ADA 2021: Dapagliflozin Use in Patients with COVID-19

Dapagliflozin has shown clinical effectiveness in some of the same metabolic processes that are affected by COVID-19, but can it help treat patients who have contracted the virus?

Dapagliflozin has shown clinical effectiveness in metabolic processes such as decreased glycolysis, decreased inflammation, and improved endothelial function, to name a few. These same processes are negatively affected by COVID-19. So, is there any benefit to using dapagliflozin in patients with or without type 2 diabetes that have COVID-19? 

COVID-19 acts systemically in patients, thus affecting multiple organ systems. This systemic coverage is especially apparent among patients with organ compromising conditions such as hypertension, type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD). Thus, while dapagliflozin may not combat the virus itself, the idea is to provide organ protection while the patient has COVID-19. This concept leads to the purpose of assessing dapagliflozin in preventing organ failure, death from any cause, and improving recovery in patients with COVID-19 that have metabolic risk factors.  

The study design included randomizing 1250 patients from seven countries into two intervention groups with a 30-day treatment period followed by a 60-day observational period.  

The treatment group [With diabetes (n=312) and Without diabetes (n=312)] had received dapagliflozin 10 mg per day. The placebo group [With diabetes (n=324) and Without diabetes (n=300)] received a placebo daily. The inclusion criteria for this clinical trial were hospitalization with COVID-19 for no more than four days, along with one or more risk factors, O2 saturation greater than 94% on five liters per minute, and chest x-rays consistent with COVID-19. The primary endpoints were the composite of death from any cause or organ dysfunction and the recovery ranking of each patient. Secondary endpoints are safety outcomes such as adverse events, including acute kidney injury (AKI) and diabetic ketoacidosis (DKA).  

In time to organ failure or death, dapagliflozin had 70 events compared to 86 events in the placebo group with an overall hazard ratio of 0.80 [95% confidence interval (CI): 0.58 to 1.10, P-value = 0.168]. When categorized by diabetes status, patients with diabetes that received dapagliflozin experienced 34 events with a hazard ratio of 0.76 (95% CI: 0.49 to 1.18, P-value = 0.225). As for patients without diabetes that received dapagliflozin, this group experienced 36 events with a hazard ratio of 0.86 (95% CI 0.55 to 1.35, P-value = 0.507). The overall win ratio for this study was 1.09 (95% CI: 0.97 to 1.22, P-value = 0.14) for the hierarchical composite endpoint. If the win ratio resulted in a number greater than one, this favored the dapagliflozin group compared to placebo. Patients with diabetes had a win ratio of 1.01 (95% CI: 0.86 to 1.18), while patients without diabetes had a win ratio of 1.18 (95% CI: 1.00 to 1.38). The all-cause mortality resulted in a hazard ratio of 0.77 (95% CI: 0.52 to 1.16), with only 41 events in the dapagliflozin group and 54 events in the placebo group.  

The safety outcomes resulted in an overall risk difference of -2.71 (95% CI: -6.37 to 0.93) for any serious adverse event. Similar results occurred in patients with and without diabetes, -1.63 (95% CI: -7.02 to 3.79) and -3.38 (95% CI: -8.39 to 1.49), respectively. The overall risk difference was -2.09 (95% CI: -4.52 to 0.23) when looking at AKI. As for DKA, the overall risk difference was 0.33 (95% CI: -0.30 to 1.18), with only two patients from the dapagliflozin group having had non-fatal DKA, which quickly resolved. While in the hospital, the data collected for serum bicarbonate, eGFR, hematocrit, and glucose levels showed no difference in levels between intervention arms.   

Dapagliflozin demonstrated fewer organ failure and mortality outcomes as well as improved recovery compared to placebo. These findings were uniform regardless of diabetes status. Notably, dapagliflozin tolerance was a positive trend as seen with the stable laboratory values and fewer adverse events than placebo, excluding the two incidences of non-fatal DKA. However, dapagliflozin use in patients with COVID-19 showed no significant difference compared to placebo despite fewer adverse events. A clinical implication of this study includes not supporting a previous recommendation that suggested discontinuing SGLT-2 inhibitor use in patients with COVID-19. Another clinical significance is that dapagliflozin showed manageable tolerance for this patient population, and continued use with appropriate monitoring is the preferred recommendation.  

Practice Pearls 

• Despite fewer events in the dapagliflozin group, there was no statistically significant difference between interventions.  
• Dapagliflozin was well tolerated in patients with COVID-19 regardless of diabetes status. 
• When indicated, dapagliflozin continuation is appropriate with proper monitoring in COVID-19 patients.  

Kosiborod, Mikhail N, et al. “Efficacy and Safety of Dapagliflozin in Patients with and without Type 2 Diabetes Hospitalized with COVID-19—Results from the DARE-19 Global Randomized Controlled Trial.” American Diabetes Association 81st Scientific Sessions, June 2021. (ADA Symposium login required) 

Alan Martinez, PharmD Candidate, University of South Florida Taneja College of Pharmacy