Dear Editor,
We read with considerable interest the comprehensive review by Abdelhamid et al. examining the therapeutic role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in heart failure (HF).1 The authors provide a thorough synthesis of evidence from cardiovascular outcome trials and dedicated HF studies, including STEP-HFpEF, STEP-HFpEF DM and SUMMIT, and they clearly articulate how GLP-1RAs improve symptoms and exercise capacity in patients with HF with preserved ejection fraction (HFpEF) and obesity. Their pragmatic emphasis on careful phenotyping and individualised selection of candidates for GLP-1RA therapy is particularly valuable for clinicians navigating this rapidly evolving field. In this correspondence we propose that integrating the emerging apelin/APJ biology into the authors’ framework could help address the residual gap in HF with reduced ejection fraction (HFrEF) and refine consideration of body composition and sarcopenic obesity during GLP-1RA therapy.
The review also highlights important uncertainties. Abdelhamid et al. rightly note that dedicated trials in HFrEF, such as LIVE and FIGHT, yielded neutral or even concerning findings, with liraglutide showing no improvement in left ventricular ejection fraction and a numerically higher incidence of arrhythmic events.1–3 Meta-analyses suggest that GLP-1RAs modestly reduce HF hospitalisations in broader type 2 diabetes populations, yet there remains no convincing evidence to support their use as primary therapy in established HFrEF.1 Against this backdrop, patients with HFrEF and cardiometabolic comorbidities continue to lack targeted incretin-based options.
Among the many potential complementary pathways, the apelin/APJ system appears promising for three reasons. First, APJ agonism uniquely combines direct cardiovascular effects (positive inotropy, vasodilation, afterload reduction) with metabolic benefits (improved glucose homeostasis, weight regulation), aligning it closely with the cardiometabolic HFpEF phenotype that GLP-1RAs target.4 Second, recent preclinical data specifically evaluating APJ agonist and incretin combinations provide a scientific rationale that is absent for most other candidate pathways.4 Third, apelin’s established role in skeletal muscle homeostasis addresses the emerging concern of sarcopenic obesity during incretin-induced weight loss, a limitation that remains clinically unresolved.5
Apelin, the endogenous ligand of the APJ receptor, has emerged as a favourable cardiovascular therapeutic target with a profile that differs in several important respects from GLP-1RAs.4 Whereas the clinical benefits of GLP-1RAs appear to arise predominantly from systemic effects such as weight loss, blood pressure reduction and improved glycaemic control, apelin signalling exerts direct actions on the myocardium and vasculature.4,6 Preclinical work indicates that apelin enhances cardiomyocyte contractility, improves lusitropy and favourably modulates calcium handling and sarcomeric function.4,6 These effects are particularly attractive in HFrEF, where impaired contractile reserve remains central to pathophysiology.
Furthermore, the recent systematic review and meta-analysis by Hasheminezhad and Mirzad strengthens this mechanistic rationale.7 Across experimental models of acute myocardial injury in rodents, early administration of exogenous apelin significantly improved multiple indices of left ventricular function: ejection fraction SMD 0.79; 95% CI [0.15–1.44]; p=0.02), maximum rate of rise of left ventricular systolic pressure (+dP/dt; SMD 2.36; 95% CI [1.58–3.15]; p<0.001) and left ventricular systolic pressure itself (SMD 2.09; 95% CI [0.82–3.36]; p<0.001), while lowering left ventricular end diastolic pressure (SMD −1.85; 95% CI [−2.81 to −0.88]; p<0.001).7 Although these data derive from acute injury models rather than human chronic HF, taken together, these observations support a rationale for early-phase APJ agonist trials in carefully phenotyped patients with HFrEF and limited haemodynamic reserve.
Several additional features of apelin biology complement the pathways discussed by Abdelhamid et al.1 Apelin signalling counterbalances the renin–angiotensin–aldosterone system and enhances endothelial nitric oxide bioavailability, producing potent vasodilation and afterload reduction.6 In experimental models, apelin improves arterial compliance and pulmonary vascular tone, and it enhances right ventricular function in pressure-overload states.4,6 These actions may be highly relevant to both HFpEF and HFrEF phenotypes, where ventricular-vascular coupling and pulmonary hypertension significantly influence symptoms and prognosis.
Beyond these haemodynamic effects, apelin signalling also interacts with endothelial and progenitor cell biology, enhancing nitric oxide-dependent vasodilation, angiogenesis and microvascular repair in experimental models.4,6,8 Such actions may be particularly relevant in HF patients with coexistent diabetes or microvascular coronary disease, groups that feature prominently in the cardiovascular outcome trials summarised by Abdelhamid et al.1
Of particular interest, given the authors’ discussion of tirzepatide as a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist, are emerging preclinical data on combination therapy with GLP-1RAs and APJ agonists. Yan et al. recently reported that azelaprag, an oral APJ agonist, produced substantial cardioprotective effects in a diet-induced obesity model of HFpEF driven by obesity and hypertension.9 In this single preclinical study, azelaprag and semaglutide monotherapies each produced substantial weight loss and prevented cardiac hypertrophy. Azelaprag further suppressed cardiac brain natriuretic peptide expression and attenuated profibrotic gene expression. Combination therapy achieved larger reductions in body weight and left ventricular dimensions than either agent alone and was associated with more favourable profiles of molecular markers of cardiac stress.9 Although reported only at abstract level, these findings suggest that APJ agonism may complement and amplify the favourable cardiac and metabolic effects of GLP-1RAs in HFpEF.9
Separate preclinical work presented at the 2025 American Diabetes Association Scientific Sessions explored metabolic effects across several models of diabetic obesity.10 Oral APJ agonist monotherapy reduced HbA1c to levels comparable to lean controls and improved oral glucose tolerance by approximately 25%, with additional glycaemic benefit when combined with tirzepatide.10 These findings imply that APJ agonists possess independent antidiabetic activity that may complement incretins, potentially permitting lower GLP-1RA doses for equivalent metabolic efficacy. In light of the thoughtful discussion by Abdelhamid et al. on the adverse effects and tolerability of GLP-1RAs, such dose-sparing potential is clinically attractive.1
A clinically important issue that receives limited attention in the review is body composition change. Abdelhamid et al. note weight reductions ranging from several kilograms with shorter-acting agents to more than 10 kg with high-dose semaglutide and tirzepatide.1 Emerging data from obesity trials suggest that a meaningful proportion of this weight loss comprises lean mass, a concern in older adults and in patients with HF who already have reduced exercise capacity and frailty.5 In this context, apelin’s role as an exercise-induced myokine, or exerkine, is particularly relevant. Vinel et al. demonstrated that apelin expression declines with age and that apelin supplementation reverses age-associated sarcopenia in mice by stimulating mitochondrial biogenesis, autophagy and anti-inflammatory signalling in myofibres, and by promoting muscle stem cell regeneration.5
These skeletal muscle effects appear to translate, at least in part, to humans. In a Phase Ib bed-rest study in adults aged 65 years and older, reported by BioAge Labs, APJ agonist therapy significantly attenuated loss of thigh circumference and vastus lateralis cross-sectional area, and preserved muscle quality and protein synthesis compared with placebo.11 These findings raise the hypothesis that APJ agonism might help preserve lean mass during pharmacological weight loss, thereby shifting the balance towards preferential fat loss and potentially mitigating the risk of sarcopenic obesity in HF populations.
We acknowledge that clinical development of APJ agonists has encountered setbacks. BioAge Labs recently reported elevations in liver transaminases without a clear dose–response relationship in the STRIDES Phase II obesity trial (NCT06515418), leading to discontinuation of azelaprag as a development candidate.11 The mechanism of this liver injury signal remains uncertain, and it will be essential for future APJ agonists to undergo careful hepatic safety evaluation. Nevertheless, next-generation APJ agonists and metabolically stable apelin analogues remain in active development.6,11 Together, these efforts support the view that the underlying target biology remains compelling even as first-in-class molecules are refined.
Finally, the vascular and microvascular actions of apelin deserve explicit consideration alongside GLP-1RA-mediated endothelial benefits. Abdelhamid et al. discuss how GLP-1RAs may improve endothelial function and reduce epicardial adipose tissue, thereby favourably influencing coronary microcirculation.1 Building directly on their discussion, apelin signalling engages overlapping yet distinct pathways, promoting nitric oxide-dependent vasodilation while also enhancing endothelial progenitor cell function, angiogenesis and microvascular regeneration in experimental models.4,6,8 Such effects could be particularly valuable in HF patients with concomitant coronary artery disease or diabetes-related microvascular dysfunction, populations that are well represented in the cardiovascular outcome trials summarised in the review.1
We emphasise that clinical data on APJ agonists in HF remain limited to small, early-phase studies without clear efficacy signals, and extrapolation from animal models to human disease requires appropriate caution. Development programmes have already encountered significant setbacks, and no APJ agonist has yet progressed to late-phase HF outcome trials. Our intent is not to overstate therapeutic readiness, but rather to highlight a mechanistically coherent target that warrants continued investigation as the field seeks to extend incretin-based therapy beyond its current boundaries.
In summary, Abdelhamid et al. have provided an authoritative and clinically relevant overview of GLP-1RAs in HF. Building on their work, we suggest that the apelin/APJ pathway may address several limitations of current incretin-based approaches.1 Specifically, APJ agonism may deliver direct inotropic and lusitropic effects pertinent to HFrEF; act synergistically with GLP-1RAs in HFpEF to enhance cardioprotective and metabolic efficacy; and favourably influence skeletal muscle during weight loss, thereby optimising body composition outcomes and potentially improving functional capacity.2–5,9–11 We would encourage future studies that systematically measure endogenous apelin levels alongside GLP-1RA therapy, including serial sampling in ongoing and future HFpEF outcome trials, to clarify whether apelin dynamics track clinical response or adverse changes in body composition. Such work would clarify whether the apelin/APJ axis can be harnessed to extend the benefits of incretin-based therapy across the broader spectrum of HF.