Dapagliflozin Proves HFpEF Benefit in DELIVER Trial

Use of dapagliflozin (Farxiga) was associated with an 18% reduction in worsening heart failure or cardiovascular death among patients with heart failure with preserved ejection fraction (HFpEF), according to the results of the phase 3 DELIVER trial.

Less than 3 months after AstraZeneca announced the trial had met its primary endpoint back in May, results of the study build on the evidence from EMPEROR-Preserved and contribute to the idea that the benefits seen in HFpEF could be a class effect for SGLT2 inhibitors.

“Taken together with previous research in heart failure patients with reduced ejection fraction, these data suggest that dapagliflozin is effective regardless of ejection fraction and support the use of SGLT2 inhibitors as foundational therapy in all patients with heart failure,” said Scott Solomon, MD, of Brigham and Women's Hospital, in a statement.

The journey of SGLT2 inhibitors from hypoglycemic agents to cardiorenal protective agent has been well-documented and, often, the European Society of Cardiology (ESC) congress has been centerstage for showcasing the milestone trials in recent years, with EMPEROR-Preserved at ESC 21 and both EMPEROR-Reduced and DAPA-CKD at ESC 20. Now, DELIVER joins that group of landmark trials with Solomon’s presentation at ESC 22.

Launched in 2018 with the intent of assessing the effects of dapagliflozin use among patients with heart failure and a left ventricular ejection fraction greater than 40%, the phase 3 DELIVER trial was designed as multicenter, parallel-group, event-driven, double-blind, randomized, controlled trial and conducted across 353 centers in 20 countries. From August 27, 2018-December 30, 2020, a total of 10,418 patients underwent screening and 6263 were deemed eligible for inclusion. These individuals were randomized in a 1:1 ratio to 10 mg once daily dapagliflozin or placebo therapy, with 3131 randomized to dapagliflozin and 3132 randomized to placebo therapy.

Among the dapagliflozin group, the mean age was 71.8±9.6 years, 43.6% were female, and 70.7% were White. The mean ejection fraction of this group was 54.0±8.6%, with 34.1% having an ejection fraction of 49% or less, 36.2% having an ejection of 50-59%, and 29.7% having an ejection fraction of 60% or greater. Among the placebo group, the mean age was 71±9.5 years, 44.2% were female, and 71.0% were White. The mean ejection fraction of this group was 54.3±8.9%, with 33.5% having an ejection fraction of 49% or less, 35.9% having an ejection fraction of 50-59%, and 30.7% having an ejection fraction of 60% or greater.

The primary outcome of the trial was the occurrence of worsening heart failure or cardiovascular death and was assessed in a time-to-event analysis using a Cox proportional hazards model. Worsening heart failure was defined as an unplanned hospitalization for heart failure or an urgent visit for heart failure. Investigators highlighted multiple secondary and safety outcomes of interest, including total number of primary outcome events.

During a median of 2.3 (IQR, 1.7-2.8) years of follow-up, a primary outcome event was identified among 16.4% (n=512) of the dapagliflozin group and among 19.5% (n=610) of the placebo group (HR, 0.82 [95% CI, 0.73-0.92]; P <.001), with investigators noting similar results observed for those with an ejection fraction of less than 60% compared to those of the overall population (HR, 0.83 [95% CI, 0.73-0.95]; P=.009). When assessing individual components of the primary outcome, a reduction in rate of hospitalization for heart failure or urgent visit for heart failure (HR, 0.79 [95% CI, 0.69-0.91]) and cardiovascular death (HR, 0.88 [95% CI, 0.74-1.05]) was observed for the dapagliflozin group compared to the placebo group.

Among secondary outcomes of interest, investigators highlighted a significant reduction in total number of worsening heart failure events and cardiovascular deaths with dapagliflozin use, with 815 such events occurring in the dapagliflozin arm and 1057 occurring in the placebo arm (HR, 0.77 [95% CI, 0.67-0.89]; P <.001). In safety analyses, serious adverse events, including death, were identified among 43.5% (n=1361) of the dapagliflozin group and among 45.5% (n=1423) of the placebo group, with investigators also noting discontinuation due to adverse events among 5.8% of the dapagliflozin group and 5.8% of the placebo group.

In an editorial published in NEJM, Kenneth B. Margulies, MD, professor of medicine at the Hospital of the University of Pennsylvania, applauded investigators of DELIVER for their efforts and contributions, but noted the rapid ascent of SGLT2 inhibitors has left unanswered questions surrounding their apparent breadth of benefit.

“Despite progress to date, more work is needed to fully define the role of SGLT2 inhibitors in patients with heart failure and a preserved ejection fraction. Owing to the very low enrollment of patients who identified as Black in both the DELIVER trial and the EMPEROR-Preserved trial, it is still not known whether this patient subgroup benefits from treatment with SGLT2 inhibitors,” Margulies wrote. “It is also unknown whether the benefits of SGLT2 inhibitors extend to patients with heart failure and a preserved ejection fraction due to cardiomyopathies, since patients with these cardiomyopathies were excluded from both trials. Finally, there is a need to better define the mechanisms by which SGLT2 inhibitors provide therapeutic benefit among patients with heart failure and a preserved ejection fraction.”

This study, “Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction,” was presented at ESC 22 and simultaneously published in the New England Journal of Medicine.