Empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure in patients with recent volume overload (HR 0.81), with a magnitude of benefit similar to those without recent volume overload (interaction p=0.34).
RCT (n=3,730)
Double-blind
1:1
Yes
Does empagliflozin reduce the composite risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and reduced ejection fraction, regardless of recent volume overload?
The clinical benefits of empagliflozin in HFrEF are not primarily mediated by diuresis, as benefits were consistent regardless of baseline volume overload.
Hazard Ratio: 0.81 (95% CI 0.66–0.99)
Absolute Event Rate: 24.8% vs 28.4%
p-value: p=0.035
BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction EMPEROR-Reduced; NCT03057977).
“The performance of these two SGLT2 inhibitors was "incredibly consistent" across the their respective trials run in HFrEF patients with and without type 2 diabetes, and the combined evidence base of the two trials makes for "really compelling evidence" of both safety and efficacy that should prompt a change to U.S. practice, with both of these drugs forming a new cornerstone of HFrEF treatment.”
Packer et al. (Mon,) conducted a rct in Heart failure with reduced ejection fraction (HFrEF) and volume overload (n=3,730). Empagliflozin vs. Placebo was evaluated on Composite of cardiovascular death or hospitalization for heart failure in patients with recent volume overload (HR 0.81, 95% CI 0.66-0.99, p=0.035). Empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure in patients with recent volume overload (HR 0.81), with a magnitude of benefit similar to those without recent volume overload (interaction p=0.34).