Key Points:
- In hospitalized COVID-19 patients, treatments targeting the virus’s pathobiology (e.g. dysregulated immune response, inflammation, etc.) has been shown to improve outcomes
- Sodium glucose co-transporter 2 (SGLT2) inhibitors affect similar pathobiology and may lead to organ protection in acute illness, but their role in hospitalized COVID-19 patients is uncertain
- In this meta-analysis, SGLT2 inhibitors did not demonstrate decreased 28-day all-cause mortality compared with usual care or placebo in hospitalized COVID-19 patients
In patients hospitalized with COVID-19, treatments targeting the virus’s pathobiology, including dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation, have all been shown to improve outcomes. Sodium glucose co-transporter 2 (SGLT2) inhibitors, which affect similar pathobiology, provide cardiovascular protection and prevent progression of kidney disease in at-risk patients (e.g. those with type 2 diabetes [T2DM], heart failure [HF], and chronic kidney disease [CKD]). Notably, SGLT2 inhibitors may also lead to organ protection in the setting of an acute illness, such as COVID-19 infection. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 is uncertain.
The previous DARE-19 trial found that the SGLT2 inhibitor dapagliflozin did not benefit patients with COVID-19 who had cardiometabolic risk factors (and therefore, were at high risk of progression to severe COVID-19), though the drug was safe. However, DARE-19 was not adequately powered for certain key outcomes, such as total mortality. To address the need for more definitive efficacy data and inform guidelines, the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using aggregate data from randomized controlled trials (RCTs) evaluating SGLT2 inhibitors in hospitalized COVID-19 patients.
This meta-analysis studied effects of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality, the primary outcome, and other efficacy endpoints in hospitalized COVID-19 patients. Primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of clinicaltrials.gov, EudraCT, and the ISRCTN registry between November 2022 and January 2023. The trial investigators provided prespecified summary outcome data overall and within subgroups of interest.
Three eligible trials were included: DARE-19, RECOVERY, and ACTIV-4A. In total, these trials randomized 6096 participants, 3025 to SGLT2 inhibitors and 3071 to usual care or placebo, across the United States (US), United Kingdom (UK), Brazil, Canada, Mexico, Argentina, India, Spain, Nepal, Indonesia, Vietnam, South Africa, and Ghana. Average participant age ranged from 62 to 73 across the trials. 2381 patients (39%) were women, and 1547 (25%) had T2DM at time of randomization.
By 28 days after randomization, there were 351 deaths among those randomized to SGLT2 inhibitors and 382 deaths among those randomized to usual care or placebo. There was no significant difference in odds of death: summary odds ratio (OR) was 0.93 (95% confidence interval [CI]: 0.79-1.08; p=0.33) for SGLT2 inhibitors. This corresponded to absolute mortality risk of 11.7% for SGLT2 inhibitors compared with assumed mortality risk of 12.4% for usual care or placebo.
For secondary endpoints, data regarding in-hospital and 90-day all-cause mortality were only available for two of the three included trials (DARE-19 and ACTIV-4A), but results were similar (OR 0.85, 95% CI: 0.60-1.22, p=0.37; HR 0.82, 95% CI: 0.79-1.06, p=0.26, respectively). There were also similar results for progression to acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO), or death (OR 0.90, 95% CI: 0.78-1.04, p=0.16), both assessed at 28 days. Primary safety outcome, ketoacidosis by 28 days, was observed in 7 patients allocated to SGLT2 inhibitors and 2 patients allocated to usual care or placebo. Incidence of reported serious adverse events was overall balanced between treatment groups.
Presenting author Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute remarked, “In this prospective meta-analysis of randomised controlled trials evaluating over 6,000 patients hospitalised 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… 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.”