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A just-launched study of the type 2 diabetes agent dapagliflozin (Farxiga, AstraZeneca) in patients with mild-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 due to 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 due to COVID-19 in patients with type 2 diabetes, cardiovascular disease, and/or mild-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, Missouri.
And "patients with COVID-19 and underlying cardiometabolic disease appear to be at the highest risk of morbid complications," he explains 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," Kosiborod continues.
However, advice to stop SGLT2 inhibitors in patients hospitalized with COVID-19, due to its associated DKA risk, has come from several channels.
Some clinicians went so far as to tell Medscape Medical News 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, diabetes, NHS England, told Medscape Medical News: "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."
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, Princeton, New Jersey, agrees with 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 told Medscape Medical News.
Leslie, who formerly worked for Bristol Myers Squibb, also said, "One wonders how these risks were assessed by the authorities that approved the DARE-19 study."
"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, Kosiborod told Medscape Medical News: "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.
Kosiborod also pointed out, "There is currently 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."
DARE-19 Design: Several Outcomes Will Be Examined
The DARE-19 trial is designed to enroll 900 adults with confirmed SARS-CoV-2 infection and oxygen saturation of 94% or greater.
Inclusion criteria include a medical history of hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and/or stage 3-4 CKD.
Exclusion criteria include current SGLT2 inhibitor treatment, type 1 diabetes, severe CKD, and severe COVID-19.
Dapagliflozin is approved in the EU for use in some patients with type 1 diabetes; this is not the case in the United States, although SGLT2 inhibitors in general are sometimes used off-label in these patients.
Patients in DARE-19 will be randomized to 10 mg/day dapagliflozin or placebo for 30 days, in addition to standard care, in participating hospital.
Primary outcomes are time to first occurrence of either death or new or worsened organ dysfunction, including respiratory decompensation, new or worsening congestive heart failure, requirement for vasopressor therapy, ventricular tachycardia, and renal failure.
Secondary outcomes include a composite of time to death from any cause, time to new/worsened organ dysfunction, clinical status at day 30, and time to hospital discharge.
Some Rationale for the Study?
Irl B. Hirsch, MD, professor and diabetes treatment and teaching chair at the University of Washington, Seattle, told Medscape Medical News he does see some logic to the trial.
Admitting that he doesn't know much about "COVID-19 cardiomyopathy" — which would be one of the targets of dapagliflozin — other than it is quite common, he said that this, along with the potential renal benefits of dapagliflozin in the setting of COVID-19, make the study "intriguing."
"Perhaps there is some rationale to it," he said.
However, he added: "My concern is these sick COVID-19 patients are often acidemic, and besides the very complex acid-base challenges we see with intubated patients, these patients likely have combination lactic and ketoacidemia, the latter at least some from starvation."
"Still, if enough dextrose and insulin are provided to prevent ketoacid accumulation, my guess is it would do at least as well as hydroxychloroquine," he quipped.
And Simon Heller, MD, professor of clinical diabetes at the University of Sheffield, UK, told Medscape Medical News: "I think it is quite a brave study, mainly because of the increased risk of DKA."
"However, on the basis that these patients will be carefully monitored, the risk of DKA shouldn't be great. I think it is important that patients with type 2 diabetes can participate whenever possible in such trials," he said.
The estimated completion date for DARE-19 is December 2020.
Kosiborod has reported receiving grant support, honoraria, and/or research support from AstraZeneca, Boehringer Ingelheim, Sanofi, Amgen, Novo Nordisk, Merck, Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia Therapeutics, Novartis, Applied Therapeutics, Amarin, and Eli Lilly. Leslie has reported owning stock in Bristol Myers Squibb, Pfizer, and Lilly. Hirsch has reported consulting for Abbott Diabetes Care, Roche, and Bigfoot Biomedical, conducting research for Medtronic, and is a diabetes editor for UpToDate. Heller has received advisory or consultation fees from Lilly, Novo Nordisk, Takeda, MSD, and Becton Dickinson; has served as a speaker for AstraZeneca, Lilly, Novo Nordisk, Boehringer Ingelheim, and Takeda; and has received research support from Medtronic UK. He is on the advisory board for Medscape. Kar has reported no relevant financial relationships.
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Cite this: New Study of Diabetes Drug for COVID-19 Raises Eyebrows - Medscape - Apr 30, 2020.