Efficacy and Safety of Empagliflozin in Patients with Heart Failure with Preserved Ejection Fraction

Introduction

Heart failure is divided into two main groups: patients with reduced left ventricular ejection fraction (EF LK) and patients with preserved EF LK. Therapeutic options for the latter group are limited.

Empagliflozin belongs to the class of gliflozins, which prevent the reabsorption of glucose and sodium in the kidneys by inhibiting the sodium-glucose cotransporter 2 (SGLT2). In addition to its beneficial effect on glucose metabolism, empagliflozin has also been shown to have a significant cardioprotective effect.

Previous clinical studies have shown that empagliflozin in patients with HFrEF helps reduce the risk of heart failure worsening events requiring outpatient treatment or hospitalization, and reduces the risk of cardiovascular death or hospitalization for heart failure. The aim of the EMPEROR-Preserved study was to supplement the missing data on the effect of empagliflozin in patients with HFpEF.

Methodology, Course, and Objectives of the Study

The randomized, double-blind, placebo-controlled, parallel group EMPEROR-Preserved study included patients ≥ 18 years of age with New York Heart Association (NYHA) Class II–IV heart failure with EF LK > 40%. Elevated levels of the N-terminal fragment of brain natriuretic peptide type B (NT-proBNP) > 300 pg/ml or > 900 pg/ml in patients with atrial fibrillation were required for inclusion in the study. Patients were randomized in a 1:1 ratio to empagliflozin therapy at a dose of 10 mg once daily or placebo. They also underwent adequate heart failure therapy, which could be adjusted according to the treating physician's decision.

The composite primary outcome included cardiovascular death or hospitalization for heart failure. Secondary objectives of the study included assessing the incidence of all heart failure hospitalizations and the rate of decline in glomerular filtration rate assessed by the eGFR parameter.

Results

The study included a total of 5,988 patients, with 2,997 receiving empagliflozin and 2,991 receiving placebo. The median follow-up period for the occurrence of the primary endpoint was 26.2 months (interquartile range [IQR] 18.1–33.1). Patient characteristics were similar in both groups at baseline, with nearly half of the patients having a history of diabetes (48.9% in the empagliflozin group vs. 49.2% in the placebo group), and half of the patients in both groups had an eGFR < 60 ml/min/1.73 m². The median EF LK was 54%, with two-thirds of patients having ≥ 50%.

Empagliflozin administration was associated with a 21% reduction in the risk of the composite endpoint, which included cardiovascular death and hospitalization for heart failure (415 vs. 511 patients; hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.69–0.90; p < 0.001). The risk reduction was primarily associated with a reduced risk of hospitalization for heart failure (259 vs. 352 patients; HR 0.71; 95% CI 0.60–0.83). The risk of cardiovascular death did not significantly differ between the two groups (219 vs. 244 patients; HR 0.91; 95% CI 0.76–1.09). The effect of empagliflozin on the primary outcome was consistent across study subgroups, both in patients with and without diabetes.

Patients on empagliflozin also had a lower incidence of total heart failure hospitalizations compared to placebo (407 vs. 541; HR 0.73; 95% CI 0.61–0.88; p < 0.001) and a slower decline in the eGFR parameter (–1.25 vs. –2.62 ml/min/1.73 m² per year; p < 0.001). Both groups had comparable rates of serious adverse events and adverse events leading to treatment discontinuation. Patients on empagliflozin more frequently experienced uncomplicated cases of urogenital infections and hypotension.

Conclusion

Findings from the EMPEROR-Preserved study indicate that empagliflozin administration in patients with HFpEF leads to a significant reduction in the risk of hospitalization for heart failure and a slower progression of renal insufficiency assessed by eGFR compared to placebo.

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Source: Anker S. D., Butler J., Filippatos G. et al.; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; 385 (16): 1451–1461, doi: 10.1056/NEJMoa2107038.