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Kosiborod M. et al. Efficacy and safety of dapagliflozin in patients with and without type 2 diabetes who were hospitalized with COVID-19 – results of the global randomized controlled trial DARE-19. Presented at: American Diabetes Association Scientific Sessions, April 25-29 June 2021 (virtual meeting).
Disclosure:
AstraZeneca funded the DARE-19 study. Berwanger reports that he has received advisory fees or research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Janssen, Merck (diabetes and cardiovascular system), Sanofi and Vifor. . Lam reports that she has received advisory or advisory fees or has served on steering committees for Abbott Diagnostic, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Bioforums, Boehringer Ingelheim, Boston Scientific, Corvia Medical, Cytokinetics, Darma Inc., Eko.ai Pte Ltd. , JanaCare, Janssen, Medtronic, Menarini Group, Merck, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Stealth Bio Therapeutics, The Corpus, Vifor Pharma and WebMD Global. Verma reports that he has received grants, research support, consultant or speaker fees from Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio has received, Sanofi and Sun Pharmaceuticals.
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The SGLT2 inhibitor dapagliflozin is well tolerated regardless of diabetes status according to new analyzes from the DARE-19 study in adults who were hospitalized with COVID-19.
The key results from DARE-19, first presented in May, showed that dapagliflozin (Farxiga, AstraZeneca) did not significantly reduce the risk of organ failure or death or recovery in adults hospitalized with COVID-19 No improvement compared to placebo, although the data showed lower event numbers in patients treated with dapagliflozin compared to placebo. However, the ever-evolving dynamics of the COVID-19 pandemic made it difficult to capture a large number of events in DARE-19 as the standard of care for hospital patients improved rapidly and fewer hospital patients were reported to have suffered organ failure or death Mikhail Kosiborod, MD, FACC, FAHA, a Cardiologist at Saint Luke’s Mid America Heart Institute and Professor of Medicine at the University of Missouri-Kansas City School of Medicine.
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In new analyzes presented at the American Diabetes Association’s Scientific Sessions, the researchers showed that these observations were consistent in patients with type 2 diabetes – about half of the patients in the study – and those without type 2 diabetes . In addition, patients treated with dapagliflozin had fewer numerical side effects during the study than patients who received placebo. This included events with acute kidney damage and was also consistent in patients with and without type 2 diabetes.
“The bottom line here is that we have shown that using SGLT2 inhibitors in acute illnesses like COVID-19 has a low risk as long as patients are monitored,” Kosiborod said during a virtual presentation. “Our results also raise the hypothesis that SGLT2 inhibitors can offer organ protection not only in COVID-19, but also in other acute diseases such as sepsis – this should be investigated in future studies.”
Role of diabetes status
DARE-19 researchers randomly identified 1,250 adults with COVID-19 and at least one risk factor for COVID-19 complications – such as high blood pressure, type 2 diabetes, heart failure, chronic kidney disease, and / or atherosclerotic cardiovascular disease – Were hospitalized to receive dapagliflozin 10 mg. n = 625; Mean age 61 years; 42% women; 50% with type 2 diabetes) or placebo (n = 625; mean age 62 years; 44% women; 52% with type 2 diabetes) for 30 days. Patients were treated at 95 centers in the US, Brazil, Mexico, Argentina, India, Canada and the UK. Treatment was started no later than 4 days after hospital admission and continued even after the patients were discharged. Patients with type 1 diabetes or previous diabetic ketoacidosis were excluded.
Dual primary endpoints were the time to onset of new or worsened organ dysfunction (respiratory, cardiovascular, or kidney) or death from any cause and the hierarchical composition of clinical recovery.
As previously reported by Healio, the study did not achieve statistical significance for the primary endpoint of prevention (measurement of organ dysfunction or all-cause mortality) or for the primary endpoint of recovery, which was a change in clinical status – from early recovery to death – after 30 days measures.
However, “fewer numbers of patients treated with dapagliflozin experienced organ failure and death, and this was consistent across all components – respiratory, cardiovascular, renal complications and death.” Otavio Berwanger, MD, PhD, Director of the Academic Research Organization at Albert Einstein Hospital in Sao Paulo, Brazil, presenting efficacy results. “No statistical heterogeneity was observed in the primary or secondary endpoints in patients with and without diabetes.”
In patients with diabetes, 34 vs. 45 patients who were assigned dapagliflozin or placebo had organ dysfunction or all-cause death at an HR of 0.76 (95% CI 0.49-1.18). In patients without diabetes, 36 vs. 40 patients who were assigned dapagliflozin or placebo had organ dysfunction or all-cause death with a HR of 0.86 (95% CI 0.55-1.35).
A total of 41 vs. 54 patients died in the dapagliflozin or placebo group with an HR of 0.77 (95% CI 0.52-1.16). Among the patients with diabetes, 22 vs. 30 patients in the dapagliflozin or placebo group died (HR = 0.76; 95% CI 0.44-1.32). Among the patients without diabetes, 19 vs. 23 patients in the dapagliflozin or placebo group died (HR = 0.82; 95% CI 0.45-1.52).
Dapagliflozin well tolerated
In DARE-19, the researchers observed no intergroup differences in any serious adverse events; Results were similar in analyzes stratified by diabetes status, Subodh Verma, MD, PhD, FRCSC, Professor and the Canada Research Chair in Cardiovascular Surgery at the University of Toronto, presenting the safety results.
In patients with diabetes, the researchers observed 39 versus 46 serious adverse events in the dapagliflozin and placebo groups, respectively. In patients without diabetes, the researchers observed 26 vs. 35 serous side effects in the dapagliflozin and placebo groups.
“In fact, participants treated with dapagliflozin had fewer serious side effects numerically than those treated with placebo,” said Verma. “Adverse events resulting in death and side effects of acute kidney damage were also numerically lower in dapagliflozin-treated patients compared to placebo-treated patients, although these did not reach statistical significance.”
Adverse events of particular concern were acute kidney injury and DKA. During the study, the researchers observed two cases of DKA in patients with type 2 diabetes treated with dapagliflozin, both of which were identified by daily protocol-based acid-base monitoring during the hospital stay. Both events were non-fatal, non-fatal, and quickly subsided, Verma said.
“The safety results were consistent in patients with and without type 2 diabetes, and laboratory parameters were stable throughout the hospital stay in patients treated with dapagliflozin and placebo regardless of diabetes status,” said Verma.
Remaining questions
The premise of DARE-19 itself was provocative at the start of the pandemic in early 2020 when it was “common wisdom” to stop using SGLT2 inhibitors for sick patients. Carolyn SP Lam, MBBS, PhD, Senior Consultant at the National Heart Center Singapore and Professor at Duke-NUS Singapore, said during an independent commentary presentation. Instead, data from DARE-19 not only showed that dapagliflozin was well tolerated, but also suggested the possibility of organ protection, which warranted further study, she said.
“This study was daring to deliver these drugs from the outset, and indeed it proved right to try,” said Lam, who also served on the independent data security and monitoring committee for DARE-19. “There were two things that worried us the most – the possibility of acute kidney damage and DKA. If anything, there was less acute kidney damage and vanishingly few cases of DKA with dapagliflozin. “
One of the key lessons learned from DARE-19 is the effects on use, be it onset or continuation of SGLT2 inhibitors in the hospital, in patients with existing indications for these agents, such as type 2 diabetes and heart failure, Lam said. In addition, questions remain about the generalizability of DARE-19 – most of the patients were recruited in Brazil – for other regions and races, as well as the question of whether dapagliflozin could be used in other acute conditions such as sepsis or earlier in the course of treatment.
“Ultimately, DARE-19 opens the door to future studies that focus on the organ protective effects of SGLT2 inhibitors, other SGLT2 inhibitors besides dapagliflozin, and other hospital patient attitudes,” said Lam.
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