Dapagliflozin ‘foundational therapy’ for HF, regardless of EF: DELIVER
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In adults with HF with mildly reduced or preserved ejection fraction, dapagliflozin significantly reduced risk for CV death and worsening HF compared with placebo, with no attenuation of treatment benefit for patients with the highest EF.
Results from the anticipated DELIVER trial, presented at the European Society of Cardiology Congress, also showed participants assigned dapagliflozin (Farxiga, AstraZeneca), an SGLT2 inhibitor originally approved to treat type 2 diabetes, experienced fewer total HF hospitalizations and a marked improvement in symptom burden compared with those assigned placebo.
The data, presented 1 year after the landmark EMPEROR-Preserved trial, mark the second time a large CV outcomes trial showed benefit for an SGLT2 inhibitor in adults with HFpEF.
“DELIVER was the largest and most inclusive of all trials in HF with mildly reduced and preserved ejection fraction, enrolling more than 6,200 patients,” Scott D. Solomon, MD, professor of medicine at Harvard Medical School, senior physician and director of noninvasive cardiology at Brigham and Women’s Hospital and a principal investigator of the DELIVER trial, told Healio. “In addition to chronic HF patients, we enrolled patients recently hospitalized with HF and those with a prior left ventricular EF under 40% that had improved to over 40%, a group excluded from all other trials. We did see an 18% significant reduction in our primary endpoint, which was a composite of CV death and worsening HF. That was true regardless of EF, across the entire spectrum.”
An inclusive HFpEF study
Solomon and colleagues randomly assigned 6,263 patients with HF and a LVEF of more than 40%, with or without type 2 diabetes, to receive 10 mg once daily dapagliflozin or placebo, in addition to usual therapy, for a median of 2.3 years. Approximately 71% of participants were white and 20% were Asian; 44% were women; most had NYHA HF class II with a mean EF of 54%. Patients who had a previous LVEF of 40% or less were eligible provided that they had an EF of more than 40% at the time of enrollment. Patients could have been enrolled either as outpatients or during HF hospitalization. The primary outcome, as assessed in a time-to-event analysis, was a composite of worsening HF, defined as an unplanned HF hospitalization or urgent HF visit, or CV death.
The findings were simultaneously published in The New England Journal of Medicine.
During follow-up, the primary outcome occurred in 16.4% of participants in the dapagliflozin group and 19.5% of participants in the placebo group, for an HR of 0.82 (95% CI, 0.73-0.92; P < .001).
Worsening HF occurred in 11.8% in the dapagliflozin group and in 14.5% in the placebo group, for an HR of 0.79 (95% CI, 0.69-0.91). CV death occurred in 7.4% and 8.3% of participants in the dapagliflozin and placebo groups, respectively (HR = 0.88; 95% CI, 0.74-1.05).
Total events and symptom burden were lower in the dapagliflozin group than in the placebo group.
In analyses stratified by EF, researchers found results were similar among patients with a LVEF of 60% or more and those with a LVEF of less than 60%. Results also persisted in prespecified subgroups, including patients with and without type 2 diabetes.
“There is remarkable consistency in every single one of the prespecified subgroups that favor dapagliflozin over placebo,” Solomon said during a press conference.
The incidence of adverse events was similar in the two groups, Solomon said.
“We now have compelling evidence that SGLT2 inhibitors should be standard of care in HF, irrespective of EF, practice setting or whether patients have type 2 diabetes or not,” Solomon said in an interview before the press conference. “We can now feel very comfortable that this class of drugs is close to universally beneficial in patients with HF. These data provide strong support for SGLT2 inhibitors as foundational therapy for HF.”
Benefits across full spectrum of HF
In a related editorial, Kenneth B. Margulies, MD, professor of medicine at the Hospital of the University of Pennsylvania, director of Penn heart failure and transplant research and co-director of the myocardial biology and heart failure program unit at the Penn Cardiovascular Institute, noted that prespecified subgroup analyses for DELIVER show new findings of benefit among patients with a LVEF of 60% or more and among those with a LVEF that had improved to more than 40%. In additional prespecified subgroup analyses, the DELIVER trial extended the results of the EMPEROR-Preserved trial by showing a clear benefit among patients with a BMI of 30 kg/m2 or higher and among those with more severe HF symptoms.
“The observed benefit of dapagliflozin among patients with symptomatic heart failure and an improved left ventricular ejection fraction merits particular attention,” Margulies wrote. “Owing to the success of the several proven treatments for patients with heart failure and a reduced ejection fraction — including medications, devices and revascularization, when appropriate — those with a left ventricular ejection fraction that has improved by at least 10%, to 40% or more, represent a growing cohort of patients with heart failure. 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 left ventricular ejection fraction have worse outcomes than patients with no history of heart failure, even when the left ventricular ejection fraction has improved to within the normal range.”
Margulies wrote that the DELIVER trial should inspire future trials of promising therapeutics for HFpEF that would include the growing contingent of patients with HF with an improved LVEF.
Consistent HF benefits across trials
In a prespecified meta-analyses of the EMPEROR-Preserved and DELIVER trials, Muthiah Vaduganathan, MD, MPH, cardiologist at Brigham and Women’s Hospital and instructor in medicine at Harvard Medical School, and colleagues found that both dapagliflozin and empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) “robustly reduced” CV death or HF hospitalization overall and across 13 subgroups of HF with mildly reduced or preserved EF. Among 12,251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite CV death or first HF hospitalization, with an HR of 0.8 (95% CI, 0.73-0.87) as well as the individual components of CV death (HR = 0.88; 95% CI, 0.77-1) and first HF hospitalization (HR = 0.74; 95% CI, 0.67-0.83).
Additionally, a second more comprehensive meta-analysis of the five large outcomes trials with more than 20,000 participants with HF, including those with HF with reduced EF, showed that SGLT2 inhibitors extended survival, reduced morbid events and symptom burden and improved overall health status. The findings were simultaneously published in The Lancet.
“These drugs rapidly and substantially conferred clinically meaningful improvements in health status, with benefits seen in just weeks to months of treatment initiation,” Vaduganathan said during a press conference.
In an analysis of pooled data from both DELIVER and DAPA-HF, published in Nature Medicine, researchers similarly found that dapagliflozin reduced risk for every assessed outcome, including CV death, all-cause death and total HF hospitalizations, in patients with HF regardless of EF.
References:
- Jhund PS, et al. Nat Med. 2022;doi:10.1038/s41591-022-01971-4.
- Margulies KB. N Engl J Med. 2022;doi:10.1056/NEJMoae2210177.
- Solomon SD, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2206286.
- Vaduganathan M, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)01429-5.
Perspective
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These results are very clear. The key problem for these patients with HF, and their physicians, is getting the pharmacy benefit plans to help pay for these expensive SGLT2 inhibitors.
Perspective
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This large, randomized trial showed that dapagliflozin reduces worsening HF events in patients with HFpEF, and it did so safely. CV death was not affected; however, this may have been due to the relatively short (2.3 years) follow-up period of this trial. This is now the second large trial demonstrating that SGLT2 inhibitors can positively impact patient outcomes and also symptoms, based on the Kansas City Cardiomyopathy Questionnaire score.
SGLT2 inhibitors should be considered in symptomatic patients with HFpEF, especially in those in whom other reversible causes of HF, such as uncontrolled hypertension, cannot be improved.
Now that two studies were able to show a clinically meaningful benefit of SGLT2 inhibitors in patients with HFpEF, further research on their mechanisms is needed. While a diuretic effect may play a role, a more complete understanding of this medication class in HF may help identify those patients who benefit most. The fact that the subgroup analysis suggested that both patients with a greater BMI and higher BP seemed to benefit most is intriguing.
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Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC
Dapagliflozin was associated with improvement in the risk of CV or HF hospitalization in patients with HFpEF. This is now the second large outcomes trial with an SGLT2 inhibitors in patients with HFpEF, confirming the role of these drugs for patients with HFpEF. We are now past the era of saying that there are no known therapies for HFpEF.
The combined results of EMPEROR-Preserved and DELIVER should make SGLT2 inhibitors a first-line therapy for patients with HFpEF, irrespective of diabetes status, chronic kidney disease or EF. Those patients with recovered EF also benefit. Unless someone has a specific disorder like hypertrophic obstructive cardiomyopathy, the use of dapagliflozin or empagliflozin should be standard of care for HFpEF in the absence of contraindications.
What is interesting is not only that both EMPEROR-Preserved and DELIVER were positive, but that the magnitude of benefit was also similar across the two trials. This further enhances confidence in the role of SGLT2 inhibitors in HF across the spectrum of EF, whether HFrEF, HF with midrange EF or HFpEF.
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Solomon SD, et al. Hot Line 4. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).
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