Key Points:
- SGLT2i therapy reduces HF hospitalizations and CV mortality in HFpEF, but the mechanism is not yet clear.
- In this single-center, double-blinded RCT, patients with HFpEF were randomized to dapagliflozin or placebo and underwent exercise and resting hemodynamics at baseline and at 24 weeks.
- Dapagliflozin resulted in reduced resting and exercise PCWP, weight, and plasma volume relative to placebo.
SGLT2i therapy has recently been shown to improve HF hospitalizations and CV mortality in HFpEF, but the mechanism is not yet established. The central hypothesis is that SGLT2i inhibitor therapy could improve outcomes through reduction of LV pressures. In a breaking presentation at the 2023 ACC Conference today, Dr. Barry Borlaug (Mayo Clinic, MN) and his team presented their study: “Evaluation Of The Mechanism Of Benefit For Dapagliflozin In HFpEF: An Invasive Hemodynamic Randomized Trial.”
This study was single-center, double-blinded randomized clinical trial examining the effects of dapagliflozin on rest and exercise hemodynamics in HFpEF. The inclusion criteria comprised any adults with NYHA II-III HFpEF with PCWP >25mmHg during exercise. Key exclusion criteria T1DM, pericardial disease, or patients with primarily non-cardiac dyspnea. Participants underwent invasive exercise testing with hemodynamics by high fidelity micromanometer catheters and total blood, plasma, and RBC volumes at baseline and 24 weeks. The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) incorporating measurements at rest and peak exercise from baseline to week 24.
A total of 43 patients were randomized; of those 17 initially assigned to placebo received such treatment and of 23 initially assigned to dapagliflozin, only 21 were treated. The average age was 67, and 66% were women. The average BMI was 35. The primary endpoint was pulmonary capillary wedge pressure (PCWP) at rest and exercise. In the overall mixed model LR, dapagliflozin significantly reduced both resting and exercise PCWP relative to placebo (p<.001). There was no significant reduction in resting RA or mPAP pressures, but there was a significant reduction with dapagliflozin with exercise (RA pressure -4.2mm Hg (-7.3 to -1.0), p =.010 and mPAP -5.9 mm Hg (-10.9 to -0.9), p=.022). Patients receiving dapagliflozin lost weight relative to placebo (treatment effect estimate -3.5lbs (95% CI -5.9 to -1.1), p=0.006). There was no difference in total blood or red cell volume, but dapagliflozin led to a significant reduction in plasma volume (-285ml (95% CI -510 to -60), p= .015). Interestingly, the changes in rest and exercise PCWP were poorly correlated with the change in plasma volume (r=0.29, p=.08 and 0.34, p=.04 respectively).
When discussing the clinical implications of the study at ACC, Dr. Borlaug stated: “Treatment with dapagliflozin for 24 weeks favorably reduced PCWP at rest and during exercise in HFpEF, improving the fundamental hemodynamic abnormality underlying this disorder. Dapagliflozin also reduced RA and PA pressures…as well as body weight and plasma volume…changes in body weight correlated with changes in PCWP. These findings provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF.”
