Dapagliflozin in COVID-19: Outcomes consistent regardless of kidney status

Secondary analysis of the DARE-19* trial presented at ASN Kidney Week 2021 has shown that the effect of dapagliflozin in patients with cardiometabolic risk factors hospitalized with COVID-19 is consistent regardless of kidney disease status.

In this pre-specified secondary analysis of the DARE-19 trial, the researchers aimed to assess the impact of dapagliflozin on kidney outcomes among patients with COVID-19. Participants were 1,250 patients with cardiometabolic risk factors** who had been hospitalized for ≤4 days with COVID-19. They were randomized 1:1 to receive either dapagliflozin (10 mg/day) or placebo for 30 days in addition to standard of care.

Of these, 18.5 percent (n=231) had an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m² (mean age 71 years, 45 percent female, mean eGFR 47 mL/min/1.73 m²), while the remaining 988 patients had eGFR ≥60 mL/min/1.73 m² (mean age 59 years, 42 percent female, mean eGFR 93 mL/min/1.73 m²).

Previously published results showed a non-significant 20 percent reduction in the primary prevention outcome ie, time to new or worsened organ dysfunction or death, with dapagliflozin vs placebo (11.2 percent vs 13.8 percent; hazard ratio [HR], 0.80, 95 percent confidence interval [CI], 0.58–1.10; p=0.17). There was also a non-significant improvement in the primary recovery outcome (change in clinical status by day 30) with dapagliflozin vs placebo (87.5 percent vs 85.1 percent; win ratio, 1.09, 95 percent CI, 0.97–1.22; p=0.14). [Lancet Diabetes Endocrinol 2021;9:586-594]

In the present secondary analysis, the effect of dapagliflozin on the primary prevention outcome was consistent regardless of whether patients had eGFR <60 or ≥60 mL/min/1.73 m² (HR, 0.79, 95 percent CI, 0.45–1.40 and HR, 0.80, 95 percent CI, 0.54–1.18, respectively; p_interaction=0.98).

Similarly, the effect of dapagliflozin vs placebo on the recovery outcome was consistent in patients with eGFR <60 and ≥60 mL/min/1.73 m² (win ratio, 1.09, 95 percent CI, 0.83–1.42 and win ratio, 1.07, 95 percent CI, 0.94–1.21; p_interaction=0.67). [ASN Kidney Week 2021, abstract P02529]

The composite kidney outcome of acute kidney injury (AKI), initiation of renal replacement therapy, or any-cause death with dapagliflozin vs placebo as seen in the main findings (7.7 percent vs 10.4 percent; HR, 0.74, 95 percent CI, 0.50–1.07) was also consistent regardless of eGFR level (HR, 0.91, 95 percent CI, 0.49–1.69 and HR, 0.65, 95 percent CI, 0.40–1.05 for patients with eGFR <60 and ≥60 mL/min/1.73 m², respectively; p_interaction=0.44).

AKI incidence was lower among patients on dapagliflozin compared with placebo, both among those with eGFR <60 mL/min/1.73 m² (HR, 0.71, 95 percent CI, 0.29–1.77) and ≥60 mL/min/1.73 m² (HR, 0.69, 95 percent CI, 0.37–1.29; p_interaction=0.98).

Serious adverse events (AEs) occurred in 19.3 and 24.1 percent of dapagliflozin and placebo recipients, respectively, with eGFR <60 mL/min/1.73 m² and 8.6 and 10.8 percent, respectively, with eGFR ≥60 mL/min/1.73 m². AEs led to death in 11.4 percent vs 12.1 percent of dapagliflozin vs placebo recipients with eGFR <60 mL/min/1.73 m² and 3.9 percent vs 6.7 percent of dapagliflozin vs placebo recipients with eGFR ≥60 mL/min/1.73 m². AE-related discontinuations occurred in 14.9 percent of dapagliflozin and 12.9 percent of placebo recipients with eGFR <60 mL/min/1.73 m² and 5.3 percent vs 7.9 percent with eGFR ≥60 mL/min/1.73 m². Seven dapagliflozin and 11 placebo recipients with eGFR <60 mL/min/1.73 m² and 14 and 22 recipients, respectively, with eGFR ≥60 mL/min/1.73 m² experienced AKI events.

“Hospitalized patients with COVID-19 infection are at high risk of AKI and renal replacement therapy, especially in the presence of chronic kidney disease (CKD),” presented Professor Hiddo Heerspink  from the University of Groningen, Groningen, Netherlands.

“The DARE-19 trial showed that in hospitalized patients with COVID-19, treatment with dapagliflozin vs placebo resulted in numerically fewer patients experiencing organ failure or death, although these differences were not statistically significant,” he continued.

“[The present analysis showed that] the effects of dapagliflozin on the primary and secondary outcomes in hospitalized patients with COVID-19 were consistent in those with or without CKD. Dapagliflozin was well tolerated and did not increase the risk of AKI in patients with or without CKD,” he concluded.

“These findings have clinical significance in light of some professional society recommendations to routinely discontinue SGLT-2*** inhibitors in acutely hospitalized patients,” he noted.