SGLT2 Inhibitors Are Shown to Reduce HF Death and Hospitalization

Heart failure (HD) is one of the most common chronic diseases associated with substantial hospital readmission, morbidity, and mortality.¹ Patients hospitalized for acute HF experience a significant burden of symptoms that may lead to physical limitations and poor quality of life.

After hospital discharge, approximately 40% of these patients are readmitted within 6 months, and 1‐year mortality post discharge is substantial.² Several randomized controlled trials have evaluated pharmacological interventions in patients hospitalized with acute HF. However, none of the therapies tested was associated with improved outcomes or readmission rates, emphasizing an urgent need to fill this gap. The sodium glucose cotransporter-2 (SGLT2) inhibitors dapagliflozin (Farxiga) and empagliflozin (Jardiance) have been shown to reduce the risk of cardiovascular death (CVD) or hospitalization for HF in patients with chronic heart failure (CHF) with a reduced left ventricular ejection fraction. Furthermore, empagliflozin has been shown to reduce the risk of CVD or hospitalization for HF in patients with CHF with a preserved left ventricular ejection fraction. The latest iteration of the heart failure guidelines include SGLT2 inhibitors for heart failure management.³ The combination of the SGLT1/2 inhibitor, sotagliflozin, has been associated with improved clinical outcomes in patients with diabetes and progressing HF. However, it was unknown whether empagliflozin provided clinical benefit in patients hospitalized for acute HF. During hospital admission for HF, therapies used to manage symptoms frequently led to considerable fluid and electrolyte shifts and hemodynamic changes. Providers often face limited available therapeutic options, and it has been uncertain whether it is safe to initiate treatment with an SGLT2 inhibitor during hospitalization.

Rationale

The phase 3 EMPULSE study (NCT04157751) assessed the clinical benefit and safety of empagliflozin compared with placebo in patients hospitalized with acute HF.⁴ EMPULSE evaluated the effects of empagliflozin on 3 central goals of care in hospitalized patients with acute HF: reduction of heart failure event (HFE), survival benefit, and
symptom improvement.

This double-blind, international, multicenter, parallel‐group, placebo‐controlled, randomized study enrolled patients between June 2020 and February 2021. During the trial, 566 patients were screened, and
530 were randomly assigned to empagli- flozin 10 mg daily (n = 265) or placebo (n = 265). To be included in the trial, patients had to have been hospitalized with acute HF, regardless of diabetes or ejection fraction status; have systolic blood pressure of 100 mm Hg or higher; have had no symptoms of hypotension within 6 hours; have not needed an increase in intravenous (IV) diuretic dose within 6 hours; have not been on IV vasodilators, including nitrates, within 6 hours; and not have had IV inotropic drugs within 24 hours. Other criteria included N-terminal pro–B-type natriuretic peptide (NT-proBNP) of 1600 pg/mL or greater or BNP of 400 pg/mL or greater during hospitalization or within 72 hours prior to admission. The median age of participants was 71 years; 47% had diabetes, 78% were White, and 34% were women. The median time from hospital admission to being randomly assigned was 3 days, with a 90-day duration of follow-up. The primary outcome was assessed using a stratified win ratio, defined as a composite numbers of death, number of HF events, time to first HF event, and change in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) from the baseline to 90 days. Clinical benefit occurred at a rate of 53.9% in the empagliflozin group compared with 39.7% in the placebo (P = .005) group. The empagliflozin effect on the primary efficacy outcome was consistent across prespecified subgroups. The secondary outcome of the incidence of cardiovascular death or HFE until the end-of-trial visit was 12.8% in the empagliflozin group and 18.5% in the placebo group. There was no major difference in the proportion of patients with a KCCQ-TSS improvement of 10 points or greater at day 90 between the 2 groups. Acute renal failure was observed in 7.7% of participants taking empagliflozin vs 12.1% in the placebo group. Furthermore, the empagliflozin group had a higher reduction in NT-proBNP concentration and body weight than patients in the placebo group.

Key Takeaways

The EMPULSE findings indicate that initiation of empagliflozin in patients hospitalized for acute HF was well tolerated and showed significant clinical benefit in the 90 days after initiating treatment. In terms of safety, adverse events were higher in the placebo arm. There were no cases of ketoacidosis reported in the study.

Conclusion

Among patients with acute decompensated HF, empagliflozin was associated with significant clinical benefit at 90 days. The EMPULSE study enrolled participants regardless of diabetes or ejection fraction, and there was no evidence for treatment interaction based on either of these variables. The benefit of empagliflozin was independent of symptomatic impairment at baseline. Empagliflozin vs placebo also was associated with fewer deaths, improvement in quality of life, and greater reduction in body weight without any safety concerns. To date, very few interventions have shown symptom improvement and functional status in the postdischarge period in patients hospitalized with acute HF. The results of the EMPULSE trial suggest that the initiation of empagliflozin will become the standard of care in eligible patients hospitalized for acute HF.

About The Author

Deepali Dixit, PharmD, BCPS, BCCCP, FCCM, is a clinical associate professor at the Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey, and a clinical pharmacy specialist, critical care, at Robert Wood Johnson University Hospital in New Brunswick, New Jersey.

References

1. Tromp J, Ferreira JP, Janwanishstaporn S, et al. Heart failure around the world. Eur J Heart Fail. 2019;21(10):1187-1196. doi:10.1002/ejhf.1585

2. Tromp J, Bamadhaj S, Cleland JGF, et al. Post-discharge prognosis
of patients admitted to hospital for heart failure by world region, and national level of income and income disparity (REPORT-HF): a cohort study. Lancet Glob Health. 2020;8(3):e411-e422. doi:10.1016/ S2214-109X(20)30004-8

3. Kosiborod MN, Angermann CE, Collins SP, et al. Effects of empagliflozin on symptoms, physical limitations and quality of life in patients hospitalized for acute heart failure - results from the EMPULSE trial. Circulation. Published online April 4, 2022. doi:10.1161/ CIRCULATIONAHA.122.059725