Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes

Abstract

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated.

Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.

Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; P_interaction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m² in patients without diabetes; P_interaction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (P_interaction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.

Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT03057951.

Keywords: death; diabetes mellitus; heart failure; hospitalization; prognosis.

Figure 1.

Forest plots for the effects of empagliflozin vs placebo on the primary end point and secondary cardiovascular end points according to the presence or absence of diabetes at baseline. n corresponds to the number of events in recurrent event analyses and the number of patients with an event for the time to first event analysis. *Recurrent event analyses are on the basis of the joint frailty model accounting for competing risk of cardiovascular death. †Time to first occurrence of (1) chronic dialysis; (2) renal transplantation; (3) sustained reduction of ≥40% in estimated glomerular filtration rate (eGFR); or (4) sustained eGFR <15 mL/min/1.73m² for patients with baseline eGFR ≥30 mL/min/1.73m² or <10 mL/min/1.73m² for patients with baseline eGFR <30 mL/min/1.73m². HHF indicates hospitalization for heart failure; HR, hazard ratio; and PY, patient-years.

Figure 2.

Effect of empagliflozin vs placebo on the primary end point of cardiovascular death or first hospitalization for heart failure in patients with and without diabetes. Effect of empagliflozin vs placebo on the primary end point of cardiovascular death or first hospitalization for heart failure in (A) patients with diabetes at baseline and (B) patients without diabetes. HR indicates hazard ratio.

Figure 3.

Effect of empagliflozin vs placebo on first and recurrent hospitalizations for heart failure in patients with and without diabetes. Effect of empagliflozin vs placebo on first and recurrent hospitalizations for heart failure in (A) patients with diabetes at baseline and (B) patients without diabetes (mean cumulative function). HR indicates hazard ratio.

Figure 4.

Effect of empagliflozin on the primary end point by baseline HbA1c as a continuous variable. The figure shows the linear association between hemoglobin A1c (HbA1c) and log hazard ratio for the primary end point. The nonsignificant interaction P value (0.26) indicates that the slope is not significantly different from zero. However, the display makes assumptions about the linearity that are difficult to validate, and the slope is strongly influenced by a relatively small number of patients with extreme values.

Figure 5.

Adjusted mean changes from baseline in eGFR (CKD-EPI) and mean slope of change in eGFR by treatment status (empagliflozin or placebo) in patients with and without diabetes at baseline. Adjusted mean changes from baseline in estimated glomerular filtration rate (eGFR) in the 2 groups are shown as calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. The bars indicate standard errors. The on-treatment data were analyzed using a mixed model for repeated measures.