Effects of empagliflozin in patients with heart failure and preserved ejection fraction according to baseline diuretic use: results from the EMPEROR-Preserved trial

Background: In the EMPEROR‐Preserved trial, empagliflozin reduced the risk of hospitalizations for heart failure (HHF) or cardiovascular (CV) death in patients with heart failure and preserved ejection fraction (HFpEF). Almost one in five patients in the trial were not on baseline diuretic therapy. Purpose: To evaluate the efficacy and safety of empagliflozin according to baseline diuretic treatment, as well as change in diuretic therapy after initiation of empagliflozin. Methods: Patients were categorized into subgroups as no diuretic and furosemide‐equivalent diuretic dose of <40, 40 and >40mg and were compared for first HHF or CV death, HHF, CV death, total HHF, change in eGFR slope, and change in Kansas City Cardiomyopathy Questionnaire ‐ Clinical Summary Scores (KCCQ‐CSS) between patients on empagliflozin vs. placebo. Changes in diuretic therapy in the two treatment groups were also compared. Results: Amongst 5815 patients with data on diuretic dose, 1179 (20%) were on no diuretic, 2039 (35%) were on <40mg, 1700 (29%) were on 40mg, and 897 (15%) were on >40mg at baseline. Patients on higher diuretic doses at baseline were more likely to be diabetic, had a higher body weight and NT‐proBNP, and lower estimated glomerular filtration rate (eGFR) on average. Patients on higher diuretic doses also had worse health status based on NYHA class and KCCQ‐CSS estimates. The reduction of the risk of CVD or HHF, total HHF, preservation of eGFR, and KCCQ‐CSS improvement with empagliflozin were consistent across all doses of diuretics (Table 1). The findings for all outcomes were consistent in patients on diuretics (any dose) vs. not on diuretics. Treatment with empagliflozin was associated with decreased rates of initiation (HR: 0.73 [0.59,0.90; p=0.004) or intensification (HR: 0.74; [0.65, 0.84]; p<0.001) of diuretics, while there were increased rates in permanent discontinuation of diuretics (HR: 1.46 [1.17, 1.82]; p<0.001) or diuretic dose reduction (HR: 1.22 [1.06, 1.42]; p=0.007). The incidence of adverse events were similar between treatment arms, irrespective of baseline use of diuretics. Volume depletion events were more common with empagliflozin amongst patients treated with diuretics (7.4 vs 5.7 events per 100 patient‐years for empagliflozin vs placebo). Conclusion: Empagliflozin improved clinical outcomes and health status in patients with HFpEF irrespective of baseline use of diuretics. Additionally, empagliflozin was associated with increased de‐escalation or discontinuation of diuretics and decreased chances of initiation or intensification.