DAPA-HF Trial: Compared to Placebo, Dapagliflozin Was Beneficial in Patients with Heart Failure and Reduced Ejection Fraction Regardless of Background Diuretic Therapy

A recent study by Dr. Alice M. Jackson M.D., published in Circulation journal, showed that the use of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with reduced ejection fraction heart failure (HF) is associated with reduced risk of cardiovascular (CV) death or a worsening HF event, and all-cause death. These effects remained consistent among different subgroups of diuretic therapy. 

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been known for their glucosuric effects. In addition to glucose, their application leads to sodium and water excretion, an action that might be beneficial in patients with heart failure. Diuretics are one of the treatment arms of heart failure. However, there is little data regarding the efficacy of adding an SGLT2 inhibitor to conventional diuretic therapy in patients with heart failure. Another issue that should be considered is the possibility of volume depletion by adding these agents to a diuretic. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) investigated the interaction between dapagliflozin and diuretic therapy in patients with heart failure and reduced ejection fraction (HFrEF).

This substudy from the trial recruited patients with HFrEF. Patients with a New York Heart Association (NYHA) class II-IV with an ejection fraction of 40% or lower and elevated N-terminal B-type natriuretic peptide (NT-proBNP) level were eligible to participate in the study. The participants received the optimal pharmacological and device therapy for HFrEF based on the guideline recommendations. The main exclusion factors were symptomatic hypotension, systolic blood pressure lower than 95mmHg, and renal function impairment or type 1 diabetes. Participants were randomized in a 1:1 ratio to receive either placebo or dapagliflozin, 10 mg daily. A history of diabetes or a glycated hemoglobin level of 6.5%  or higher at the screening was used for stratification of the individuals into two groups. Follow-up sessions were held at 14 days, 2 and 4 months, and 4-monthly thereafter. The primary outcomes of the study were an unplanned hospitalization or an event leading to intravenous therapy due to heart failure or, cardiovascular (CV) death. Safety events included all serious adverse events as well as an event resulting in study drug discontinuation.

The study resulted in 4616 patients, 3880 had received an identifiable diuretic. Of those receiving diuretics, 1365 patients were taking a “furosemide equivalent” dose of 40 mg. Other participants either received a dose less or greater than 40 mg or a non-loop diuretics. The data demonstrated that compared to placebo, dapagliflozin use was associated with a reduction in primary outcomes irrespective of status and dose of background diuretic. The hazard ratio (HR) across the subgroups of diuretic use was as follows: No diuretic use (HR:0.57 [95% CI:0.36-0.92]), diuretic dose equivalent to furosemide <40mg daily (HR: 0.83 [95% CI:0.63-1.10]), 40mg daily (HR: 0.77 [95% CI:0.60-0.99]), and >40mg daily (HR: 0.78 [95% CI:0.63-0.97]).

According to this trial, dapagliflozin use was beneficial among all the subcategories of diuretic use despite noticeable differences in patients demographics between the subgroups. Participants receiving the highest dose of diuretic had the highest risk of primary outcomes compared to those receiving no diuretics. The safety component of the study was variable among the different subgroups of diuretic use. However, compared to placebo, dapagliflozin safety, and tolerability were consistent across the various subgroups. And treatment with dapagliflozin did not lead to a change in the dose or status of diuretic use during the follow-up period.

Finally, the results of this research should be interpreted in light of the following limitations: First, the dose of furosemide equivalent diuretic was not available for all the participants. Second, there might be some changes in the diuretic dosage in the participants that were not considered in the analysis. Third, the results of this study may not be generalizable to patients not fulfilling the inclusion criteria of the study.