Clinical Nutrition ESPEN · Nov 5, 2026

Semaglutide Versus Diet-Based Weight Loss in Obesity and Heart Failure with Reduced Ejection Fraction (FIT-HF): Protocol for a Randomized Controlled Trial

By El-Sheikh M, Bandholm T, Jørgensen NB et al.

Background & Aims Obesity is common in heart failure with reduced ejection fraction (HFrEF), but the functional, mechanistic, and safety consequences of intentional weight loss remain uncertain. Incretin-based therapies improve symptoms and functional capacity in obesity-related heart failure with preserved ejection fraction, whereas evidence in HFrEF is limited, and prior glucagon-like peptide-1 receptor agonist trials have raised safety concerns. The FIT-HF trial tests whether semaglutide-based weight loss is superior to intensive diet-based weight loss for improving exercise capacity in adults with obesity and stable HFrEF. Methods FIT-HF is an investigator-initiated, randomized, parallel-group, open-label, assessor-blinded, active-comparator superiority trial enrolling 100 adults with body mass index ≥30 kg/m², left ventricular ejection fraction ≤40%, New York Heart Association class I–III symptoms, and stable guideline-directed heart failure therapy. Participants are randomized 1:1 to once-weekly subcutaneous semaglutide, titrated to a target dose of 2.4 mg, or low-calorie total dietary replacement of approximately 800 kcal/day for 8 weeks followed by a dietitian-led weight-maintenance program. Both groups receive lifestyle counseling, heart failure care, and structured physical training from week 16. Follow-up is 52 weeks. The primary endpoint is the adjusted between-group difference in change in weight-indexed peak oxygen uptake (VO₂peak) from baseline to week 52, assessed by cardiopulmonary exercise testing. Supportive secondary endpoints include Kansas City Cardiomyopathy Questionnaire score, 6-minute walk distance, left ventricular end-systolic volume assessed by cardiovascular magnetic resonance, high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide. Exploratory work packages assess safety, cardiac/pulmonary physiology, body composition, physical activity, and metabolic/biomarker responses. Discussion FIT-HF is the first direct comparison of these weight-loss strategies in obesity and HFrEF, integrating VO₂peak with multimodal phenotyping to interpret physiological profiles alongside achieved weight loss and body composition. Clinical trial registration European Clinical Trials Information System: European Union trial number: CT-2023-503753-35-01; ClinicalTrials.gov identifier: NCT06423599.

doi.org/10.1016/j.clnesp.2026.105216 Open access PubMed 42988221 Interventions