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Symptoms of heart failure with preserved ejection fraction (HFpEF) improved with dapagliflozin (Farxiga) therapy, the PRESERVED-HF trial showed.

After 12 weeks of treatment, Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary scores were 5.8 points higher for patients randomized to the SGLT2 inhibitor over placebo (P=0.001), bringing scores from the low 60s at baseline to the high 60s, reported Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute in Kansas City, Missouri.

"The treatment effect was large, clinically meaningful, and statistically significant," Kosiborod concluded of the 324-person study during a late-breaking trial session at the Heart Failure Society of America (HFSA) meeting held both virtually and in Denver. He mentioned that the study manuscript is in press at Nature Medicine.

In PRESERVED-HF, dapagliflozin helped with symptoms and physical limitations of all HFpEF subgroups regardless of diabetes status or left ventricular ejection fraction (LVEF). Furthermore, Kosiborod's group calculated a number needed to treat of just 9 for a patient to have a clinically meaningful improvement in health status at 12 weeks.

People entered the trial with a baseline median 6-minute walking distance of just 244 meters, and the dapagliflozin group was able to increase their results by 20.1 meters over placebo after 12 weeks of therapy (P=0.007).

"PRESERVED-HF, to our knowledge, is the first trial to demonstrate that SGLT2 inhibitor dapagliflozin significantly improves symptoms, physical limitations, and 6-minute walking distance in patients with HFpEF," noted Kosiborod.

"This is really impressive. This is unprecedented. This is the largest KCCQ benefit ever recorded in any trial with a drug for HFrEF [heart failure with reduced ejection fraction] or HFpEF. And it is the size of effect, consistency of effect," said Milton Packer, MD, of Baylor University Medical Center in Dallas, during the discussion portion of the HFSA session.

The trial is in line with the large outcomes trials that have supported the role of SGLT2 inhibitors in heart failure and led to the FDA approvals of dapagliflozin and empagliflozin (Jardiance) for treating HFrEF.

An indication for SGLT2 inhibition for HFpEF appears likely following EMPEROR-Preserved, in which empagliflozin was shown to reduce cardiovascular deaths and heart failure hospitalizations in these patients with notoriously few treatment options.

PRESERVED-HF was a randomized double-blind trial conducted at 26 U.S. centers. Investigators randomized 324 HFpEF patients to dapagliflozin 10 mg daily or placebo for 12 weeks. Randomized participants had a median age of 70 years at baseline; 57% were women, and just under one-third were Black.

Eligible patients had to have LVEFs of at least 45% and meet one of three enrichment factors: recent heart failure hospitalization or urgent heart failure visit requiring IV diuretic, elevated filling pressures by right or left heart catheterization, or structural heart disease by echocardiography.

The trial cohort suffered New York Heart Association class II to IV symptoms despite being on standard heart failure medications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta-blockers, and loop diuretics.

Kosiborod characterized the cohort as "much more functionally impaired, symptomatically impaired" than peers in prior SGLT2 inhibitor trials. Over half of the cohort had type 2 diabetes and another half had atrial fibrillation. Moreover, median BMI was 35, which he described as "much higher than previous HFpEF trials."

Dapagliflozin was "well tolerated" in PRESERVED-HF, he noted, citing the well-balanced safety event rates between groups.

The SGLT2 inhibitor did not make a difference in N-terminal prohormone of brain natriuretic peptide (NTproBNP), brain natriuretic peptide, hemoglobin A1c, or systolic blood pressure levels. There was, however, a modest weight reduction of 0.72 kg (1.59 lbs) at 12 weeks with dapagliflozin compared with placebo.

"What's really impressive is you're getting [dapagliflozin's benefits] at a time when there's no change on natriuretic peptide," Packer pointed out.

"I for one do not believe that SGLT2 inhibitors exert most of their benefit through NTproBNP reduction or diuretic effects," Kosiborod said, noting that the SGLT2 inhibitor trials have been consistent in showing just a small effect on this biomarker.

PRESERVED-HF's findings may not be generalizable to people who were not included in the trial: people within a week from a recent heart failure hospitalization and those with advanced kidney disease, a history of type 1 diabetes or diabetic ketoacidosis, or recent or planned heart procedures.

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