Reframing obesity-related HFpEF as a multiorgan syndrome: incretin-based therapies and imaging endpoints

Obesity-related heart failure with preserved ejection fraction (HFpEF) is increasingly recognised as a multiorgan cardio–renal–hepatic–metabolic (CRHM) syndrome. Obesity promotes HFpEF through metabolic dysfunction, systemic inflammation, haemodynamic overload and ectopic adiposity. Increased visceral and epicardial fat has been linked with downstream involvement of the heart, liver and kidneys, resulting in a distinct phenotype with high symptom burden and functional limitation. Incretin based therapies such as glucagon-like peptide-1 receptor agonist (GLP-1 RA) are growing in popularity in CRHM conditions owing to positive effects on glycaemia, weight loss and systemic inflammation, leading to reduced adverse clinical outcomes. In obesity-related HFpEF, emerging data suggest GLP-1 RA and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonists (also called incretin-based therapies) improve symptoms, exercise capacity, congestion, and reduce heart failure events, while also leading to reduced ectopic fat depositions in multiple organs and favourable cardiac remodelling. Incretin-based, weight-directed therapies therefore represent a promising strategy for a therapeutically challenging HFpEF phenotype. Future clinical trials incorporating multiorgan imaging endpoints across the heart, liver, adipose tissue and kidneys are needed to clarify the mechanisms of benefit and to better define the role of weight-reduction therapies in obesity-related HFpEF.