Can dapagliflozin be continued in patients with COVID-19?
The SGLT2 inhibitor dapagliflozin did not result in a reduced incidence of organ failure or death in patients with cardiometabolic risk factors who were hospitalized with COVID-19, according to the phase III DARE-19* trial. However, this finding does not support discontinuation of SGLT2 inhibitors in COVID-19 patients.
“[T]reatment with dapagliflozin did not achieve statistical significance for the dual primary endpoints,” said principal investigator Professor Mikhail Kosiborod from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, US, at ACC.21.
“[However,] numerically fewer patients treated with dapagliflozin experienced organ failure and death,” he noted.
Participants in this international, double-blind trial were 1,250 adults who had been hospitalized for ≤4 days with COVID-19 who had ≥1 risk factor** for COVID-19 complications and oxygen saturation ≥94 percent while on low-flow supplemental oxygen (≤5 L/minute). They were randomized 1:1 to receive dapagliflozin 10 mg/day (mean age 61 years, 42 percent female) or placebo (mean age 62 years, 44 percent female) for 30 days.
Patients with type 1 diabetes, critical illness, history of diabetic ketoacidosis (DKA), or estimated glomerular filtration rate <25 mL/min/1.73 m2 were excluded. Oxygen saturation was 96 and 95 percent in the dapagliflozin and placebo groups, respectively.
More than 80 percent of the population had hypertension and about half had type 2 diabetes (T2D). About one-third of patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or insulin.
There was a numerical, albeit non-significant, reduction in the incidence of organ failure and death with dapagliflozin vs placebo (11.2 percent vs 13.8 percent; hazard ratio [HR], 0.80, 95 percent confidence interval [CI], 0.58–1.10; p=0.168). [ACC.21, abstract 21-LB-21223-ACC]
The results were consistent across multiple prevention outcomes specifically new or worsening organ dysfunction (HR, 0.80), respiratory decompensation warranting mechanical ventilation and/or extracorporeal membrane oxygenation (HR, 0.85), cardiac decompensation (new or worsening congestive heart failure, sustained ventricular tachycardia or fibrillation, need for vasopressors, and/or inotropic or mechanical circulatory support; HR, 0.81), kidney decompensation (creatinine doubling or initiation of dialysis; HR, 0.65), or death (HR, 0.77).
“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,” remarked Kosiborod.
The recovery outcome, a hierarchical composite endpoint of death, organ failure, clinical status if still hospitalized at day 30, and time to hospital discharge before day 30, was also comparable between dapagliflozin and placebo (win ratio, 1.09, 95 percent CI, 0.97–1.22; p=0.14).
The incidence of the composite kidney endpoint was numerically lower with dapagliflozin vs placebo (7.7 percent vs 10.4 percent; HR, 0.74, 95 percent CI, 0.50–1.07).
Severe adverse event (AE) incidence was numerically lower among dapagliflozin than placebo recipients (n=65 vs 82; risk difference [RD], -2.71), as was AEs leading to death (n=32 vs 48; RD, -2.57), AE-related discontinuations (n=44 vs 55; RD, -1.75), and acute kidney injury (n=21 vs 34; RD, -2.09). Two dapagliflozin recipients with a history of T2D experienced DKA compared with none of the placebo recipients.
No need to discontinue SGLT2is in COVID-19
“There were concerns at the beginning of the pandemic about the safety of SGLT2 inhibitors in patients hospitalized with COVID-19, and some groups were recommending discontinuation of these medications in this setting, even in individuals with chronic conditions in which they have known benefits, such as T2D and heart failure,” said Kosiborod.
“Our findings show that dapagliflozin is well tolerated in patients hospitalized with COVID-19, with no new safety issues observed.”
“[O]ur results do not support discontinuation of SGLT2 inhibitors in this setting, as long as patients are monitored,” he noted.
“Our study opens the door to asking additional questions,” Kosiborod continued. “The idea for DARE-19 was quite unorthodox when we started [as] 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,” he said.