2 inhibitors as a treatment for COVID-19. However, the drug was generally safe and well tolerated in this patient population, suggesting that, with monitoring, SGLT2 inhibitors may be continued in patients who were already being treated but subsequently developed COVID-19 requiring hospitalization.
There has been substantial interest in repurposing existing medications as potential treatments for COVID-19. Although this therapy did not demonstrate significant improvement in outcomes, the hypothesis that SGLT2 inhibitors provide organ protection received some support from this trial, in that every component of the composite endpoint was directionally favorable for dapagliflozin.
Patients who have proven outcome benefits with SGLT2 inhibitors, including patients with type 2 diabetes, patients with HF with reduced ejection fraction and patients with chronic kidney disease are at higher risk for COVID-19 hospitalizations, complications and mortality. Highly encouraging these patients to undergo COVID-19 vaccination remains a critical strategy to effectively protect these patients.
Perspective
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James Januzzi Jr., MD, FACC, FESC
At a time when many people were falling into the nihilism that a multicenter trial for candidate therapies for COVID-19 could not be possible, the DARE-19 investigators were able to stand up and complete a high-quality, multicenter randomized controlled trial. This is critically important, because therapies are still in use presently that have been subsequently found to be worthless, such as hydroxychloroquine and some monoclonal antibody therapies.
Treatment with SGLT2 inhibition among a sick, hospitalized patient population was quite safe. This is not an insignificant finding, because presently there is a habit of discontinuing these agents when people are admitted because of fear of diabetic ketoacidosis (DKA). This shows discontinuation of SGLT2 inhibitors should not be done, as long as monitoring for DKA is undertaken. The ramifications of discontinuation of a beneficial therapy in patients with HF, chronic kidney disease or diabetes might expose the patient to risk. Indeed, although not meeting significance, the third point is treatment with dapagliflozin was routinely associated with lower event rates compared with placebo. So, while the investigators did not achieve statistical significance, the consistency of the findings should not be ignored. There appears to be a “there” there.
A well-powered study, perhaps focused on COVID-19 or another respiratory ailment in subsequent outbreaks, would certainly be a rational follow-up to this.
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Kosiborod M, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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