A just-launched study of the type 2 diabetes agent dapagliflozin (Farxiga, AstraZeneca) in patients with mild to moderate COVID-19 is raising eyebrows, given that several expert groups have advised that drugs in this class – the sodium-glucose cotransporter 2 (SGLT2) inhibitors – be stopped in all patients hospitalized with COVID-19 because of the increased risk for diabetic ketoacidosis (DKA).
The randomized, double-blind, placebo-controlled, phase 3 Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19) study is sponsored by AstraZeneca and Saint Luke’s Mid America Heart Institute.
The trial will assess whether dapagliflozin reduces the risks of disease progression, clinical complications, and death because of COVID-19 in patients with type 2 diabetes, cardiovascular disease, and/or mild to moderate chronic kidney disease (CKD).
“Dapagliflozin has demonstrated cardio- and renal-protective benefits and improved outcomes in high-risk patients with type 2 diabetes, heart failure with reduced ejection fraction, and CKD,” said the principal investigator of DARE-19, Mikhail N. Kosiborod, MD, a cardiologist at Saint Luke’s Mid America Heart Institute, Kansas City, Mo.
And “patients with COVID-19 and underlying cardiometabolic disease appear to be at the highest risk of morbid complications,” he explained in an AstraZeneca statement.
“Through DARE-19, we hope to decrease the severity of illness, and prevent cardiovascular, respiratory, and kidney decompensation, which are common in patients with COVID-19,” Dr. Kosiborod continued.
However, advice to stop SGLT2 inhibitors in patients hospitalized with COVID-19 because of its associated DKA risk has come from several channels.
These include initial guidance from Diabetes UK; experts who spoke during an American Diabetes Association webinar; and most recently, an international panel of diabetes experts.
Some clinicians went so far as to say that they view the trial as potentially dangerous, while others said they could see some logic to it, as long as it is carefully managed.
“A dangerous proposition – a DARE I would not take”
Partha Kar, MD, of Portsmouth Hospitals NHS Trust and national clinical director of diabetes at NHS England, said in an interview: “It’s interesting to see [AstraZeneca] embark on a study with a particular class of drug whereby … [in] the UK we have said that if you get sent to hospital with COVID-19 you should stop [SGLT2 inhibitors] immediately.”
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It “sounds like a risky proposition to go ahead with, [and it] definitely made me raise an eyebrow,” he added.
Nephrologist Bruce R. Leslie, MD, of Seventh Doctor Consulting in Princeton, N.J., agreed with Dr. Kar.
“Giving SGLT2 inhibitors to patients in the DARE-19 study is a dangerous proposition because these drugs can induce ketoacidosis during the stress of acute illness such as COVID-19. … Moreover, ketoacidosis is associated with hypercoagulability which could be especially dangerous in COVID-19, given that it has been causing thrombophilia with large-vessel occlusive strokes in young patients,” he said in an interview.
“One wonders how these risks were assessed by the authorities that approved the DARE-19 study,” said Dr. Leslie, who formerly worked for Bristol-Myers Squibb.
“How does the sponsor intend to secure informed consent given the risks? This is a DARE I would not take,” he said.
Asked to address these concerns, Dr. Kosiborod said in an interview that “the DARE-19 trial will assess both the efficacy and the safety of dapagliflozin in this patient population in a closely monitored environment of a rigorously designed randomized clinical trial. The trial protocol excludes patients with type 1 diabetes or at high risk for DKA.
“Furthermore, the protocol includes detailed specific instructions to ensure careful monitoring for DKA, including frequent assessments of acid-base status in the hospital setting. The safety data will be closely monitored by an independent data-monitoring committee,” he continued.
Dr. Kosiborod also pointed out that there is “no systematically collected information on the use of dapagliflozin or any other SGLT2 inhibitor in patients being treated for COVID-19, including the associated potential benefits, possible risks such as DKA, and the balance of these potential benefits and risks.”