Diabetes Distilled: Who DAREs wins. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19

SGLT2 inhibitor cardiovascular and renal outcome studies, such as EMPA-REG OUTCOME (empagliflozin), DAPA-HF (dapagliflozin) and DAPA-CKD (dapagliflozin), have demonstrated significant reductions in major adverse cardiovascular and renal outcomes, including cardiovascular and renal death. In contrast, multi-organ failure and death are tragic consequences of COVID-19 infection, and cardiac, renal and metabolic comorbidities have been associated with poorer outcomes and death in people hospitalised with COVID-19.

The DARE-19 trial hypothesised that the SGLT2 inhibitor dapagliflozin might protect against multi-organ failure and death in people hospitalised with COVID-19 with at least one cardiometabolic risk factor (e.g. atherosclerotic cardiovascular disease or chronic kidney disease), as well as improve recovery. Notably, individuals living with and without type 2 diabetes were recruited to DARE-19. Those living with type 1 diabetes or who had a history of diabetic ketoacidosis (DKA) were excluded, as were those with evidence of critical illness (e.g. mechanical ventilation or oxygen saturation <94% on 5 L/min supplemental oxygen) or eGFR <25 mL/min/1.73 m².

DARE-19 was a multicentre, randomised, double-blind placebo-controlled trial to assess the effect of dapagliflozin 10 mg for 30 days in hospitalised individuals aged ≥18 years with COVID-19. DARE-19 randomised 625 patients into each arm of the trial. Mean age was 61 years and around half of participants were living with type 2 diabetes. After the last dose of dapagliflozin or placebo on day 30, individuals were observed for a further 60 days. The latter observational data will be published at a future date. Of note, the study was funded by AstraZeneca, which manufactures dapagliflozin.

DARE-19 had dual primary efficacy outcomes: prevention (time to new or worsened organ failure or death) and clinical recovery (change in clinical status by day 30). Safety outcomes and adverse events were also assessed.

Overall, fewer patients taking dapagliflozin suffered organ failure or died, but the trial did not achieve statistical significance for this dual primary endpoint at 30 days. The authors admit that event rates were lower than anticipated, resulting in an inadequately powered study, which may account for the lack of statistical significance.

Reassuringly, dapagliflozin was well tolerated, with no new safety issues identified. Overall, there were fewer serious adverse events in the dapagliflozin group compared to placebo. Specifically, “non-severe” DKA was reported in two patients in the dapagliflozin group, both of whom were living with type 2 diabetes. This is a well-established adverse effect of SGLT2 inhibitors. Moreover, 21 safety events of acute kidney injury were reported in the dapagliflozin group and 34 in the placebo group, which is consistent with past findings that SGLT2 inhibitors have a protective effect against acute kidney injury. Again, this reduction did not reach statistical significance.

The authors concluded that routine discontinuation of dapagliflozin in the setting of COVID-19 is not required, as long as patients are monitored. However, the setting and close daily monitoring in DARE-19 cannot easily be replicated in primary care and similar healthcare settings and, as such, in my opinion, sick-day guidance for SGLT2 inhibitors should remain unchanged in primary care.

New analyses of DARE-19 were presented at the 81^st Scientific Sessions of the American Diabetes Association in June 2021, and it was demonstrated that the main DARE-19 findings outlined above were consistent among patients with and without type 2 diabetes.

DARE-19 was a bravely conducted study at the height of the pandemic, and the authors should be commended for providing reassuring evidence about the use and safety of dapagliflozin in hospitalised patients with COVID-19, irrespective of their diabetes status. As with all good studies, DARE-19 raises more questions than answers. It tantalisingly hints at the possibility of organ protection with dapagliflozin in acute COVID-19 infection.

Indeed, very recently, it has been announced that empagliflozin is to be investigated as a possible treatment for COVID-19 in the RECOVERY trial. It is anticipated that this will be a larger trial than DARE-19 and will explore the impact of empagliflozin on risk of death, duration of hospital stay or need for mechanical ventilation. Perhaps RECOVERY will provide more robust evidence to guide the use of SGLT inhibitors in people hospitalised with COVID-19.

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