EMPEROR - Preserved (empagliflozin in preserved ejection fraction heart failure)

Heart failure is classified on the basis of whether the ejection fraction is reduced (<=40%), mildly reduced (41 to 49%), or preserved (>=50%)

Sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the development and progression of heart failure in patients with type 2 diabetes and in those with heart failure and a reduced ejection fraction (1,2).

Sotagliflozin (a combined SGLT1 and SGLT2 inhibitor) improved clinical outcomes after an episode of decompensated heart failure both in patients with a reduced ejection fraction and in patients with a preserved ejection fraction (3)

Anker et al undertook the EMPEROR-Preserved trial which aimed to evaluate the efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo, on top of standard of care, in patients with chronic HF and LVEF >40%, with and without T2DM:

• EMPEROR-Preserved enrolled 5988 patients (aged >=18 years, NYHA class II-IV, elevated NT-proBNP, eGFR >=20, T2DM and non-T2DM) from 622 centers in 23 countries to receive either empagliflozin 10 mg once daily + standard of care (n=2997), or placebo + standard of care (n=2991)
• average age of included patients was 72 years
• average LVEF was 54%, 45% were women and 49% had T2DM
• primary composite endpoint was time to first event of adjudicated CV death or adjudicated HF hospitalization
• secondary endpoints were total (first and recurrent) adjudicated HF hospitalizations, and slope of change in eGFR from baseline
• median follow-up was 26 months

Main results:

• empagliflozin significantly reduced the risk of the primary composite endpoint of CV death or HF hospitalization by 21%, compared to placebo (HR 0.79, 95%CI 0.69-0.90, P=0.0003)
  • effect was primarily driven by a risk reduction in HF hospitalization in the empagliflozin group
  • number needed to treat to prevent one primary outcome event during the median study period of 26 months was 31 (95%CI 20-69).
• effects of this treatment on the primary endpoint were consistent across all pre-specified subgroups, including patients with and without T2DM and patients with LVEF >40 to <50%, >= 50 to <60%, and >=60%
• empagliflozin significantly reduced the first secondary endpoint of first and recurrent HF hospitalizations by 27% (P=0.0009).
• second secondary endpoint of slope of decline in eGFR from baseline was also significantly reduced by empagliflozin (difference: 1.36 mL/min/1.73m² per year, P<0.0001)
  • note though that the favorable effect of empagliflozin with respect to the primary outcome (a composite of major adverse renal outcomes [profound and sustained decreases in eGFR or renal-replacement therapy]) was significantly lower in the EMPEROR-Preserved trial than in the EMPEROR-Reduced trial
• uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin

Study authors concluded:

• empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes
• noted that "..Treatment with empagliflozin led to a lower incidence of hospitalization for heart failure, but it did not appear to affect the number of deaths from cardiovascular or other causes in the current trial. It is noteworthy that the percentage of patients who discontinued treatment for reasons other than death was 23% overall and was similar in the two treatment groups; this high rate of discontinuation may have driven the effect size toward the null hypothesis.."

Reference:

1. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393: 31-9.
2. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020; 396: 819- 29.
3. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117-128.
4. Anker SD et al. EMPEROR-Preserved: effect of empagliflozin on cardiovascular death and heart failure hospitalisations in patients with heart failure with a preserved ejection fraction, with and without diabetes. NEJM August 27, 2021 DOI: 10.1056/NEJMoa2107038