Kosiborod M, et al. Efficacy and safety of dapagliflozin in patients with and without type 2 diabetes hospitalized with COVID-19 — results from the DARE-19 global randomized controlled trial. Presented at: American Diabetes Association Scientific Sessions, June 25-29, 2021 (virtual meeting).
AstraZeneca funded the DARE-19 trial. Berwanger reports he received advisory board fees or research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pfizer, Sanofi and Servier.Kosiborod reports he received grants or served on advisory board or as consultant for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Janssen, Merck (Diabetes and Cardiovascular), Sanofi and Vifor. . Lam reports she received consultant, advisory board fees or 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 he received grants, research support, consultant or speakers fees from Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi and Sun Pharmaceuticals.
The SGLT2 inhibitor dapagliflozin is well-tolerated in adults hospitalized with COVID-19, regardless of diabetes status, according to new analyses from the DARE-19 trial.
The main findings from DARE-19, first presented in May, showed dapagliflozin (Farxiga, AstraZeneca) did not significantly reduce risk for organ failure or death or improve recovery among adults hospitalized with COVID-19 vs. placebo, although data showed lower event numbers among patients treated with dapagliflozin compared with placebo. However, 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, according to 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.
In new analyses presented at the American Diabetes Association Scientific Sessions, researchers demonstrated that these observations were consistent among patients with type 2 diabetes — about half of patients in the trial — and without type 2 diabetes. Furthermore, patients treated with dapagliflozin experienced numerically fewer adverse events during the trial than those who received placebo. This included acute kidney injury events and was again consistent among those with and without type 2 diabetes.
“The bottom-line message here is we have demonstrated that using SGLT2 inhibitors in the setting of acute illness, such as COVID-19, has little risk as long as patients are monitored,” Kosiborod said during a virtual presentation. “Our findings also raise the hypothesis that SGLT2 inhibitors may provide organ protection not just in the setting of COVID-19, but also in other types of acute illness, such as sepsis — this should be investigated in future trials.”
Role of diabetes status
DARE-19 researchers randomly assigned 1,250 adults hospitalized with COVID-19 and at least one risk factor for COVID-19 complications — such as hypertension, type 2 diabetes, heart failure, chronic kidney disease and/or atherosclerotic CVD — to 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 sites in the U.S., Brazil, Mexico, Argentina, India, Canada and the U.K. 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.
Dual primary endpoints were time to new or worsened organ (respiratory, cardiovascular or kidney) dysfunction or death from any cause, 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 or for the primary endpoint of recovery measuring a change in clinical status — from early recovery to death — at 30 days.
However, “numerically fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across the components — respiratory, cardiovascular, kidney complications and death,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization at Albert Einstein Hospital in Sao Paulo, Brazil, said when presenting efficacy outcomes data. “No statistical heterogeneity was observed in those with and without diabetes for the primary or secondary endpoints.”
Among patients with diabetes, organ dysfunction or all-cause death occurred in 34 vs. 45 patients assigned dapagliflozin or placebo, respectively, for an HR of 0.76 (95% CI, 0.49-1.18). Among patients without diabetes, organ dysfunction or all-cause death occurred in 36 vs. 40 patients assigned dapagliflozin or placebo, respectively, for an HR of 0.86 (95% CI, 0.55-1.35).
Overall, 41 vs. 54 patients died in the dapagliflozin and placebo groups, respectively, for an HR of 0.77 (95% CI, 0.52-1.16). Among those with diabetes, 22 vs. 30 patients died in the dapagliflozin and placebo groups, respectively (HR = 0.76; 95% CI, 0.44-1.32). Among those without diabetes, 19 vs. 23 patients died in the dapagliflozin and placebo groups, respectively (HR = 0.82; 95% CI, 0.45-1.52).
In DARE-19, researchers observed no between-group differences in any serious adverse events; results were similar in analyses stratified by diabetes status, Subodh Verma, MD, PhD, FRCSC, professor and the Canada Research Chair in Cardiovascular Surgery at the University of Toronto, said when presenting the safety outcomes data.
Among patients with diabetes, researchers observed 39 vs. 46 serious adverse events in the dapagliflozin and placebo groups, respectively. Among patients without diabetes, researchers observed 26 vs. 35 serous adverse events in the dapagliflozin vs. placebo groups, respectively.
“In fact, there were numerically fewer serious adverse events in participants treated with dapagliflozin vs. placebo,” Verma said. “Adverse events with the outcome of death, and adverse events of acute kidney injury, were also numerically fewer in dapagliflozin-treated vs. placebo-treated patients, though these did not achieve statistical significance.”
Adverse events of special interest were acute kidney injury and DKA. During the study, researchers observed two cases of DKA among patients with type 2 diabetes treated with dapagliflozin, both detected via protocol-mandated daily monitoring of acid-base balance during hospitalization. Both events were nonfatal and non-severe and rapidly resolved, Verma said.
“Safety outcomes were consistent in those with and without type 2 diabetes, and laboratory parameters were stable during hospitalization in patients treated with dapagliflozin and placebo, regardless of diabetes status,” Verma said.
The premise of DARE-19 itself was provocative at the start the pandemic in early 2020, when it was “common wisdom” to discontinue SGLT2 inhibitors for sick patients, Carolyn S.P. Lam, MBBS, PhD, senior consultant at the National Heart Centre Singapore and professor at Duke-NUS Singapore, said during an independent commentary presentation. Instead, data from DARE-19 not only demonstrate that dapagliflozin was well tolerated, but hint at the possibility of organ protection, warranting further study, she said.
“This trial was daring in giving these medications in the first place, and in fact, it proved right to try this,” Lam, who also served on the independent data safety and monitoring committee for DARE-19, said. “There were two things we were most concerned over — the possibility of acute kidney injury and DKA. If anything, there were fewer acute kidney injury events with dapagliflozin, and vanishingly few events of DKA.”
One of the most important takeaways from DARE-19 is the implications for use, whether it be initiation or continuation of SGLT2 inhibitors in hospitalized settings for those patients that have existing indications for these agents, such as type 2 diabetes and heart failure, Lam said. Additionally, there are remaining questions regarding the generalizability of DARE-19 — most patients were recruited in Brazil — for other regions and races, as well whether dapagliflozin could be used in other types of acute illness, such as sepsis, or used earlier in the course of treatment.
“At the end of the day, DARE-19 opens the door to future trials which focus on the organ protection effects of SGLT2 inhibitors, other SGLT2 inhibitors aside from dapagliflozin and other settings of hospitalized patients,” Lam said.