Effect of SGLT2i on hemodynamics in patients with HFrEF
Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction
Introduction and methods
SGLT2 inhibition significantly improves CV outcomes in patients with type 2 diabetes with or without a history of HF [1-4]. Also extended studies with SGLT2i treatment in patients with HFrEF showed a risk reduction in CV death and hospitalization for HF [5,6]. However, the mechanism of SGLT2i leading to improved CV outcomes remains unknown. Possible hypothetical mechanisms for these positive outcomes based on preclinical data are reverse cardiac remodeling, alternation in plasma volume, myocardial substrate switch, and effects on myocardial mitochondrial function [7-9].
Increased left ventricular (LV) filling pressure coexists with inadequate cardiac output (CO) in rest or during exercise is a characteristic of HFrEF . Thus, the relationship between LV filling pressure and CO gives insight into the hemodynamic adaptation of the heart during exercise. This study assessed the effects of SGLT2i treatment on hemodynamics in patients with HFrEF by examining the ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at rest and during exercise.
This study is part of the investigator initiated double-blind, placebo-controlled, randomized trial Empire HF. Patients with HFrEF were included from March 6, 2018, to September 10, 2019, from the Odense University Hospital, Odense, Denmark. Patients with stable HFrEF, New York Heart Association (NYHA) functional class II to III symptoms and LVEF ≤40% were recruited. Patients (n=70; 18 to 85 years) were randomized (1:1) to empagliflozin (10 mg once daily), added to the patient’s standard HF treatment, or matching placebo. Patients underwent right heart catherization (RHC) during rest and exercise to measure the PCWP and transthoracic echocardiography at rest to determine LV volume. PCWP was measured as the average of ≥3 cardiac cycles at rest and >10 cardiac cycles with exercise. CO was divided by body surface area to calculate the CI. The primary outcome was PCWP to CI ratio at maximal exercise after a 12 weeks follow-up. Secondary endpoints included the between-group changes in ratio of PCWP to CI and the individual components at all stages of exercise.
- There was no treatment-effect on PCWP to CI ratio at peak exercise in patients treated with empagliflozin compared to patients treated with placebo (-0.15 mm Hg/L/min/m², 95% CI: -1.63 to 1.34 mm Hg/L/min/m²).
- The PCWP to CI ratio at rest in the group with empagliflozin was significantly reduced after 12 weeks compared to baseline (0.86 mm Hg/L/min/m², 95% CI: 1.71 to 0.02 mm Hg/L/min/m², P=0.045), but not in the placebo group. However, no treatment effect was observed.
- The empagliflozin group showed a significant reduction in PCWP after peak exercise (4.14 mm Hg, 95% CI: 6.86 to 1.42 mm Hg, P=0.003) and at all stages of exercise (3.38 mm Hg, 95% CI: 4.48 to 2.28, P<0.001) compared to baseline.
- Patients treated with empagliflozin had a significant improvement in PCWP at all exercise loads compared to patients on placebo (-2.40 mm Hg, 95% CI: -3.96 to -0.84 mm Hg, P=0.003).
- PCWP at rest in patients treated with empagliflozin for 12 weeks was reduced with 17% compared to baseline (2.16 mm Hg, 95% CI 3.84 to 0.47 mm Hg, P=0.01). Resting PCWP in the placebo group after 12 weeks of treatment was comparable to baseline values. However, no significant between-group effects were observed.
- 12 Weeks of empagliflozin treatment had no effect on CI at rest or during (peak) exercise.
- Empagliflozin treatment resulted in a rightward shift in LV end diastolic pressure volume relationship and a decreased calculated LV chamber stiffness (β coefficient: 7.5, 95% CI: 0.64 to 14.30 mm Hg, P=0.03). Though, no significant treatment effects were observed.
This investigator-initiated study showed that 12 weeks of empagliflozin treatment in patients with HFrEF had no effect on the PCWP to CI ratio at rest or during exercise compared to placebo. There was, however, a significant treatment-effect of empagliflozin on PCWP over the full range of exercise loads, suggesting a reduction in LV pressure in these patients.