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Randomized Controlled Trial
. 2022 May;17(5):643-654.
doi: 10.2215/CJN.14231021. Epub 2022 Apr 28.

Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial

Hiddo J L Heerspink  1   2 , Remo H M Furtado  3   4 , Otavio Berwanger  3 , Gary G Koch  5 , Felipe Martinez  6 , Omar Mukhtar  7 , Subodh Verma  8   9 , Samvel B Gasparyan  10 , Fengming Tang  11 , Sheryl L Windsor  11 , Vicente Cés de Souza-Dantas  12 , Mildren Del Sueldo  13 , Robert Frankel  14 , Ali Javaheri  15 , Rafael A Maldonado  16 , Caryn Morse  17 , Marco Mota-Gomes  18 , Douglas Shemin  19 , Osvaldo Lourenço Silva Jr  20 , Alexandre Pereira Tognon  3 , Marcel Twahirwa  21 , Joan Buenconsejo  22 , Russell Esterline  22 , Jan Oscarsson  10 , Philip Ambery  10 , Anna Maria Langkilde  10 , Mikhail N Kosiborod  2   11   23
Affiliations
Randomized Controlled Trial

Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial

Hiddo J L Heerspink et al. Clin J Am Soc Nephrol. 2022 May.

Abstract

Background and objectives: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR.

Design, setting, participants, & measurements: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2.

Results: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2.

Conclusions: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.

Keywords: COVID-19; acute kidney injury; cardiovascular disease; chronic kidney disease; diabetes; heart failure; hospitalization; mortality risk; outcomes; randomized controlled trials.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Effects of dapagliflozin compared with placebo on the primary outcome in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. The prevention outcome is shown in participants with baseline eGFR <60 ml/min per 1.73 m2 (A) and ≥60 ml/min per 1.73 m2 (B). The recovery outcome is shown in participants with baseline eGFR <60 ml/min per 1.73 m2 (C) and ≥60 ml/min per 1.73 m2 (D). 95% CI, 95% confidence interval.
Figure 2.
Figure 2.
Effects of dapagliflozin compared with placebo on the kidney composite outcome and its component in the overall population and in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. aDefined as either a doubling of serum creatinine during hospitalization or an adverse event of AKI after discharge through to day 30. Participants may experience multiple composite kidney outcomes. The total number of each component are reported in the forest plot. One participant in the placebo group died after withdrawing informed consent. This participant was included in the analysis of all-cause mortality, but not included in the analysis of the composite kidney outcome, because the occurrence of AKI or initiation of KRT could not be ascertained in this participant after withdrawal of consent.
Figure 3.
Figure 3.
“Swimmer plots” of time to death or hospital discharge for participants with a composite kidney end point event. Data are shown by the overall population (A) and in participants with eGFR <60 (B) and ≥60 ml/min per 1.73 m2 (C). Plots present the first event of AKI or KRT.
Figure 4.
Figure 4.
Least squares mean eGFR (standard error) at protocol mandated timepoints in participants with eGFR <60 and ≥60 ml/min per 1.73 m2.
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