Dapagliflozin Boosts Health Status Across LVEF Range

MADRID, Spain—Dapagliflozin improves symptoms and physical limitations in people with heart failure across the spectrum of ejection fractions, according to a pooled analysis of the DEFINE-HF and PRESERVED-HF trials.

“The effects were large, clinically meaningful, and statistically significant,” said Mikhail Kosiborod, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), who presented the results Sunday at the European Society of Cardiology 2022 Heart Failure congress. “Collectively, these results provide support for the use of dapagliflozin in patients with heart failure, regardless of ejection fraction.”

Speaking with TCTMD, Kosiborod stressed that trials in heart failure patients with reduced ejection fraction (HFrEF) have shown that dapagliflozin (Farxiga; AstraZeneca), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces the risk of cardiovascular deaths and hospitalizations while improving health status and quality of life. For patients with HF and preserved ejection fraction (HFpEF), however, “the picture has been a little bit less consistent,” he acknowledged.

“We’ve had some trials that clearly showed a marked benefit. PRESERVED-HF, that we presented at [the Heart Failure Society of America] conference last year and published in Nature Medicine, had a very large benefit of dapagliflozin, but there were some other trials like EMPERIAL-Preserved and DETERMINE-Preserved that did not show a significant benefit.”

EMPEROR-Preserved, using empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), did show a statistically significant benefit of SGLT2 inhibition in improving Kansas City Cardiomyopathy Questionnaire (KCCQ) score, though “the actual magnitude of the benefit was quite modest,” Kosiborod said.

Another area of uncertainty, he added, is whether the benefits of SGLT2 inhibitors attenuate above a certain threshold of ejection fraction. An analysis of KCCQ scores in a recent pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved, for example, suggests that there is no benefit of SGLT2 inhibition when ejection fractions are 65% or higher.

”There’s been very active controversy about whether there is actual clinical benefit and a health status benefit above 60%,” Kosiborod said. “And that’s a very critical question because a large proportion of our patients with HFpEF have ejection fractions in the normal range, and to date we’ve had very limited treatments available for them.”

Across the EF Spectrum

Definitive answers will come from DELIVER, the large, pivotal trial intended to pave the way for a HFpEF indication for dapagliflozin from the US Food and Drug Administration. Top-line results from DELIVER, released earlier this month, indicate that the trial met its primary endpoint, with the SGLT2 inhibitor significantly lowering the risk of cardiovascular death or worsening heart failure in patients with mildly reduced ejection fraction (HFmrEF) or HFpEF. Change in KCCQ total symptom score is a secondary endpoint in DELIVER.

The FDA granted a HFpEF indication to empagliflozin back in February 2022.

For the current analysis, investigators pooled findings from the 263 patients in DEFINE-HF with ejection fractions of 40% or lower and the 324 patients from PRESERVED-HF with ejection fractions of 45% or higher. As Kosiborod reminded his audience here, KCCQ clinical summary score (CCS) was a primary endpoint in both trials.

The pooled cohort included 43% women and 33% African Americans; mean LVEF was 50%. Thirty-seven percent of patients were in NYHA functional class III-IV at baseline, and mean KCCQ-CSS was 67.

Over 12 weeks of therapy, KCCQ-CCS for patients in this analysis improved on average by 5.0 points compared with placebo, a “clinically meaningful” gain, said Kosiborod. Importantly, he continued, this was seen across the spectrum of LVEF. A similar improvement with therapy was seen when KCCQ components, including total symptoms or physical limitations, were analyzed individually. And here again, Kosiborod stressed, “benefits were highly consistent across the entire range of LVEF, with no attenuation in those with very low or high ejection fraction.”

A responder analysis confirmed that while 20.1% of dapagliflozin-treated patients reported a deterioration in KCCQ-CCS over the course of the trial, a larger proportion, nearly 50%, had improvements ranging from small (14.1% vs 13.0% with placebo) to very large (14.5% vs 7.0% with placebo).

Following Kosiborod’s late-breaking presentation, session moderator Andrew Coats, MD (University of Warwick, Coventry, England), pointed to the conflicting results from different trials. “Which is closer to the truth in real-life practice? The large effect you get in this study,” he asked, “or the smaller effect seen in the large trials?”

“Each trial gets the result that it gets and the data are what the data are,” Kosiborod replied. “Ultimately the largest reason why we see bigger treatment effects here, in my opinion, is that we have a much more symptomatic and functionally impaired patient population. In our HFpEF trial, for example, double the proportion of patients had NYHA class III or IV versus larger global trials where only about 20% of [patients were] in NYHA class III or IV.”

KCCQ scores were much lower at baseline in this analysis than in other studies, he added. “If you take a much more symptomatic patient population and you have an efficacious intervention, you are likely to see a bigger effect.”

Elaborating to TCTMD, Kosiborod said that he’s not convinced that the lack of a quality-of-life benefit seen in EMPEROR-Preserved was real. “In my mind, I think this raises a big question mark whether the signals from EMPEROR-Preserved were true signals, or potentially an aberration that can happen in clinical trials sometimes . . . . That happens when you do subgroup analyses: there’s always a danger that what you think is a real effect turns out not to be and it’s just the play of chance,” said Kosiborod.

“With that acknowledged,” he continued, “EMPEROR-Preserved is a much larger trial, but you can see how consistent our data look. There is absolutely no inflection at all. Ultimately the final arbiter of whether there is attenuation or not is going to come from DELIVER.”

Large and Meaningful

Commenting on the study for TCTMD, Carlos G. Santos-Gallego, MD (Icahn School of Medicine at Mount Sinai, New York, NY), called the improvements in KCCQ scores seen in this pooled analysis “large and, speaking from a clinical point of view, of high clinical relevance.”

He drew attention to the subgroup analyses presented by Kosiborod showing that the quality-of-life benefits appeared to be consistent across multiple subgroups, independent of age, gender, race, body mass index, renal function, baseline medication, and HF severity.

In my mind, he said, “SGLT2 inhibitors are the gift that keeps giving. Not only do they improve HF hospitalizations, but also a parameter so valued by patients—quality of life.”

Other data have shown that SGLT2 inhibitors also appear to ameliorate comorbidities, including renal dysfunction, obesity, and congestion; reduce rates of hyperkalemia, allowing mineralocorticoid receptor antagonists and sacubitril-valsartan (Entresto; Novartis) to be optimized; and have benefits in both acute HF and chronic, stable patients.

“The hot topic is now implementation,” said Santos-Gallego. “The evidence of the benefits of SGLT2 inhibition is overwhelming. What we need now is to prescribe these drugs to patients, improve affordability by the patient, and [obtain] proper coverage by insurance companies.”

Kosiborod, too, highlighted the importance of maximizing implementation and patient uptake, calling the slow progress to date a “complex phenomenon” related both to physician inertia and the financial and logistic hurdles faced by patients. He made the case for a system-wide shift towards team-based care to help patients navigate the often-complicated pathways to streamline costs and access, emphasizing prevention over acute care. “The bottom line is when you change the care delivery model and you squarely focus on prevention and you prioritize it, you can get remarkable improvements,” Kosiborod said.