Meta-analysis shows SGLT2 inhibitors not beneficial in treating COVID-19
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Key takeaways:
- SGLT2 inhibitors do not reduce risk for death or other outcomes for inpatients with COVID-19.
- Data show the drugs are safe for patients with COVID-19 and do not need to be discontinued.
A meta-analysis of three trials assessing the use of SGLT2 inhibitors for inpatients with COVID-19 showed the drug class did not reduce risk for death or other outcomes compared with usual care or placebo, but was safe.
“The fundamental pathobiology of COVID-19 infection and organ damage includes many pathophysiologic properties that, at least theoretically, could be impacted in a favorable way by SGLT2 inhibitors, including inflammation, endothelial damage and other pathways,” Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, said during a press conference at the European Society of Cardiology Congress. “Early in the pandemic, we hypothesized that treating patients hospitalized with COVID-19 with organ damage or at risk for organ damage could be potentially beneficially impacted by the use of SGLT2 inhibitors. Subsequently, a number of trials were done to test that hypothesis.”
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Kosiborod and colleagues analyzed data from participants in three large randomized controlled trials under the leadership of WHO that looked at SGLT2 inhibitor use vs. placebo or usual care among people hospitalized with confirmed or clinically suspected COVID-19: DARE-19, assessing dapagliflozin (Farxiga, AstraZeneca) in 1,250 patients; RECOVERY, assessing empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) in 4,271 patients; and ACTIV-4a, assessing dapagliflozin, empagliflozin, canagliflozin (Invokana, Janssen) or ertugliflozin (Steglatro, Merck) in 575 patients.
As Healio previously reported, DARE-19 showed dapagliflozin did not significantly reduce risk for organ failure or death or improve recovery among adults hospitalized with COVID-19 vs. placebo, though data showed lower event numbers among treated patients.
In the meta-analysis, SGLT2 inhibitors had no impact on the primary endpoint of all-cause mortality at 28 days (OR = 0.93; 95% CI, 0.79-1.08; P = .33); or on the prespecified secondary outcomes of in-hospital all-cause mortality (OR = 0.85; 95% CI, 0.6-1.22; P = .37); 90-day all-cause mortality (OR = 0.82; 95% CI, 0.62-1.1; P = .18) or renal or invasive mechanical ventilation outcomes. Kosiborod noted that data on in-hospital and 90-day mortality were not available from the RECOVERY trial.
The findings were consistent across all subgroups.
In safety analyses, ketoacidosis incidence was rare across the three trials, Kosiborod said during the press conference, noting ketoacidosis was a concern with SGLT2 inhibitor use early in the pandemic.
“Our findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalized with COVID-19,” Kosiborod said. “Our data suggest that there is no compelling need to discontinue SGLT2 inhibitor use in the setting of acute illness in patients being managed for chronic conditions, such as HF, chronic kidney disease or type 2 diabetes that happen to be hospitalized for other reasons.”
Perspective
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Gregg C. Fonarow, MD, FACC, FAHA, FHFSA
SGLT2 inhibitors provide substantial clinical benefits to patients with heart failure, patients with chronic kidney disease and patients with type 2 diabetes. For patients with HF, across the entire spectrum of left ventricular ejection fraction, early in-hospital initiation of SGLT2 inhibitor therapy improved clinical outcomes and was generally safe and well-tolerated.
However, in clinical trials and clinical series, there has been a small risk for diabetic ketoacidosis (DKA) and euglycemic diabetic ketoacidosis. The incidence of DKA with SGLT2 inhibitors may be in the range 0.1 to 0.8 per 1,000 patient-years.
Hospitalization or major surgery may be a trigger for DKA in vulnerable patients. Currently, the FDA label recommends holding SGLT2 inhibitors for 3 to 5 days prior to planned surgeries. However, some also have recommended not starting or discontinuing SGLT2 inhibitors in hospitalized patients not undergoing planned surgery.
This new analysis of three randomized controlled trials involved over 6,000 patients randomly assigned to an SGLT2 inhibitor or matching placebo while hospitalized with COVID-19. While these studies did not demonstrate a benefit for treating COVID-19, these findings can be used to evaluate safety. There were no unexpected safety signals with SGLT2 inhibitors used in patients hospitalized with COVID-19.
These findings further suggest that there is not a need to routinely discontinue SGLT2 inhibitors in the setting of hospitalization for an acute illness. Further, these findings also suggest SGLT2 inhibitors can be safely initiated de novo in-hospital, if otherwise indicated, with overall tolerability comparable with placebo.
Nevertheless, clinicians should be aware that euglycemic DKA is a rare but important complication that can occur with these medications. Clinicians should be aware of the symptoms of DKA and know how to manage this condition.
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Kosiborod MN, et al. Hot line 9. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting).
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