Effects of Dapagliflozin, Semaglutide, and Their Combination in Heart Failure Patients With Prosthetic Heart Valves

This is a single-center, prospective, randomized, open-label, blinded-endpoint (PROBE), parallel-group, Phase IIb proof-of-concept clinical trial conducted at Kafrelsheikh University Hospital. The study evaluates the clinical efficacy, safety, and tolerability of combining the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, compared against dapagliflozin monotherapy, in patients presenting with heart failure (HF) who have a history of surgical prosthetic heart valve replacement.

A total of 160 eligible patients are randomized in a strict 1:1 allocation ratio to one of two parallel treatment arms:

Combination Therapy Arm: Patients receive oral semaglutide escalated according to standard clinical protocol, administered in addition to a stable baseline regimen of dapagliflozin (10 mg once daily).

Monotherapy Control Arm: Patients continue to receive standard-of-care dapagliflozin monotherapy (10 mg once daily).

The primary objective is to determine if dual metabolic pathway modulation via combined SGLT2 inhibition and GLP-1 receptor agonism provides superior optimization of cardiovascular outcomes over SGLT2 inhibition alone. Key secondary and surrogate clinical outcomes assessed across the treatment duration include changes in New York Heart Association (NYHA) functional class, evaluation of fluid retention and diuretic requirements, echocardiographic parameters evaluating cardiac structure and function, and standardized quality-of-life assessment scores. Safety and tolerability profiles-including adverse event rates and systemic hemodynamic responses-will be rigorously monitored across both treatment cohorts.

Inclusion criteria

• Age is at least 18 years at the time of screening.
• Confirmed diagnosis of heart failure.
• Documented history of surgical prosthetic heart valve replacement.
• Patient is currently on a stable baseline regimen of dapagliflozin (10 mg once daily).
• Patient is willing and able to provide written informed consent prior to any study-related procedures.

Exclusion criteria

• Known hypersensitivity or allergy to semaglutide, dapagliflozin, or any of their excipients.
• Type 1 diabetes mellitus.
• Severe renal impairment (e.g., eGFR < 25 or 30 mL/min/1.73m², depending on your exact protocol threshold) or currently requiring dialysis.
• Active pregnancy, breastfeeding, or intent to become pregnant during the 12-week study period.
• Participation in another conflicting interventional clinical trial within the past 30 days.