Finally, A Foundational Heart Failure Drug That Works Across the Spectrum of EF

BARCELONA — With a major win in DELIVER, dapagliflozin (Farxiga) closed the gap on the types of heart failure (HF) proven to be treated safely by SGLT2 inhibition.

People with HF with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) alike had a reduced risk of cardiovascular (CV) death and worsening HF over a median 2.3 years when if randomized to dapagliflozin instead of placebo (16.4% vs 19.5%, HR 0.82, 95% CI 0.73-0.92), according to Scott Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School.

With a number needed to treat of just 32 in these patients, the efficacy of SGLT2 inhibition is likely to extend across the full range of left ventricular ejection fraction (LVEF), Solomon said in a presentation at the European Society of Cardiology (ESC) meeting. The results were simultaneously published in the New England Journal of Medicine (NEJM). Developer AstraZeneca announced topline results in May 2022.

Ten other publications from the DELIVER group were released, including large meta-analyses pooling the new data with DAPA-HF and EMPEROR-Preserved. In totality, the evidence supported the use of SGLT2 inhibitors for HF regardless of LVEF.

“Provided they have no contraindications, dapagliflozin could be prescribed to patients before ejection fraction is measured, speeding up access to this life-saving medication,” said Pardeep Jhund, MBChB, PhD, of University of Glasgow, who analyzed DELIVER and DAPA-HF together.

“This is important clinically as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” he added.

There was no uptick in serious adverse events (including death) or assigned treatment discontinuation associated with dapagliflozin in DELIVER.

Dapagliflozin’s benefits were consistent for people above and below LVEF 60% — unlike empagliflozin (Jardiance) in the EMPEROR-Preserved trial — and people with or without diabetes.

Moreover, the primary efficacy result was driven by a reduction in worsening HF, defined as unplanned hospitalizations or urgent visits for HF. The selective oral SGLT2 inhibitor did not significantly reduce CV deaths.

SGLT2 inhibitors were originally developed as diabetes drugs that lower blood sugar. By orders of the FDA to monitor their CV safety, they were subsequently and surprisingly shown to work for HF with reduced ejection fraction.

Even better, both dapagliflozin and empagliflozin can now be said to improve outcomes of people with HFpEF, a group that historically hasn’t responded to other HF medications.

Solomon concluded at an ESC press conference that the strength of the evidence suggests “very strongly” clinicians should be using these drugs in the vast majority of patients with HF. The question now is how to put this in practice.

“The next frontier is to equitably implement SGLT2 inhibitors, and other therapies, by overcoming barriers to delivery of optimal care. If done right, the future can surely be brighter for longer life and better health for all patients with heart failure,” wrote Katherine Tuttle, MD, of the University of Washington in Seattle, and Janani Rangaswami, MD, of George Washington University School of Medicine in Washington, in a Lancet comment.

U.S. guidelines currently list SGLT2 inhibitors as class IIA (level B) for the treatment of HFpEF and HFmrEF. A stronger recommendation may be warranted on the basis of DELIVER, suggested ESC communications chair Carlos Aguiar, MD, of Hospital Santa Cruz in Lisbon.

DELIVER was conducted at 350 sites in 20 countries. The study cohort counted 6,263 individuals averaging age 72, with 44% being women. The two groups were well matched at baseline, according to the authors.

Investigators had participants randomized to dapagliflozin 10 mg once daily or placebo atop usual HF medications.

Dapagliflozin required no substitution of existing therapy and did perform worse in users of mineralocorticoid receptor antagonists.

Notably, DELIVER featured broad enrollment that included HF patients who were hospitalized or recently hospitalized. All were required to have LVEF over 40% at the time of enrollment — and it didn’t matter if LVEF had previously fallen before recovering back over the threshold.

“Such patients are typically excluded from clinical trials of treatments for heart failure and a preserved ejection fraction. However, recent reviews and guidelines highlight the fact that patients with heart failure and an improved LVEF have worse outcomes than patients with no history of heart failure, even when the LVEF has improved to within the normal range,” commented Kenneth Margulies, MD, of University of Pennsylvania in Philadelphia, in a NEJM editorial.

Dapagliflozin users had improved symptoms that tracked with their better clinical outcomes throughout the trial.

Despite the broadness of heart failure cohorts benefiting from SGLT2 inhibitors, there are still groups in whom the drug was not sufficiently studied. These include Black people and people with kidney disease, complained Tuttle and Rangaswami.

Margulies added that it is also unknown whether the benefits of SGLT2 inhibitors extend to patients with HFpEF due to cardiomyopathies.

The mechanism by which this class of drugs help in HF also remains a mystery.