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BARCELONA -- The heart benefits of sodium-glucose co-transporter (SGLT)-2 inhibitors are not only no longer limited to those with type 2 diabetes but also appear independent of other newer heart failure treatments, based on further findings from DAPA-HF.

In the phase III trial of dapagliflozin (Farxiga) in a mix of patients with or without type 2 diabetes and heart failure with reduced ejection fraction, there was a 26% reduced risk for a composite endpoint of worsening heart failure or cardiovascular death compared with placebo (HR 0.74, 95% CI 0.65-0.85).

Those results presented by John McMurray, MD, of the University of Glasgow, Scotland, here at the European Association for the Study of Diabetes meeting (EASD) were largely the same as those presented earlier this month at the European Society of Cardiology meeting in Paris, but now simultaneously published in the .

Along with the previously reported comparison suggesting no benefit to dapagliflozin between patients with and without type 2 diabetes, a post-hoc subgroup analysis showed similar benefit whether patients were on an angiotensin receptor-neprilysin inhibitor (ARNI) at baseline or not -- HR 0.75, 95% CI 0.50-1.13 and HR 0.74, 95% CI 0.65-0.86, respectively.

Another newly-reported finding was that dapagliflozin yielded 29% reduced risk for worsening renal function, defined as a composition of a sustained 50% more reduction in estimated glomerular filtration rate, end-stage renal disease, or renal-caused death (HR 0.71, 95% CI 0.44-1.16).

Dapagliflozin also appeared to be safe in these patients, without any increased risk for adverse events including for amputation, fracture, or major hypoglycemia.

These benefits overall can't be attributed to hemoglobin (Hb)A1c, McMurray noted: "I can tell you for sure [the mechanism is] not glucose; 55% of our patients didn't have diabetes, and in those patients, there was zero effect on HbA1c."

In the study, only 16.3% of patients on dapagliflozin progressed to worsening heart failure or CV death over a median of 18.2 months vs 21.2% of those on placebo. This included a 30% reduced risk for experiencing a first event of worsening heart failure during follow-up (HR 0.70; 95% CI 0.59-0.83; 10% vs 13.7% of placebo).

Overall, the number needed to treat with dapagliflozin to prevent one of these heart failure events was only 16, the researchers reported.

While the preliminary findings of the trial were McMurray told reporters during a press conference at the EASD meeting that the full findings were slated to be presented at the American Heart Association meeting in November in Philadelphia. "We got the data about 4 weeks ago," he said. "When I saw the data and we analyzed the data, I felt we couldn't sit on that until November," he said, underscoring the poor prognosis that patients with heart failure have.

The trial included over 4,700 individuals with New York Heart Association class II, III, or IV symptomatic heart failure with an ejection fraction of 40% or less. Patients also had a minimum N-terminal pro b-type natriuretic peptide (NT-proBNP) of 600 pg/mL, or 400 pg/mL if they were hospitalized for heart failure in the past 12 months. Individuals with atrial fibrillation or flutter had an minimum NT-proBNP of 900 pg/mL.

All patients were receiving some form of standard therapy for heart failure at baseline, including a diuretic, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, sacubitril/valsartan, beta-blocker, mineralocorticoid receptor antagonist, implantable cardioverter-defibrillator, or cardiac resynchronization therapy.

At baseline, only 45% of the participants randomized to each treatment had type 2 diabetes. They saw a 27% reduced risk for worsening heart failure or cardiovascular death (HR 0.73, 95% CI 0.60-0.88).

Overall, participants on dapagliflozin had a significant risk reduction for several heart failure-related outcomes, as follows:

• Hospitalization for heart failure: HR 0.70 (95% CI 0.59-0.83)

• Urgent heart failure visit: HR 0.43 (95% CI 0.20-0.90)

• Cardiovascular death: HR 0.82 (95% CI 0.69-0.98)

• All-cause mortality: HR 0.83 (95% CI 0.71-0.97)

Patients also reported experiencing fewer symptoms after 8 months, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score (HR 1.18, 95% CI 1.11-1.26). More patients on dapagliflozin reported a 5+ point improvement in symptoms on the KCCQ after 8 months (58% vs 51%), and fewer reported a 5+ point deterioration in symptoms (25% vs 33%).

Writing in an , James Fang, MD, of the University of Utah Health in Salt Lake City, called the results "compelling," but noted that there are many lingering questions that require future clarification.

"Almost all the patients had moderate heart failure, so the benefit and side effect profile in patients with more severe heart failure will need further study," he said. In addition, only 10% of these patients were adding dapagliflozin to sacubitril-valsartan, in which case the "definitive conclusions about the benefits and side effects associated with SGLT2 inhibition in combination with sacubitril-valsartan remain unclear."

He also recommended that future research specifically take into account the individual doses of heart failure therapies that dapagliflozin was added onto, since in this study the higher doses of heart failure medications may have reduced the magnitude of the benefit shown.

Still, Fang said, despite these remaining questions, there is a potential benefit the drug could have for patients with heart failure and reduced ejection fraction: "It behooves us as clinicians to learn more about using such newer agents effectively, but we have a long way to go."

McMurray noted that the findings will be revised by regulators "very soon," and will thereafter be reviewed by guidelines committees before hopefully being incorporated into clinical practice.

Earlier this week, the for the risk reduction of cardiovascular death, or worsening of heart failure, in adults with heart failure with reduced ejection fraction -- based upon these findings -- as well as with preserved ejection fraction, based on the .