DARE-19: Dapagliflozin could target key mechanisms activated in COVID-19
Click Here to Manage Email Alerts
SGLT2 inhibitors could potentially target key mechanisms activated in COVID-19, increasing lipolysis, reducing glycolysis, inflammation and oxidative stress, and improving endothelial function to reduce organ damage, according to a speaker.
“We know that favorable effects on mechanisms such as endothelial function, a key driver of adverse outcomes in COVID-19, can occur very quickly after treatment with SGLT2 inhibitors,” Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute, professor of medicine at the University of Missouri-Kansas City School of Medicine, said during an online presentation during the virtual Heart in Diabetes conference. “If you think through these mechanisms and the fact that SGLT2 inhibitors can have a positive impact on many of them, what becomes clear is that testing SGLT2 inhibitors as potential agents for organ protection in COVID-19 may be one of the key hypotheses.”
The concept is relatively simple, Kosiborod said. Viral replication and spread after COVID-19 infection trigger metabolic derangements that lead to inflammatory “overdrive,” endothelial injury and, ultimately, organ damage leading to complications and death. Data suggest antiviral treatments can work in the early phase of the disease; anti-inflammatory medications show promise during the mid-phase of the disease.
“The idea is that metabolic mediation and organ protection can be effective in that intermediate phase of the disease, prior to occurrence of organ damage,” Kosiborod said. “SGLT2 inhibitors can be one of the important links in organ protection that needs to be tested.”
DARE-19 study design
Recruitment for a global phase 3 trial, DARE-19, is already underway to assess the potential of the SGLT2 inhibitor dapagliflozin (Farxiga) as a treatment to reduce COVID-19 complications and death among adults with cardiovascular, metabolic or renal risk factors, Kosiborod said.
The trial design is supported by extensive data on the protective effect of dapagliflozin among adults with heart failure with reduced ejection fraction (HFrEF), chronic kidney disease or type 2 diabetes.
“We already know SGLT2 inhibitors provide organ protection,” said Kosiborod, also a principal investigator for DARE-19. “We know because we have done randomized clinical trials in patients with cardiometabolic disease, such as type 2 diabetes, those with HF and those with CKD. We know they have substantial cardioprotective and nephroprotective properties.”
DARE-19 is an international, parallel-group, randomized double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of dapagliflozin in addition to background, local standard of care therapy on the risk for all-cause death or disease progression and complications among adults hospitalized with COVID-19 at the time of trial enrollment. Patients enrolled in DARE-19 also have a medical history of hypertension, atherosclerotic CVD, HFrEF, HFpEF, type 2 diabetes or stage 3 or 4 CKD. The primary efficacy outcome is time to first occurrence of death from any cause or new or worsening organ dysfunction through 30 days of follow-up. The DARE-19 trial is open for enrollment in the U.S. and European countries with a high COVID-19 burden and aims to recruit approximately 900 patients.
Kosiborod said the trial protocol excludes people with type 1 diabetes or with prior history of diabetic ketoacidosis. Concern has been raised during previous trials about the risk for DKA with use of SGLT inhibitors for treatment of type 1 diabetes.
“We have built in robust safety measures to minimize any risk for DKA,” he said.
Debunking SGLT2 ‘misconceptions’
Kosiborod said there is a common misconception about SGLT2 inhibitors: The benefits of the drug class take time to be realized, making such drugs a less-than-ideal choice in the setting of an acute illness like COVID-19, Kosiborod said.
“In fact, that is not entirely true,” he said. “If we look at data from DAPA-HF, for example, we see the benefits emerge quite early — in the first few days — and become statistically significant after 28 days.”
Additionally, as disease severity progresses, the benefits of SGLT2 inhibitors appear more pronounced, at least for HF, he said. He added that the benefits do not appear to be related entirely to a diuretic effect, another common misconception.
“Looking at patients that had HF in the last 12 months [in DAPA-HF as compared to those without recent HF hospitalization]... you can see certainly that the absolute benefits, and possibly even the relative benefits, of SGLT2 inhibitors preventing disease progression actually are amplified in patients with greater disease severity, with nearly 10% absolute risk reduction for CV death or worsening HF,” Kosiborod said.
Kosiborod said recruitment for DARE-19, currently taking place in the U.S. and Brazil and soon to be expanded to other countries, may be complete by the end of this year.
“Successful treatment approach to COVID-19 will likely require a broad array of interventions, and strategies aimed at organ protection should clearly be pursued along with antiviral and anti-inflammatory agents,” Kosiborod said.
Perspective
Back to Top
Collapse
Kosiborod M. Ongoing research of COVID-19 complications and management — Focus on DARE-19. Presented at: Heart in Diabetes CME Conference; Aug. 21- 24, 2020, 2019; (virtual meeting).
Read more about
Click Here to Manage Email Alerts