Dapagliflozin DELIVERs across full HF spectrum regardless of LVEF

The selective, oral sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of cardiovascular (CV) death or worsening heart failure (HF) in patients with HF and mildly reduced or preserved ejection fraction (HFmrEF or HFpEF) in the phase III DELIVER* trial, touted as the largest and most inclusive thus far in this patient group.

After a median follow-up of 2.3 years, there was an 18-percent reduction in the risk of the primary composite endpoint of CV death or worsening HF (hospitalization for HF [HHF] or urgent HF visit) with dapagliflozin vs placebo (16.4 percent vs 19.5 percent; hazard ratio [HR], 0.82; 95 percent confidence interval [CI], 0.73–0.92; p=0.0008).

“Looking at each component of the primary endpoint, there was a 21-percent significant reduction in the risk of worsening HF (HR, 0.79, 95 percent CI, 0.69–0.91; p=0.001),  and a 12-percent nonsignificant reduction in the risk of CV death (HR, 0.88, 95 percent CI, 0.74–1.05; p=0.17),” reported Professor Scott Solomon of Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US at ESC 2022.

Total HF events and symptom burden measured by the Kansas City Cardiomyopathy Questionnaire total symptom score were also lower with dapagliflozin than with placebo.

No attenuation of benefits with higher LVEF

“The results did not differ between patients with an LVEF above or below 60 percent. In the primary endpoint, for example, the hazard ratio was 0.77 among patients with an LVEF of ≥60 percent and 0.83 among those with lower LVEF,” Solomon shared. “With a number needed to treat of 32 over the course of the trial, the efficacy of SGLT2 inhibition extends across the full range of EF.”

This is an important finding as the EMPEROR-Preserved trial of another SGLT2 inhibitor, empagliflozin, reported at ESC 2021, though positive overall, suggested an apparent attenuation of benefits at the upper end of LVEF.

In DELIVER, dapagliflozin was also as effective in patients with recent HHF and those with prior HFrEF that had improved to >40 percent. Serious adverse events and adverse events leading to discontinuation were comparable between dapagliflozin and placebo.

“These data provide further evidence to support the use of an SGLT2 inhibitor as a foundational therapy for HF patients, regardless of care setting or LVEF,” Solomon concluded.

DELIVER is a multicentre, double-blind, placebo-controlled, event-driven trial that included 6,263 patients aged ≥40 years with NYHA class II–IV HF and an LVEF of >40 percent, evidence of structural heart disease, and elevated natriuretic peptides, enrolled either as ambulatory patients or during HHF. Patients with prior LVEF of ≤40 percent but had improved to >40 at the time of enrolment were allowed to enter the trial. [ESC 2022, Hotline Session 4; N Engl J Med 2022;doi:10.1056/NEJMoa2206286]

Patients received dapagliflozin 10 mg once daily (n=3,131) or placebo (n=3,132), on top of usual therapy, and were followed for a median of 2.3 years.

DELIVER and DAPA-HF pooled analysis

Meanwhile, a patient-level pooled meta-analysis of the DELIVER and DAPA-HF trials, also presented at ESC 2022, further bolstered the case for dapagliflozin in HF regardless of LVEF.

Study investigator Dr Pardeep Jhund from the University of Glasgow, Scotland said there was a wide range of EF (between 16 and 74 percent, mean 44 percent) among 11,007 patients included in the DAPA-HF and DELIVER trials. [Nat Med 2022;doi:10.1038/s41591-022-01971-4]

After a median follow-up of 22 months, there were significant reductions in CV death (HR, 0.86; p=0.01), all-cause death (HR, 0.90; p=0.03), total HHF (rate ratio [RR], 0.71; p<0.001), and major adverse cardiovascular events (CV death, MI, or stroke; HR, 0.90; p=0.045) with dapagliflozin vs placebo.

Similar with DELIVER alone, there was no indication that LVEF influenced the beneficial effect of dapagliflozin. This is important clinically as LVEF is not always measured in time, Jhund pointed out. “Patients often have to wait for a heart scan to measure EF and decide which therapies to take. Provided these patients have no contraindications, dapagliflozin could be prescribed before EF is measured, speeding up access to this life-saving medication.”