Understanding the expanding influence of glucagon-like peptide-1 (GLP-1) signalling in heart failure (HF) offers an opportunity to revisit how cardiology conceptualises a syndrome increasingly shaped by metabolic and inflammatory disruption.
As obesity, insulin resistance, chronic kidney disease and systemic inflammation become more prevalent globally, the clinical expression of HF with preserved ejection fraction (HFpEF) now frequently reflects a broad cardiometabolic disorder rather than isolated cardiac dysfunction. In this evolving landscape, GLP-1 receptor agonists – originally developed to improve glycaemic control – have emerged as therapies that intersect with several biological mechanisms central to HFpEF.
The analyses included in this special collection provide complementary perspectives that, together, form a cohesive and contemporary understanding of how GLP-1 signalling may influence HF pathophysiology and patient-centred outcomes.
The pathophysiological foundations of HFpEF are explored in detail in the contribution by Bykova et al., who describe HFpEF as a syndrome driven by systemic metabolic overload, endothelial impairment and chronic inflammation.1 Their synthesis highlights how visceral and epicardial adipose tissue exert mechanical effects on the heart while also generating pro-inflammatory signals that contribute to impaired relaxation and increased ventricular stiffness. These observations underscore that cardiac dysfunction in HFpEF is often the downstream manifestation of systemic biological disturbances.
The authors also emphasise the interaction between metabolic dysregulation and autonomic imbalance, both of which amplify haemodynamic stress. GLP-1 receptor agonists, which improve endothelial function, reduce adipose-tissue burden and attenuate inflammatory signalling, map closely onto these mechanisms.¹ This alignment provides a strong biological rationale for considering GLP-1 therapies as part of an expanded HFpEF treatment strategy.
Beyond pathophysiology, the clinical relevance of GLP-1 signalling becomes evident when considering patient-centred outcomes. In their analysis, Shchendrygina et al. examine the functional and symptomatic effects of GLP-1 receptor agonists in individuals with obesity-related HFpEF.2 Improvements reported in exercise capacity, dyspnoea severity and health-related quality of life point to meaningful clinical benefit – especially in a syndrome where patients often experience substantial limitations despite preserved systolic function.
These gains are likely multifactorial. While weight reduction plays a role, enhancements in inflammatory status, ventricular loading conditions and haemodynamic reserve are equally important.² Reductions in epicardial adipose-tissue thickness may further translate into improved myocardial mechanics by relieving external strain and decreasing local inflammatory activity. Taken together, these findings reinforce the central role of metabolic and inflammatory modulation in improving functional status in HFpEF.2
A complementary viewpoint is provided by Abdelhamid et al., who address the practical challenge of identifying individuals most likely to benefit from GLP-1 receptor agonists.3
HFpEF encompasses a broad spectrum of phenotypes, and aligning therapy with underlying biology is key to optimising outcomes. The phenotype characterised by obesity, visceral adiposity, elevated filling pressures and systemic inflammation appears especially congruent with the mechanisms of GLP-1 receptor agonism. Improvements in insulin sensitivity, reductions in inflammatory tone and decreases in adipose-tissue burden directly target the systemic processes that drive symptoms in this population.³
Although uncertainties remain regarding potential direct myocardial effects, current evidence supports the notion that the most robust benefits arise from systemic metabolic modulation. By emphasising targeted therapy rather than uniform application, this perspective echoes the broader movement toward personalised HF management.
Expanding on these mechanistic and clinical considerations, Bonfioli et al. situate GLP-1 receptor agonists within the broader framework of contemporary HFpEF management.4 As therapeutic options evolve – including sodium-glucose cotransporter 2 inhibitors (SGLT2is), refined blood-pressure strategies, tailored diuretic approaches and interventions addressing AF – the question becomes how GLP-1-based therapies complement existing modalities.
Bonfioli et al.’s analysis highlights the unique capacity of GLP-1 receptor agonists to modulate adipose-tissue biology and systemic inflammation – domains not directly addressed by traditional HF pharmacology.4 Particularly noteworthy is the potential effect on epicardial adipose tissue, which may influence ventricular compliance and contribute to symptomatic improvement.
At the same time, evidence indicating a lack of benefit and possible concerns in HF with reduced ejection fraction underscores the importance of phenotype-specific application rather than broad generalisation across all HF categories. This measured, evidence-aligned positioning strengthens the case for integrating GLP-1 receptor agonists selectively within HFpEF care.
Taken collectively, the contributions in this issue converge on a shared insight: HFpEF is fundamentally a cardiometabolic condition, shaped by systemic factors that influence cardiac structure, haemodynamics and symptoms. This perspective shifts the therapeutic focus from solely managing congestion and afterload toward addressing the metabolic and inflammatory environment in which the heart functions.
Improvements in exercise capacity, symptom burden, inflammatory status and adipose-tissue distribution observed in recent trials demonstrate that metabolic-directed therapies can yield clinically meaningful benefits in appropriately selected HFpEF phenotypes. The alignment between disease mechanisms and therapeutic action helps explain why GLP-1 receptor agonists show particular promise in HFpEF populations with metabolic dysfunction, while offering limited benefit in phenotypes dominated by structural myocardial injury.
This evolving understanding also prompts reflection on what constitutes therapeutic success in HFpEF. While traditional endpoints such as mortality and hospitalisation remain essential, symptomatic improvement and enhanced functional capacity are equally important measures of therapeutic impact.
Many individuals with HFpEF experience chronic dyspnoea, exercise intolerance and a reduced quality of life without frequent decompensations. For these patients, therapies that alleviate metabolic stress, reduce inflammatory burden and support improved daily functioning hold substantial value.
In this context, GLP-1 receptor agonists are a meaningful addition to the therapeutic landscape, not as replacements for foundational therapies but as agents that target pathways previously underserved in heart failure management.
Looking ahead, several avenues offer potential to expand the role of GLP-1-based therapies. Combining GLP-1 receptor agonists with SGLT2is may bring together complementary mechanisms, addressing metabolic load, renal-cardiac interaction and haemodynamic balance. Emerging incretin-based therapies with dual or triple agonism could further amplify effects on weight, inflammation and adipose-tissue distribution.
Advances in imaging, particularly in the characterisation of epicardial adipose-tissue volume and inflammatory activity, may refine phenotyping and guide more precise therapy selection. Incorporating metabolic biomarkers and inflammatory signatures into clinical assessment could enhance personalised HFpEF management by identifying those most likely to respond to metabolic-modulating therapy.
As cardiology continues to intersect with metabolic medicine, the insights presented in this issue highlight the need for a broader approach to HFpEF – one that integrates cardiovascular physiology with metabolic health, inflammation and adipose-tissue biology.
GLP-1 receptor agonists exemplify this integrated paradigm, offering a biologically coherent and clinically meaningful strategy for addressing several key mechanisms of HFpEF. Ongoing research will further define their long-term impact, optimal place in therapeutic algorithms and potential role in shaping future guideline-directed management.