Among patients with heart failure (HF) and a mildly reduced or preserved ejection fraction, dapagliflozin resulted in a lower risk of worsening HF or cardiovascular death compared with placebo, according to findings from the DELIVER trial. The results, presented at ESC Congress 2022 and simultaneously published in the New England Journal of Medicine, add to the evidence surrounding SGLT2 inhibitors in patients with a higher left ventricular ejection fraction (LVEF).

The study, which was presented by Scott D. Solomon, MD, FACC, enrolled 6,263 patients with HF and a LVEF of more than 40% from 350 sites in 20 countries. Participants were randomly assigned to receive either dapagliflozin (10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening HF or cardiovascular death, as assessed in a time-to-event analysis. The median follow-up was 2.3 years.

Results found the primary outcome occurred in 512 of the 3,131 patients (16.4%) in the dapagliflozin group and in 610 of the 3,132 patients (19.5%) in the placebo group. Researchers observed worsening HF in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group. Cardiovascular death occurred in 231 patients (7.4%) in the dapagliflozin group and 261 patients (8.3%) in the placebo group.

In other findings, total events and symptom burden were lower in the dapagliflozin group. In addition, researchers noted that overall results were consistent across prespecified subgroups, including those defined according to LVEF and those with or without diabetes.

"These data provide further evidence to support the use of an SGLT2 inhibitor as essential therapy in patients with HF, regardless of the presence or absence of type 2 diabetes mellitus or LVEF," said Solomon and colleagues. They added the results from DELIVER "may inform future guidelines and provide further guidance for their broader use in clinical practice."

In a related editorial comment, Kenneth B. Margulies, MD, writes that "the DELIVER trial should inspire future trials of promising therapeutics for HF with a preserved ejection fraction (HFpEF) that would include the important and growing contingent of patients with HF and an improved LVEF." However, he cautions that despite the progress being made "more work is needed to fully define the role of SGLT2 inhibitors" in patients with HFpEF. He highlights the low enrollment of patients identifying as Black in both DELIVER and EMPEROR-Preserved, as well as limited data on the benefits of SGLT2 inhibitors in patients with HFpEF due to cardiomyopathies.

Related DELIVER analyses were also published in JACC, JACC: Heart Failure, Circulation and Lancet. Highlights from these papers include:

• Dapagliflozin similarly and safely reduced risk of worsening HF or cardiovascular death in patients with and without history of a recent hospitalization for HF, according to research from Jonathan W. Cunningham, MD, MPH, et al., and published in JACC. Researchers noted that starting dapagliflozin during or shortly after HF hospitalization in patients with preserved or mildly reduced LVEF appears safe and effective.
• A secondary analysis conducted by John J. V. McMurray, MD, FACC, and Jawad H. Butt, MD, and published in JACC, found clinical events and symptoms were not modified by atrial fibrillation (AFib) at baseline, irrespective of definition or type of AFib. "These findings provide further evidence for dapagliflozin as a new treatment option for patients with HF and mildly reduced or preserved ejection fraction," they explain.
• In a pre-specified analysis published in JACC, researchers applied validated nonparametric age-based methods to find that event-free survival was greater with dapagliflozin than with placebo across a wide starting age range and across 14 subgroups. Estimated event-free survival for an individual aged 65-years was 12.1 years with dapagliflozin and 9.7 years with placebo, representing a 2.3 year event-free survival gain (p=0.002).
• Meanwhile, a post-hoc analysis published in JACC: Heart Failure assessed the treatment effect of dapagliflozin across baseline levels of NT-proBNP and found higher NT-proBNP levels were linearly associated with a greater risk of cardiovascular death or worsening events. The results were consistent regardless of AFib or atrial flutter status. Additionally, researchers noted "the clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations." They added that "the effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles."
• A prespecified analysis conducted by Jawad H. Butt, MD, et al., looked at the efficacy and safety of dapagliflozin according to frailty in patients with HF and mildly reduced or preserved ejection fraction. The findings, published in Circulation, found "the benefit of dapagliflozin was consistent across the range of frailty studied and that improvements in health-related quality of life with dapagliflozin occurred early and was greater in patients with greater frailty."
• A meta-analysis of five randomized clinical trials, including DELIVER, conducted by Muthiah Vaduganathan, MD, and published in the Lancet found "SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalizations for HF in a broad range of patients with HF, supporting their role as a foundational therapy for HF, irrespective of ejection fraction or care setting."

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ESC Congress, ESC22, ACC International, Stroke Volume, Heart Failure, Glucosides, Benzhydryl Compounds

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