Urgency to Expand SGLT2i Use in HF Heightened by More DELIVER Data

NATIONAL HARBOR, Md. — The benefits of dapagliflozin (Farxiga) persisted in various secondary analyses of the DELIVER trial, building confidence for real-world benefits from the SGLT2 inhibitor for heart failure (HF) patients across the spectrum of ejection fraction.

Dapagliflozin had been deemed a new foundational drug for HF when DELIVER’s main finding was reported in August, showing that dapagliflozin significantly cut combined risk of cardiovascular death and worsening HF in patients with HF with preserved and mildly reduced ejection fraction (HFpEF, HFmrEF) alike over more than 2 years of follow-up.

Here at the Heart Failure Society of America (HFSA) annual meeting, additional findings from DELIVER showed that dapagliflozin was associated with:

• Consistent treatment effects between patients with HF and improved ejection fraction (HFimpEF) and those with EF persistently above 40%, with no treatment heterogeneity by EF
• A mortality benefit apparently driven by reductions in sudden death and HF deaths when pooling the DELIVER and DAPA-HF trials
• A time to clinical benefit starting around day 16 and sustained onwards

Dapagliflozin’s rapid clinical benefit creates “some urgency” for broader implementation in HF, argued Akshay Desai, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, who reported the pooled cause-specific mortality analysis at the meeting. Those findings also appeared online in JAMA Cardiology alongside another paper on the time-to-benefit analysis.

“I don’t think the urgency is felt,” he told the room. “We need to be asking the question of why that is the case.”

Dapagliflozin initially entered the market as a diabetes drug and has since gained FDA approved for patients with chronic kidney disease at risk of progression and for heart failure with reduced ejection fraction. It now awaits FDA’s verdict on an indication across the spectrum of ejection fraction on whether it can join fellow SGLT2 inhibitor empagliflozin (Jardiance) in treating HFpEF.

For a look at real-world generalizability, Muthiah Vaduganathan, MD, MPH, of Brigham and Women’s and Harvard, after presenting the time-to-benefit data also reported on an analysis of the national Get With the Guidelines-HF registry.

It projected that more than 75% of Medicare beneficiaries hospitalized for HFmrEF or HFpEF would have been eligible to enter DELIVER. If the trial’s 1-year results hold up in the real world, that large population would have seen an estimated 9% absolute risk reduction in the primary composite endpoint with a number needed to treat of just 11.

DELIVER included 6,263 patients (mean age 72, 44% women) in 20 countries who were randomized to dapagliflozin 10 mg once daily or placebo atop usual HF medications. The broad enrollment criteria included HF patients who were hospitalized or recently hospitalized and had an EF over 40% at the time of enrollment — even if it had previously fallen before recovering back over the threshold.

However, even if FDA did approve the expanded indication, the question is whether dapagliflozin would really be adopted in broad swaths of HF patients.

HFSA session co-moderator Palak Shah, MD, of Inova Fairfax Hospital in Falls Church, Virginia, said he worried that uptake will be low 5 years on, as it has been for guideline-directed medical therapy (GDMT) for HF in general.

Dapagliflozin does have the advantage of better ease of use compared to other GDMT — given its once-daily dosing and lack of need for titration — which could sway primary care and other clinicians to initiate the drug, Vaduganathan said.

On the other hand, cost and access are the main barriers to adoption. In the U.S., that may take the form of high copays even for those with insurance.

Another important question regarding SGLT2 inhibitors is the mechanism of their cardiovascular benefit, along with whether this is a class effect.

It has been proposed that SGLT2 inhibition provides rapid benefits for the heart by reducing epicardial adipose tissue, shifting myocardial metabolism, or a number of other mechanisms.

In DELIVER, the primary endpoint advantage of dapagliflozin was driven by a reduction in worsening HF (defined as unplanned hospitalizations or urgent visits for HF) without significant improvement in CV deaths.

A similar pattern was seen with empagliflozin in EMPEROR-Preserved, as well as with investigational dual SGLT1 and SGLT2 inhibitor sotagliflozin in the SOLOIST-WHF trial among diabetes patients with HF.