Efficacy and safety of dapagliflozin in severe chronic HF

In a pooled analysis of DAPA-HF and DELIVER, severe HF was associated with increased risk of CV death or worsening HF events regardless of LVEF. Dapagliflozin treatment appeared to be safe and effective in reducing this risk compared with placebo regardless of severe HF status.

This summary is based on the publication of Inciardi RM, Lu H, Claggett BL, et al. - Severe Heart Failure and Treatment With Dapagliflozin Across the Ejection Fraction Spectrum: DAPA-HF and DELIVER. JACC Heart Fail. 2025 Apr;13(4):618-627. doi: 10.1016/j.jchf.2024.11.023.

Introduction and methods

Background

Despite maximum GDMT, some patients with chronic HF develop persistently severe symptoms, resulting in high morbidity and mortality [1,2]. In addition, as HF progresses, patients may become less tolerant to these medications due to hypotension or kidney dysfunction. SGLT2 inhibitors decrease both morbidity and mortality risks in chronic HF patients irrespective of LVEF [3], but it is unknown whether they are an effective and safe treatment for those with severe HF.

Aim of the study

The study aim was to investigate the safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with severe HF across the LVEF spectrum.

Methods

This was a post-hoc pooled, participant-level analysis of 2 global, double-blind, placebo-controlled, phase 3 RCTs among patients with symptomatic HF: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure). In the DAPA-HF trial, 4744 ambulatory patients with NYHA class II–IV HF symptoms, LVEF ≤40%, and elevated NT-proBNP levels were included [4], whereas the DELIVER trial comprised 6263 ambulatory and hospitalized patients with NYHA class II–IV HF symptoms, LVEF >40%, elevated NT-proBNP levels, and evidence of structural heart disease [5]. In both trials, participants were randomized to dapagliflozin 10 mg once daily or placebo, in addition to usual therapy.

Severe HF was defined according to the ESC Heart Failure Association criteria: (1) NYHA class III–IV HF symptoms; (2) evidence of HFrEF, HFmrEF, or HFpEF; (3) HF hospitalization ≤12 months prior; and (4) impaired health status as measured with the KCCQ – Total Symptom Score (i.e., <75 points) [6]. Data to identify severe HF were available for 10,948 patients, of whom 730 (6.7%) met the definition of severe HF (296/4722 (6.2%) with LVEF ≤40%, 192/2101 (9.1%) with LVEF 41%–49%, and 232/4125 (5.6%) with LVEF ≥50%). Median follow-up time of the combined dataset was 22 months.

Outcomes

The primary efficacy endpoint in both trials was the composite outcome of CV death or worsening HF events (i.e., unplanned HF hospitalization or urgent HF visit requiring intravenous therapy). Secondary efficacy endpoints of the current analysis were the individual components of the primary endpoint, HF hospitalization, and all-cause mortality.

Safety assessment included the frequencies of adverse events, serious adverse events, major hypoglycemic events, diabetic ketoacidosis, and serious renal adverse events.

Main results

Efficacy

• In a Cox proportional hazards analysis stratified by diabetes status and trial and adjusted for baseline variables such as age, sex, and LVEF, the incidence rate of the primary endpoint (CV death or worsening HF events) was 19.8 per 100 patient-years (95%CI: 17.4–22.5) in patients with severe HF and 9.7 per 100 patient-years (95%CI: 9.2–10.2) in those with nonsevere HF (adjusted HR: 1.85; 95%CI: 1.60–2.12), with no interaction by LVEF (P for interaction=0.98).
• Treatment with dapagliflozin reduced the risk of the primary endpoint compared with placebo in both patients with severe HF (HR: 0.73; 95%CI: 0.56–0.95) and those with non-severe HF (HR: 0.79; 95%CI: 0.72–0.87), with no interaction between severe HF status and treatment effect (P for interaction=0.48). The beneficial effects of dapagliflozin were consistent across LVEF categories (≤40% vs. >40%) regardless of severe HF status (3-way P for interaction with continuous LVEF=0.52).
• For the secondary endpoints, the treatment effects of dapagliflozin versus placebo were also consistent regardless of severe HF status (all P for interaction>0.05).

Safety

• The frequencies of adverse events leading to discontinuation of the study drug and serious adverse events were similar between patients treated with dapagliflozin and placebo-treated patients regardless of severe HF status (both P for interaction>0.05).
• Additionally, the rates of serious renal adverse events and volume depletion were similar between both treatment groups in patients with and with no severe HF (both P for interaction>0.05).

Conclusion

In this post-hoc pooled, participant-level analysis of the DAPA-HF and DELIVER trials, 7% of the patients with symptomatic HF had severe HF, and this was associated with increased risk of the primary composite outcome of CV death or worsening HF events regardless of LVEF. Treatment with dapagliflozin reduced this risk compared with placebo regardless of severe HF status and LVEF category. The safety profile of dapagliflozin was consistent regardless of severe HF status. The authors conclude their “data support the role of SGLT2 inhibitors in patients with more advanced HF stages for whom current treatment options might be limited or not well tolerated.”

Find this article online at JACC Heart Fail.

References

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