Dapagliflozin in patients with COVID-19: mind the kidneys

We read the DARE-19 trial by Mikhail Kosiborod and colleagues,¹ published in The Lancet Diabetes and Endocrinology with interest. The DARE-19 trial was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19. Key inclusion criteria were hospitalisation with laboratory confirmed or clinically suspected SARS-CoV-2 infection no more than 4 days before screening, requirement of oxygen supplementation of 5 L/min or less to achieve an oxygen saturation of at least 94%, and one or more cardiometabolic risk factors including chronic kidney disease (estimated glomerular filtration rate [eGFR] between 25–60 mL/min per 1·73 m²). Praiseworthy logistics were applied resulting in recruitment of 1250 patients from 95 sites in seven countries, with 60% of participants from Brazil.

Adding dapagliflozin 10 mg versus placebo to usual care did not affect the two primary outcomes: reduction in organ dysfunction or death and improvement in clinical recovery. Development of acute kidney injury was hierarchically the most important secondary outcome. The authors concluded that dapagliflozin did not increase the risk of acute kidney injury because there was no difference in the proportion of patients with serum creatinine concentrations two times that reported at baseline. However, doubling of serum creatinine represents acute kidney injury stage 2 according to current Kidney Disease: Improving Global Outcomes (KDIGO) criteria² and does not exclude stage 1 acute kidney injury or worse stages that manifest only as oliguria. A retrospective cohort study of patients hospitalised with COVID-19 confirmed that acute kidney injury occurred in 1835 (46%) of 3993 individuals.³ Morality was significantly worse in those with acute kidney injury. Of note, 716 (39%) of 1835 patients with acute kidney injury cohort in the retrospective study would not have met the acute kidney injury criteria used in DARE-19 and would have been missed. In DARE-19, acute kidney injury occurred in only 62 (5%) of 1250 patients, but the true incidence of was likely much higher.

Dapagliflozin is a SGLT2 inhibitor associated with a haemodynamically driven reduction in eGFR.⁴ Patients hospitalised with COVID-19 are at high risk of developing kidney injury for various reasons, such as dehydration and hypotension (70%), and viral sepsis (22%).3, 5 In this context, starting a drug that might reduce glomerular perfusion could have a detrimental effect. In our opinion, it is premature to claim that dapagliflozin is safe with respect to kidney function in patients who are acutely ill. To avoid potentially misleading conclusions and to prevent iatrogenic acute kidney injury in high risk patients, we strongly recommend that appropriate criteria are applied in future clinical trials. Furthermore, studying the effect of dapagliflozin using biomarkers of glomerular and tubular injury would add granularity to the functional criteria (serum creatinine elevation or urine output decline).⁶ We strongly suggest that full KDIGO criteria be used (possibly with the inclusion of biomarkers of kidney damage) in upcoming investigations.

TR received consulting fees from Baxter and Contatti Medical (CytoSorbents) and payment or honoraria from AstraZeneca, Baxter, Contatti Medical (CytoSorbents), B Braun, Jafron, and Eurofarma. MO received lecture fees to their institution from bioMérieux, Fresenius Medical, and Baxter, and payment to their institution for participation on the advisory board for NxStage. AZ received grants from Baxter, bioMérieux, consulting fees from Guard Therapeutics, AM Pharma, and Piaon, payment or honoraria from Fresenius, Baxter, and bioMérieux, payment for participation in advisory boards for Guard Therapeutics, AM Pharma, and Fresenius, and payment for leadership on boards for ESAIC, A&A, and Anästhesist. JAK received grants or contracts, consulting fees, and payment or honoraria from Astute Medical/bioMérieux. CR received consulting fees and payment or honoria from ASAHI, Baxter, bioMérieux, B. Braun, CytoSorbents, ESTOR, Fresenius Medical Care, General Electric, Medtronic, and Toray.