Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction - CAMEO-DAPA

Aug 13, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC; Anthony A. Bavry, MD,MPH,FACC
Trial Sponsor:
AstraZeneca
Date Published:
08/05/2024
Date Updated:
08/13/2024
Original Posted Date:
08/16/2023
References

Contribution To Literature:

Highlighted text has been updated as of August 13, 2024.

The CAMEO-DAPA trial showed that in patients with HFpEF, dapagliflozin 10 mg daily reduces both resting and exercise PCWP compared with placebo.

Description:

The goal of this trial was to assess whether dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), affects rest and exercise pulmonary capillary wedge pressure (PCWP) in patients with heart failure with preserved ejection fraction (HFpEF).

Study Design

  • Single-center
  • Double-blind
  • Randomized
  • Placebo-controlled

Patients with HFpEF and documented elevation in exercise PCWP were randomized to receive dapagliflozin 10 mg daily (n = 21) or matching placebo (n = 17). Rest and exercise PCWP were obtained at baseline and follow-up visits. Exercise PCWP was obtained at peak exercise tolerance on a supine ergometer. Workload was increased at 20-W increments at 3-minute intervals until volitional exhaustion.

  • Total number of enrollees: 38
  • Duration of follow-up: 24 weeks
  • Median patient age: 68 years
  • Percentage female: 66%
  • Obese: 71%

Inclusion criteria:

  • Age ≥18 years
  • New York Heart Association (NYHA) class II-III dyspnea
  • Left ventricular ejection fraction (LVEF) ≥50%
  • Elevated baseline exercise PCWP ≥25 mm Hg

Exclusion criteria:

  • Type 1 diabetes mellitus (DM)
  • Poorly controlled type 2 DM
  • Hospitalization <30 days or revascularization <90 days
  • Suspected alternate cause of dyspnea, including constrictive pericarditis or a primary cardiomyopathy
  • Hemoglobin <9 g/dL
  • Greater than moderate left-sided valvular disease
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2

Other salient features/characteristics:

  • Percentage body mass index ≥30 kg/m2: 71%
  • Percentage NYHA functional class III: 68%
  • Baseline mean exercise PCWP, dapagliflozin vs. placebo: 33.5 vs. 32.0 mm Hg

Principal Findings:

Primary outcome, change in PCWP at 24 weeks, for dapagliflozin vs. placebo:

  • At rest: -6.6 vs. -0.4 mm Hg (p = 0.027)
  • With exercise: -2.5 vs. +1.1 mm Hg (p = 0.029)

Secondary outcomes for dapagliflozin vs. placebo, change in:

  • Exercise right atrial pressure: -3.4 vs. +0.8 mm Hg (p = 0.011)
  • Exercise mean pulmonary artery (PA) pressure: -5.2 vs. +0.7 mm Hg (p = 0.024)
  • Exercise PA compliance: +0.41 vs. -0.17 mL/mm Hg (p = 0.02)
  • Exercise PA elastance: -0.13 vs. +0.04 mm Hg/mL (p = 0.001)
  • Exercise PA pulsatility index: +0.2 vs. -0.1 (p = 0.01)
  • Exercise right ventricular (RV) systolic velocity (s’)/PA mean: +0.04 vs. -0.05 cm·s-1/mm Hg (p = 0.01)
  • Exercise systolic blood pressure (SBP): -15.3 vs. +3.5 mm Hg (p = 0.04)
  • Total arterial compliance index: +0.05 vs. -0.04 mL/mm Hg·m2 (p < 0.001)
  • Estimated stressed blood volume (eSBV)/total blood volume (TBV): -6.7 vs. +0.6% (p = 0.02)
  • Body weight: -3.7 vs. -0.2 kg (p = 0.006)
  • Plasma volume: -170 vs. +115 mL (p = 0.014)
  • Peak oxygen consumption: -0.1 vs. -0.8 mL/(kg·min) (p = 0.37)
  • Peak workload: -4 vs. -4 W (p = 0.99)

Interpretation:

The CAMEO-DAPA trial demonstrates that dapagliflozin is associated with decreased rest and exercise PCWP compared with placebo in HFpEF patients. Although peak exercise capacity and oxygen consumption did not improve, reduction in PCWP particularly with exercise may explain the improvement in patient-reported symptoms and submaximal exercise tolerance associated with SGLT2i in the DELIVER and PRESERVED-HF trials. This single-center study of a small population nevertheless provides granular, invasive hemodynamic data to support larger established data of patient symptoms and functional status.

The authors note that the exact mechanism by which dapagliflozin is associated with reduced PCWP is not clear. They observed only a weak correlation (r = 0.29) with change in plasma volume, suggesting pleiotropic effects beyond simply increased diuresis. Further, dapagliflozin was associated with greater weight loss in this primarily obese population. This may suggest the effect of SGLT2i on elevated PCWP, and associated exertional dyspnea may extend to the extracardiac and metabolic dysfunction that plays a key role in HFpEF.

Indeed, a subsequent analysis demonstrated increases in total arterial compliance and venous capacitance, measured by eSBV/TBV, at peak exercise following treatment with dapagliflozin. Attenuation of hypertensive response to exercise correlated with observed decreased arterial stiffness as well as exercise PCWP. Extracardiac vascular remodeling by SGLT2i may therefore play a role in decreased left ventricular filling pressures with exercise and associated symptomatic improvements.

A planned secondary analysis of right heart hemodynamics demonstrated improvements in exercise PA compliance, RV function, and RV-PA coupling (measured by RV s’ indexed to PA mean) with dapagliflozin versus placebo. These findings may be due to both decreased PCWP as well as direct effects of SGLT2i on the pulmonary vasculature. Resting PA mean was above 20 mm Hg in 84% of participants at baseline, reflecting the prevalence of mixed pulmonary hypertensive disease in HFpEF. Improved RV-PA coupling during exertion may therefore further contribute to the symptomatic improvements observed with dapagliflozin and potentially other agents in this class.

References:

Tada A, Burkhoff D, Nasar JA, et al. Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial. Circulation 2024;Aug 5:[Epub ahead of print].

Reddy YN, Carter RE, Sorimachi H, et al. Dapagliflozin and Right Ventricular–Pulmonary Vascular Interaction in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol 2024;Jul 24:[Epublished].

Borlaug BA, Reddy YN, Braun A, et al. Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The CAMEO-DAPA Trial. Circulation 2023;148:834-44.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Exercise

Keywords: Exercise, Heart Failure, Metabolic Syndrome, Sodium-Glucose Transporter 2 Inhibitors


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