SGLT2 Inhibitors Not Associated With Improved Survival in Patients Hospitalized With COVID-19


In a previous trial, DARE-19, investigators reported that the SGLT2 inhibitor dapagliflozin did not benefit patients with COVID-19 who had cardiometabolic risk factors.

Treatment with sodium glucose co-transporter-2 (SGLT2) inhibitors did not result in lower 28-day all-cause mortality compared with usual care or placebo among patients hospitalized with COVID-19, according to new research.

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Several key treatments have been shown to improve key outcomes among patients hospitalized with COVID-19, including treatments targeting COVID-19 pathobiology, such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation. SGLT2 inhibitors modulate similar pathobiology, provide cardiovascular protection, and prevent the progression of kidney disease among those at risk of these events. They may also lead to organ protection in acute illness, such COVID-19.

In a previous trial, DARE-19, investigators reported that the SGLT2 inhibitor dapagliflozin did not benefit patients with COVID-19 who had cardiometabolic risk factors, although it was not adequately powered for certain key outcomes, such as total mortality.

To address the need for more definitive efficacy data and to inform clinical practice guidelines, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies Working Group conducted a prospective meta-analysis using aggregate data from randomized controlled trials evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

“In this prospective meta-analysis of randomized controlled trials evaluating over 6000 patients hospitalized with COVID-19, we found no convincing evidence that administration of SGLT2 inhibitors, compared with usual care or placebo, reduces 28-day all-cause mortality, or improves other pre-specified efficacy outcomes,” said presenting author Mikhail Kosiborod, MD, of Saint Luke’s Mid America Heart Institute, in a press release.

The meta-analysis evaluated the effects of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality and other efficacy endpoints. The primary safety outcome was ketoacidosis by 28 days.

The DARE-19, RECOVERY, and ACTIV-4A trials were included. In total, the trials randomized 6096 participants—3025 to SGLT2 inhibitors and 3071 to usual care or placebo. The average age ranged between 62 and 73 years, 2381 (39%) patients were women, and 1547 (25%) had type 2 diabetes at the time of randomization.

By 28 days after randomization, there were 351 deaths among patients randomized to SGLT inhibitors and 382 deaths among those randomized to usual care or placebo. The summary odds ratio was 0.93 for SGLT2 inhibitors, with consistency across the 3 trials. This corresponds to an absolute mortality risk of 11.7% for SGLT2 inhibitors compared with an assumed mortality risk of 12.4% for usual care or placebo.

Data on in-hospital and 90-day all-cause mortality were only available for 2 of the 3 trials (DARE-19 and ACTIV-4A), but the results were similar. The results were also similar for the secondary outcomes of progression to acute kidney injury, requirement for dialysis, or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

Ketoacidosis by 28 days was observed in 7 patients randomized to SGLT2 inhibitors and 2 patients randomized to usual care or placebo. Overall, the incidence of reported serious adverse events was balanced between treatment groups.

“These findings do not support the use of SGLT2 inhibitors as standard care in this clinical setting,” Kosiborod said in the press release. “No new safety signals were observed with the use of SGLT2 inhibitors in this patient population, and their routine discontinuation during acute illness for patients that receive them for other indications such as heart failure, chronic kidney disease, or type 2 diabetes does not appear to be warranted.”


SGLT2 inhibitors not linked with improved survival in hospitalized COVID-19 patients. News release. EurekAlert. August 29, 2023. Accessed August 30, 2023.

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