Hot Line - SGLT2 inhibitors deliver in patients with preserved and mildly reduced ejection fraction

Patients with preserved or mildly reduced ejection fraction (LVEF >40%) now represent the majority of patients with heart failure (HF). Although they experience a comparable burden of poor outcomes to those with LVEF ≤40%, there has been a large clinical unmet need for effective therapies.¹

Professor Scott Solomon (Brigham And Women's Hospital, Harvard Medical School - Boston, USA) began a Hot Line session yesterday by presenting eagerly awaited results from the DELIVER trial, which was designed to determine whether the SGLT2 inhibitor, dapagliflozin, could decrease CV morbidity and mortality in these patients.

This event-driven, double-blind international trial included 6,263 patients aged ≥40 years with symptomatic HF and LVEF >40% who were either chronic outpatients, hospitalised or recently hospitalised, and also included patients who previously had LVEF ≤40% (i.e. HF with improved LVEF). Patients were randomised 1:1 to receive dapagliflozin 10 mg once daily or placebo, in addition to standard of care. The primary endpoint was a composite of CV death or worsening HF event (HF hospitalisation or urgent HF visit).

Across the total study population, the average age was 72 years and 44% were women. Average LVEF was 54% and 18% of patients had previously had an LVEF ≤40%. At randomisation, 77% of patients were taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or angiotensin receptor neprilysin inhibitor, 83% were taking a beta-blocker and 43% were taking a mineralocorticoid receptor antagonist.

Over a median 2.3 years, the occurrence of CV death or a worsening HF event was reduced with dapagliflozin (16.4%) versus placebo (19.5%; hazard ratio [HR] 0.82; 95% CI 0.73 to 0.92; p<0.001).

Dapagliflozin also reduced components of the primary endpoint, primarily worsening HF, which occurred in 11.8% of patients in the dapagliflozin group and 14.5% of patients in the placebo group (HR 0.79; 95% CI 0.69 to 0.91), while CV death occurred in 7.4% and 8.3% of patients, respectively (HR 0.88; 95% CI 0.74 to 1.05). Reductions were seen in key secondary outcomes in patients receiving dapagliflozin compared with placebo, including total HF hospitalisations and CV death (rate ratio 0.77; 95% CI 0.67 to 0.89) and total symptom burden, assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference in the KCCQ total symptom score 2.4; 95% CI 1.6 to 3.2).

Summing up the findings, Prof. Solomon says: “We found that dapagliflozin significantly reduced the primary composite endpoint by 18%, with numerically lower rates of all components of the primary endpoint. These benefits were consistent across prespecified subgroups, with similar benefits in patients with LVEF at, below, or above 60%, those with HF with improved LVEF, as well as in patients who were hospitalised recently, and improvement in symptoms was observed.”

Next, Professor Pardeep Jhund (University of Glasgow - Glasgow, UK) presented a pooled analysis that investigated the effects of dapagliflozin 10 mg across the full spectrum of ejection fractions. This was a prespecified patient-level meta-analysis of data from DELIVER in patients with LVEF >40% and data from the already published DAPA-HF trial in patients with reduced LVEF (≤40%).² The first aim was to assess the effect of dapagliflozin on several secondary outcomes that each trial alone was not powered to examine. The second aim was to evaluate if dapagliflozin was effective across the entire LVEF range, since the EMPEROR-Preserved trial previously suggested that the effect of another SGLT2 inhibitor, empagliflozin, may be attenuated in patients with higher ejection fraction.³

Across the 11,007 patients in the two trials and with median follow up of 1.8 years, dapagliflozin reduced the risk of CV death by 14% (HR 0.86; 95% CI 0.76 to 0.97; p=0.01), and there were reductions in all-cause death (HR 0.90; 95% CI 0.82 to 0.99; p=0.03), total hospital admissions for HF (relative risk 0.71; 95% CI 0.65 to 0.78; p<0.001) and major adverse cardiovascular events (CV death, myocardial infarction or stroke; HR 0.90; 95% CI 0.81 to 1.00; p=0.045). There was no evidence that the effect of dapagliflozin differed by LVEF for any of the outcomes. Prof. Jhund remarks, “Our findings confirm that all patients with HF, regardless of ejection fraction, may benefit from dapagliflozin in addition to any other HF therapy they are receiving.”

Delving further into the class effects of SGLT2 inhibitors in HF patients with mildly reduced and preserved ejection fraction, Doctor Muthiah Vaduganathan (Brigham And Women's Hospital, Harvard Medical School - Boston, USA) presented a prespecified meta-analysis of participant-level data from DELIVER (dapagliflozin) and from EMPEROR-Preserved (empagliflozin).

When the data were pooled (n=12,251), the SGLT2 inhibitors were shown to reduce the risk of the primary outcome of CV death or first hospitalisation for HF by 20% (HR 0.80; 95% CI 0.73 to 0.87; p<0.001). Substantial reductions in HF hospitalisations were observed (HR 0.74; 95% CI 0.67 to 0.83), with more modest reductions in CV death (HR 0.88; 95% CI 0.77 to 1.00). SGLT2 inhibitors reduced total HF hospitalisations by 27%, urgent HF visits by 35% and all-cause hospitalisations by 7%, but with no significant effect on all-cause death. Treatment effects were consistent across all 12 subgroups including patients at the highest end of the ejection fraction spectrum and those already treated with other HF medicines. The drugs also improved multiple domains of health-related quality of life as assessed by the KCCQ.

Dr. Vaduganathan concludes, “This meta-analysis summarises the totality of evidence on SGLT2 inhibitors in HF with an LVEF above 40% and supports their use as foundational therapy in this population,” providing a fitting overview of the Hot Line session.