The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: a potential avenue for improving heart failure with preserved ejection fraction (HFpEF)

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and complex condition with limited effective treatments. Endothelial dysfunction is a significant component of HFpEF pathophysiology, and glucagon-like peptide-1 receptor (GLP-1R) agonists have shown potential benefits in improving endothelial function. This study aims to explore the relationship between endothelial dysfunction in HFpEF and the mechanisms of action of GLP-1R agonists, highlighting their potential therapeutic benefits. A comprehensive review of the literature was conducted to examine the etiology of HFpEF, the role of endothelial dysfunction, and the effects of GLP-1R agonists on endothelial function and heart failure outcomes. The findings indicate that HFpEF is associated with various comorbidities, such as obesity, diabetes mellitus, and hypertension, which contribute to endothelial dysfunction. GLP-1R agonists, including semaglutide and liraglutide, have demonstrated significant cardioprotective effects, such as improving vascular endothelial function, reducing inflammation, and preventing atherosclerosis. Clinical trials, such as the STEP-HFpEF trial, have shown positive results in reducing symptoms and physical restrictions in HFpEF patients. GLP-1R agonists present a promising therapeutic option for HFpEF by targeting endothelial dysfunction and other pathophysiological mechanisms. Further research is needed to elucidate the precise mechanisms through which GLP-1R agonists exert their benefits and to establish their long-term safety and efficacy in diverse HFpEF populations.

Introduction

Heart failure (HF) affects approximately seven million adults in the United States, with one-third to half experiencing heart failure with preserved ejection fraction (HFpEF) [1,2,3,4]. The prevalence of HFpEF is rising, increasing from 33 to 39% between 2005 and 2010, with projections suggesting it will soon become the most common form of HF [5, 6].

The standard treatment for HFpEF includes sodium-glucose cotransporter 2 inhibitors (SGLT2i), such as empagliflozin and dapagliflozin, supported by the EMPEROR-Preserved (2021) and DELIVER (2022) trials [7, 8]. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have also emerged as a potential therapy. While the LIVE and FIGHT trials explored their effects on heart failure with reduced ejection fraction (HFrEF), the STEP-HFpEF trial demonstrated that GLP-1RAs improve HFpEF outcomes by reducing symptoms, physical limitations, and body weight [9].

Despite these promising results, the STEP-HFpEF trial did not clarify the mechanisms underlying these benefits. Capone et al. discussed the cardiometabolic effects of GLP-1RAs in HFpEF, focusing on obesity [10]. However, HFpEF is multifactorial, and GLP-1RA mechanisms extend beyond obesity management. This study aims to explore the link between endothelial dysfunction, a key component of HFpEF, and the therapeutic actions of GLP-1RAs.

Review

Etiology of HFpEF

Based on population-based studies conducted in the United States, more than 6 million people over the age of 20 have HF at this time. Patients diagnosed with diastolic heart failure (HFpEF) account for approximately half of heart failure hospitalizations. From 2005 (33%) to 2010 (39%), the prevalence increased (from 3.1 cases per person-year in the age group 65–69 years to 14.5 cases per person-year in the age group > 80 years). An increase in the diagnosis of HFpEF was noted in both sexes [3, 4].

The definition of HFpEF includes a combination of previous or current symptoms and/or signs of structural and functional abnormalities with the presence of congestion (including the level of NPs or radiological, ultrasound signs (LVEF ≥ 50%, E/E′ > 15, regurgitant or obstructive valvular injury, ventricular hypertrophy) [1, 2].

There is a shifting trend in the risk factors associated with heart failure in epidemiological studies from classic smoking and hypertension as risk factors for ischemic heart disease and heart failure with reduced ejection fraction, to morbid obesity, diabetes mellitus, and metabolic syndrome in the aging population as risk factors for heart failure with preserved ejection failure [5]. Over the past decade, it has been demonstrated that myocardial structure, cardiomyocyte function, and intramyocardial signaling undergo specific alterations in heart failure with preserved ejection fraction (HFpEF); however, a new paradigm for HFpEF development proposes that a systemic proinflammatory state, induced by comorbidities, is responsible for these myocardial structural and functional changes [11]. The cormorbidities often associated with HFpEF such as obesity, diabetes mellitus, and hypertension as well as the metabolic changes associated with them are known to induce a state of inflammation that affects cardiac metabolism, as well as coronary vascular injury and ischemia [5]. This new HFpEF paradigm thus shifts the focus from LV afterload excess to coronary microvascular inflammation.

Role of endothelial dysfunction in the development of HFpEF

Endothelial dysfunction plays a critical pathophysiological role in heart failure with preserved ejection fraction (HFpEF). This dysfunction affects not only the endothelial cells of the coronary vessels but more crucially those in the intramyocardial capillaries and endocardium, where they interact directly with adjacent cardiomyocytes [12]. Experimental post-infarction models have demonstrated that both cardiac and pulmonary vascular endothelial dysfunction contribute to heart failure development; however, data specifically regarding HFpEF are limited [13, 14].

Key risk factors for HFpEF, such as hypertension and diabetes, are associated with endocardial and myocardial capillary endothelial abnormalities in experimental models [15, 16].

The impact of aging endothelial cells has been explored using mouse models, revealing that mice with accelerated senescence exhibit endothelial cellular dysfunction, impaired relaxation, and interstitial fibrosis, leading to HFpEF. This is correlated with increased endothelial inflammation, characterized by intercellular adhesion molecule 1 expression, and enhanced endothelial senescence at the molecular level. Aged mice in the study showed signs of endothelial dysfunction, increased vascular stiffness, and impaired coronary microcirculation, which are hallmarks of HFpEF [17].

These endothelial abnormalities may account for the impaired left ventricular relaxation observed in pressure-overload hypertrophy [18]. Additionally, the coronary endothelium has been shown to influence left ventricular diastolic function through paracrine effects in both healthy individuals and post-transplant patients [19].

The combined stiffening of the ventricular and vascular systems, including both systemic and pulmonary circulations, significantly contributes to the pathophysiology of HFpEF [20, 21].

In the systemic circulation, endothelial dysfunction, detectable in healthy individuals with normal brachial blood pressure, is associated with increased central pulse pressure and systemic arterial stiffening. This suggests that systemic endothelial dysfunction may be a primary factor in the development of systemic hypertension and its pathological consequences, such as increased left ventricular wall stress, hypertrophy, diastolic dysfunction, and HFpEF [22]; similarly, in the pulmonary circulation, endothelial dysfunction has been identified as an early event leading to the development of pulmonary hypertension in the context of experimental heart failure [21].

A study by Akiyama et al. highlighted the prognostic significance of endothelial dysfunction in HFpEF. The study found that peripheral endothelial dysfunction independently correlated with future cardiovascular events, thus providing additional clinical significance for risk stratification in HFpEF patients. The prognostic impact of the reactive hyperemia index (RHI) in HFpEF patients suggests that endothelial dysfunction may not be merely a passive finding, but rather that endothelial function plays an active and crucial pathophysiological role in HFpEF [23].

Coronary microvascular dysfunction in HFpEF

Understanding the relationship between coronary microvascular dysfunction (CMD) and heart failure with preserved ejection fraction (HFpEF) is crucial. The association between HFpEF and CMD was first proposed in 2013 [11]. Since then, multiple studies have investigated CMD in HFpEF patients. Sucato et al. [24] found that HFpEF patients exhibited more significant microcirculation involvement compared to those without HFpEF. An autopsy study revealed a higher prevalence of coronary microvascular rarefaction, microscopic fibrosis, and hypertrophy in HFpEF patients [25].

Response of the coronary microvascular bed to acetylcholine is diminished in HFpEF. This diminished vasodilator response is correlated with left ventricular diastolic dysfunction [26]. Similar paracrine interactions between the endocardium and myocardium have been previously reported [12]. Recent studies have highlighted the significance of a deficient systemic vasodilator response in contributing to the reduced exercise tolerance observed in HFpEF patients [27].

According to Rush et al [28] CMD is common and often underrecognized in HFpEF patients and may represent a therapeutic target. A metanalysis by Lin et al. summarized and analyzed all research on the prevalence of CMD in HFpEF patients, finding a high pooled prevalence of 71% [29].

GLP-1 agonists and their cardioprotective effects

Incretins are gut hormones that enhance insulin secretion in response to meals, in a glucose- dependent manner. The two most studied incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate insulin release through specific G-protein-coupled receptors predominantly found on islet β cells. These receptors are also present in non-islet cells and contribute to various metabolic effects in the brain, liver, adipose tissue, and gastrointestinal tract. Two primary strategies to enhance incretin receptor signaling have been explored for type 2 diabetes treatment; one involves inhibiting dipeptidyl peptidase-4 (DPP-4), the enzyme that deactivates GIP and GLP-1; the other strategy includes injectable GLP-1R agonists that mimic human GLP-1 or nonmammalian GLP-1R agonists. The insulin-enhancing effects of GIP and GLP-1 were discovered over 25 years ago, yet new roles for incretin hormones continue to emerge [30].

There is a wide range of cardioprotective benefits to GLP-1R agonists in addition to their metabolic effects on blood glucose, adiposity, serum lipids, and blood pressure [31]. Despite the limited expression of GLP-1 receptors in the cardiac tissue, they tend to enhance the myocardial function through multiple mechanisms, including optimizing the coronary vascular smooth muscle cells, and endothelial function of the coronary microvasculature and the peripheral vessels as well, in addition to improving blood glucose control and providing alternative energy substrates like ketones and lactate. At the level of the vascular smooth muscle cells, they protect against pathogenic, proliferative remodeling of the vascular smooth muscle cells, thus delaying plaque formation and stabilizing existing lesions. They also enhance the cardiac mitochondrial function leading to improved outcomes under hypoxic conditions and reduced pathologic remodeling [31].

The G protein-coupled receptor of GLP-1 (GLP-1R) originally identified in islet β-cells is widely expressed in extrapancreatic tissues as well including the lungs, kidney, brain, the enteric and peripheral nervous system, lymphocytes, smooth muscle cells (SMCs), and atrial cardiomyocytes [32] The specific identity of GLP-1 receptor-positive (GLP-1R+) cells in the heart remains uncertain. Immunohistochemical studies in monkeys and humans found GLP-1R+ cells mainly in the sinoatrial node and atrial tissue, with higher expression in the right atrium. However, varied detection methods show inconsistent GLP-1R localization across heart tissues. While murine models suggest atrial GLP-1R expression, the precise cardiac cell types expressing GLP-1R, especially in humans, are yet to be conclusively identified [33].

Role of GLP-1 agonists in managing comorbidities in HFpEF

Beyond their cardioprotective properties, GLP-1 receptor agonists exert a beneficial impact on HFpEF by influencing other organ systems and mitigating comorbid conditions that contribute to its progression, including metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease, and pulmonary disorders.

Liver disease in heart failure with preserved ejection fraction

The relationship between heart failure (HF) and liver disease is characterized by bidirectional interactions where one condition exacerbates the other. HF can lead to liver complications such as congestive hepatopathy and ischemic liver injury, primarily through hemodynamic changes, including hepatic congestion and hypoperfusion. Conversely, liver conditions like metabolic dysfunction-associated steatotic liver disease (MASLD), also known as non-alcoholic fatty liver disease (NAFLD) can increase the risk of HF due to systemic inflammation, oxidative stress, and metabolic disturbances [34, 35].

MASLD contributes to HFpEF through several interconnected mechanisms; ectopic fat deposition in the liver and epicardium triggers inflammation, disrupts myocardial energy metabolism, and promotes fibrosis, contributing to cardiac dysfunction and diastolic impairment. Hepatic insulin resistance further exacerbates cardiovascular risk by impairing lipid and glucose metabolism, leading to atherogenic dyslipidemia, vascular inflammation, and endothelial dysfunction. Systemic inflammation driven by steatosis and necro-inflammatory changes in MASLD activates pathways such as toll-like receptors (TLR) and Nuclear Factor-kappa B (NF-κB), causing cardiac and vascular tissue damage. Parallel fibrogenesis in the liver and myocardium adds to ventricular stiffness and diastolic dysfunction, while gut dysbiosis from a Western diet heightens systemic inflammation and endotoxemia, worsening cardiac and hepatic dysfunction. Additionally, genetic factors, including TM6SF2 variants, intensify hepatic fibrosis and dyslipidemia, increasing cardiovascular susceptibility. Collectively, these mechanisms establish a connection between MASLD and diastolic dysfunction, arrhythmias, and a heightened risk of HFpEF [36]. In an animal study, using a mouse model with different age groups, non-alcoholic steatohepatitis (NASH) was induced, revealing age-dependent effects on cardiac function. NASH caused hepatomegaly, fibrosis, and inflammation in all mice, with aged mice showing increased heart weight, left ventricular volumes, and subtle systolic and diastolic dysfunction, thus NASH tends to worsen age-related cardiac dysfunction [37].

In a previous metanalysis, GLP-1 agonists were found to improve hepatic parameters in patients with NAFLD [38]. Multiple studies have demonstrated that patients with MAFLD are at an increased risk of developing heart failure (HF) compared to those without MAFLD. This association persists even in the absence of traditional cardiovascular disease (CVD) risk factors, suggesting a direct relationship between MAFLD and the risk of new-onset HF [39].

GLP-1 receptor agonists (GLP-1RAs) offer therapeutic potential in this interplay. GLP-1RAs improve glucose homeostasis, reduce liver fat, and mitigate hepatic inflammation. These effects help slow the progression of liver fibrosis and reduce cardiovascular risks [34]. Additionally, they may indirectly benefit HF by modulating systemic inflammation and improving metabolic profiles [35].

In a study that examined the effects of GLP-1 receptor agonists (GLP-1 RAs) on liver fibrosis in type 2 diabetes (T2DM) patients with nonalcoholic fatty liver disease (NAFLD). GLP-1 RAs may modestly slow liver fibrosis progression in T2DM patients with NAFLD [40]. In another study, GLP-1 RA use was associated with a lower risk of cirrhosis progression, reduced complications, and lower mortality in non-cirrhotic patients [41].

There is a significant link between NAFLD and an increased risk of new-onset heart failure, regardless of the presence or absence of Type 2 diabetes and other associated cardiometabolic risk factors. The risk magnitude rises with the severity of liver disease in NAFLD, particularly at higher fibrosis stages [42].

GLP-1 receptor agonists (GLP-1 RAs) improve glycemic control, delay gastric emptying, and promote weight loss. These properties make them an attractive therapeutic option for managing non-alcoholic fatty liver disease (NAFLD), particularly in individuals with concurrent diabetes mellitus and obesity.

GLP-1 receptor agonists, such as liraglutide, show promise in treating non-alcoholic fatty liver disease (NAFLD), particularly in individuals with type 2 diabetes (T2DM) and obesity. Clinical trials demonstrate that liraglutide reduces liver fat, improves liver function, and decreases inflammatory markers, though its effects on epicardial adipose tissue (EAT) are inconsistent. GLP-1 receptor agonists also exhibit cardiovascular and anti-inflammatory benefits, potentially reducing the risk of heart failure with preserved ejection fraction (HFpEF). However, further studies are needed to fully understand their effects, particularly on EAT and HFpEF [43].

A multicenter, randomized, double-blind, placebo-controlled trial demonstrated that liraglutide was associated with the resolution of non-alcoholic steatohepatitis (NASH) without worsening fibrosis. Improvements in steatosis and hepatocyte ballooning scores were also observed. Additionally, liraglutide and exenatide have been shown to reduce trunk fat content, particularly in the android region, a critical area linked to NAFLD and cardiovascular disease (CVD) risk [44].

A 12-month interventional study demonstrates the beneficial effects of semaglutide, both oral and subcutaneous, on body weight, insulin resistance, liver function, lipid profile, and hepatic steatosis. Significant improvements were also observed in fibrosis markers, including FIB-4, CAP, and LSM, supporting the potential for broader clinical use of semaglutide in NAFLD patients with type 2 diabetes and obesity.

Further randomized trials with larger sample sizes, including NAFLD patients with and without diabetes and incorporating active control groups, are needed to confirm these findings [45].

Chronic kidney disease in heart failure with preserved ejection fraction

In the pooled analysis of the SUSTAIN 6 and LEADER trials, with median follow-up periods of 2.1 and 3.8 years respectively, semaglutide and liraglutide demonstrated significant renal benefits compared to placebo. Both drugs reduced albuminuria by 24% over two years, with the most substantial reduction observed with semaglutide 1.0 mg (33%). Additionally, the decline in estimated glomerular filtration rate (eGFR) was significantly slowed by 0.87 mL/min/1.73 m² per year with semaglutide and 0.26 mL/min/1.73 m² per year with liraglutide. These effects were more pronounced in patients with baseline eGFR below 60 mL/min/1.73 m². Both drugs also significantly reduced the risk of persistent eGFR reductions of 40% and 50%, while showing similar trends for 30% and 57% reductions. Among patients with baseline eGFR between 30 and < 60 mL/min/1.73 m², the likelihood of persistent reductions across all thresholds was further decreased, ranging from a 29% to 46% risk reduction depending on the threshold [46].

The “Evaluate Renal Function with Semaglutide Once Weekly” (FLOW) trial, published earlier this year, is the first to specifically investigate kidney outcomes with GLP-1 receptor agonists. Similarly, the “Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity” (SELECT) trial demonstrated a significant reduction in cardiovascular events in individuals with overweight or obesity, with subsequent analysis addressing prespecified kidney endpoints. Together, these studies offer valuable new evidence supporting the use of GLP-1 receptor agonists for kidney and cardiovascular protection in individuals at risk for or with established chronic kidney disease.

The FLOW trial demonstrated clear kidney and cardiovascular protection with GLP-1 receptor agonist (GLP-1RA) treatment in individuals with type 2 diabetes and chronic kidney disease (CKD). It also highlighted significant weight loss benefits, which are particularly valuable for overweight or obese patients with CKD. While the trial showed potential additive benefits when combined with SGLT2 inhibitors (SGLT2i) or finerenone, conclusive evidence for these effects is lacking. However, limitations included the restricted inclusion criteria (eGFR range of 20–75 mL/min/1.73 m² and albuminuria requirements), which limit generalizability to patients with higher or lower eGFR or preserved eGFR without albuminuria. These findings position GLP-1RAs as a potential fourth pillar of kidney-protective therapy in diabetes, alongside renin-angiotensin system inhibitors (RASi), SGLT2i, and finerenone, and suggest a shift toward rapid initiation of combination therapies for maximum kidney protection.

The SELECT trial provided the first evidence of kidney protection with GLP-1RA treatment in individuals without diabetes, although this was a prespecified secondary endpoint. It showed potential benefits for CKD patients, particularly those who are overweight or obese. However, the trial's low event rate and reliance on serum creatinine to assess eGFR, which may be influenced by muscle mass changes, limit the robustness of its conclusions. Despite these limitations, the findings support recommending GLP-1RAs to facilitate weight loss and improve outcomes in CKD patients with obesity, even in the absence of diabetes.

Together, the FLOW and SELECT trials underscore the potential of GLP-1RAs to address multimorbidity in CKD by impacting obesity, cardiovascular disease, and kidney health. These therapies offer a promising new approach to improving overall health in CKD patients. Further studies and economic evaluations are warranted to refine combination treatment strategies and maximize cost-effectiveness while addressing individual patient needs [47].

Emerging dual agonists, such as survodutide and cotadutide, which target GLP-1 and glucagon receptors, are being explored for treating metabolically associated fatty liver disease and may also address fatty kidney, a key factor in CKD related to visceral obesity [48].

Chronic lung disease in heart failure with preserved ejection fraction

In a nationwide cohort study, it was demonstrated that GLP-1 RAs were associated with a reduced risk of cardiopulmonary complications and all-cause mortality compared to non-GLP-1 RAs in patients with T2D and COPD. GLP-1 RAs may offer a beneficial approach for managing diabetes in individuals with COPD [49]. There is also additional evidence supporting the role of GLP-1 agonists in reducing exacerbations of respiratory diseases [50].

GLP-1RAs may effectively alleviate clinical symptoms in COPD patients, improve airflow limitation, mitigate airway damage, fibrosis, and remodeling, shorten hospital stays, reduce the economic burden, and lower the risk of COPD-related complications. These effects contribute to better long-term prognoses and highlight the potential therapeutic and preventive role of GLP-1RAs in COPD management, offering a promising new target for its treatment and prevention [51].

GLP-1RA markedly enhance lung function in COPD patients, as demonstrated by improved spirometry results. Furthermore, both GLP-1RA and SGLT-2i are linked to a reduced risk of moderate and severe exacerbations in COPD and may lower the incidence of respiratory conditions such as asthma and pneumonia. While the exact mechanisms driving these benefits remain unclear, they likely involve diverse effects, including anti-inflammatory properties and mitigation of oxidative stress [52]. Role in reversing lung fibrosis and improving lung function in experimental models [53, 54].

In preclinical studies, Glucagon-like peptide-1 (GLP-1) has demonstrated its protective effects in lung disease models, potentially mediated by atrial natriuretic peptide (ANP). Using a chronic obstructive pulmonary disease (COPD) mouse model, researchers investigated the relationship between GLP-1 and ANP through genetic GLP-1 receptor (GLP-1R) knockout, pharmaceutical GLP-1R blockade, and exogenous GLP-1 administration. Treatment with a GLP-1R agonist improved lung function and reduced inflammation but did not mitigate emphysema. It also significantly increased ANP expression and reduced endothelin-1, a bronchoconstrictor. Both ANP and GLP-1R agonists showed bronchodilatory effects, with stronger responses in COPD mice. This study suggests a functional link between GLP-1 and ANP in improving lung function and reducing inflammation in COPD, highlighting their therapeutic potential [55].

Effects of GLP-1 agonists on vascular endothelium

Enhancing endothelial function

A review of the literature revealed multiple preclinical studies on GLP-1R agonists in animal models demonstrating the molecular mechanisms behind their pharmacological effects.

One protective mechanism of GLP-1 receptor (GLP1R) agonists offers protection by boosting insulin sensitivity, which subsequently enhances endothelial function. In states of insulin resistance, impairments in phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways can disturb the balance between nitric oxide (NO) production and endothelin-1 secretion, resulting in endothelial dysfunction [56,57,58] (refer to Fig. 1).

Fig. 1

Effects of GLP-1 agonists on vascular endothelium*. NOX-4 (NADPH oxidase 4), LOX-1 (lectin-like ox-LDL receptor-1), ROS (reactive oxygen species), oxLDL (oxidized LDL), VCAM-1 (vascular cell adhesion molecule-1), ICAM-1 (intercellular adhesion molecule-1), NO (nitric oxide), eNOS (endothelial nitric oxide synthase), AMPK (AMP-activated protein kinase), NLRP3 (NOD-like receptor family, pyrin domain-containing 3), PPARγ (peroxisome proliferator-activated receptor γ). The GLP-1 agonists effects demonstrated in this figure are mediated through GLP-1 receptors in the vascular endothelium. *This illustration was created using Servier Medical Art for medical illustrations

More clinical evidence can be found on the role of GLP1R agonists such as exenatide can improve vascular endothelial dysfunction in diabetic patients, as has been found in this clinical trial by Hu et al., results suggested that exenatide improved the endothelial dysfunction reflected by digital reactive hyperemia index in newly diagnosed patients with T2DM, and the effect was not inferior to single metformin [59]. In another study that examined the role of exenatide in improving coronary endothelial function in newly diagnosed type 2 diabetic patients in a randomized controlled trial, the coronary endothelial function was assessed by measuring the coronary flow velocity reserve (CFVR) which was improved significantly after 12 weeks of treatment with exenatide, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C), this was also associated with a decrease in serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) was remarkably decreased in the exenatide treatment group compared with the baseline and the control group emphasizing the anti- inflammatory effects of exenatide. The same study investigated the effects of exenatide in human umbilical vein endothelial cells, and it significantly increased NO production, and endothelial.

NO synthase (eNOS) phosphorylation Furthermore, exenatide reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation which further contributed the improvement of coronary endothelial function in diabetic patients [58]. Similar findings were demonstrated by liraglutide, which was also found to exert endothelial protective properties in human vascular endothelial cells (hVECs) through inhibition of stimulated plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression. Liraglutide treatment also increased endothelial nitric oxide synthase (eNOS) and reduced intercellular adhesion molecule-1 (ICAM-1) expression in the aortic endothelium of atherogenic mice models ApoE^−/− mice model [60]. This was supported by another study in which liraglutide attenuated the TNF or high-glucose-mediated induction of PAI-1, ICAM-1, and VCAM-1 expression in human vascular endothelial cells, the proposed molecular mechanism underlying this effect may involve the regulation of NUR77 expression [61], which is a nuclear receptor and transcription factor involved in regulating gene expression related to cell growth, apoptosis, metabolism, and inflammation. It influences glucose and lipid metabolism, modulates inflammatory responses, and impacts vascular endothelial function, playing a role in cardiovascular diseases. In the context of liraglutide treatment, Nur77 regulation may help reduce endothelial cell dysfunction in type 2 diabetes and metabolic syndrome [62].

Another study compared the effects of the glp-1 receptor agonist exenatide and metformin on endothelial function in obese individuals with pre-diabetes. both exenatide and metformin had similar effects on microvascular endothelial function measured by the reactive hyperemic index (RHI), as well as levels of inflammatory and oxidative stress markers including C-reactive protein (CRP), oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) levels [63].

Exenatide was found to lower the levels of high sensitivity-C-reactive protein and endothelin-1 in comparison to glargine insulin in another study [63]. Another protective mechanism exerted by exenatide on the endothelium is through its action through opening the KATP channels thus protecting against impairment in endothelium-dependent vasodilatation induced by ischemia–reperfusion (IR) injury [64].

A recent study demonstrated the protective role of GLP-1R receptors against hyperglycemia- induced endothelial to-mesenchymal transformation which is a crucial component of diabetic endothelial injury in cardiomyopathy, nephropathy, and retinopathy; as liraglutide was found to suppress neointima formation through upregulating the endothelial AMPK-nitric oxide pathway [65].

Recent studies have demonstrated new anti-inflammatory properties for GLP1-R agonists; one example is through the suppression of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, which is an inflammatory complex containing three components, including NLRP3, caspase-1, and apoptosis-associated speck-like protein (ASC), resulting in the maturation and secretion of the proinflammatory cytokines Activation of the NLRP3 inflammasome plays an important role in high glucose-induced endothelial dysfunction in patients with type 2 diabetes mellitus and cardiovascular disorders. Dulaglutide was found to suppress this complex by reducing the expression of NLRP3, ASC, and cleaved caspase 1 (p10), in addition to mitigating oxidative stress by inhibiting the expression of NADPH oxidase 4 (NOX-4) and lowering the levels of reactive oxygen species (ROS) as has been demonstrated in human umbilical vein endothelial cells [66] (refer to Fig. 1).

GLP1-R agonists have been shown to provide anti-inflammatory and endothelial protective benefits through the activation of peroxisome proliferator-activated receptor γ (PPARγ). This activation inhibits intracellular serine/threonine kinases, like JNK, which in turn reduces insulin receptor substrate (IRS)-1 serine phosphorylation, a major contributor to insulin resistance, and decreases atherosclerosis. Additionally, PPARγ activation inhibits transcription factors like NF- κB, preventing atherosclerosis by suppressing the expression of cytokines and adhesion molecules in endothelial cells. This effect was observed in human umbilical vein endothelial cells treated with exendin-4 [67].

Preventing atherosclerosis

In a study that examined the effects exerted by liraglutide on the endothelium in mice models with early onset, low-burden atherosclerotic disease, liraglutide treatment in apolipoprotein E deficient (ApoE^−/−) mice inhibited the progression of early onset, low-burden atherosclerotic disease and enhanced plaque stability in a partially GLP-1R-dependent manner, without significantly affecting late onset, high-burden atherosclerotic disease. Liraglutide significantly reduced lipid deposition and increased vascular smooth muscle cell and collagen content in plaques, thus enhancing plaque stability. The additional, indirect, GLP1R agonist effects on both weight and blood pressure further contributed to mitigating the progression of atherosclerosis [60].

In another study that examined the molecular mechanisms behind the effects of liraglutide on oxidized low-density lipoprotein in endothelial cells [68], liraglutide was found to suppress LDL-induced immune cell adhesion to the endothelial cells by inhibiting the expression of vascular adhesion molecules including E-selectin and VCAM-1 both of which have been related to the development of atherosclerosis [68,69,70,71] (refer to Figure one). Similar effects were exerted by Exendin-4 [72].

Liraglutide has also been found to protect against LDL-induced endothelial hyperpermeability by influencing the expression of the cellular junction protein Occludin and thus maintaining vascular permeability. It also maintains the vascular tone by enhancing the levels of endothelial nitric oxide (NO). Liraglutide also antagonizes the effects of oxidized LDL in hyperlipidemia through the ERK-5-KLF2 signals axis which is a transcription regulator with a wide range of regulatory functions in the vascular endothelium including tone, permeability, and inflammation [73]. Dulaglutide has shown similar effects, potentially preventing the atherosclerotic impacts of ox-LDL by inhibiting the suppression of KLF2 by the p53 protein in human aortic endothelial cells which is known to play a crucial role in protecting vascular endothelial cells from damage caused by ox-LDL. R Liraglutide also protects against the effects of oxidized LDL by downregulating lectin-like ox-LDL receptor-1(LOX-1) expression thus inhibiting LOX-1- mediated oxidative stress and inflammation [68].

One key component of atherosclerosis is vascular smooth muscle proliferation, previous studies have demonstrated the effects of GLP-1 agonists in reducing vascular remodeling in murine models. This effect appears to be driven by anti-inflammatory and proliferative mechanisms independent of receptor activation/signaling in the resident vascular cells [74,75,76].

GLP-1R agonists in HFpEF; review of literature

Given the pathophysiological heterogeneity of HFpEF, our understanding has been constrained by limited access to human samples and the absence of animal models that fully replicate the human HFpEF phenotype. While existing animal models, which replicate specific phenotypes by targeting individual organ systems, offer the closest approximation to the HFpEF pathology, they still fall short of fully recapitulating the human condition. Nonetheless, these animal models remain valuable research tools for elucidating the mechanistic underpinnings of the disease [77, 78].

The following is a review of the preclinical and clinical studies examining the role of GLP-1R agonists on the vascular endothelium and HFpEF:

Data from preclinical studies

In a study on non-diabetic mice models with arterial hypertension (simulating preconditions for HFpEF), Liraglutide treatment improved blood pressure and cardiac hypertrophy in angiotensin II-induced arterial hypertension independent of glucose/insulin modulation leading to the reversal of cardiac hypertrophy. Liraglutide also decreased angiotensin II-induced oxidative stress by increasing the levels of NADPH oxidase activity, increasing endothelial NO availability, and reducing immune cell infiltration by reducing the levels of F4/80 (a macrophage marker F4/80 with proinflammatory properties) expression in cardiac tissue thus reducing the overall level of oxidative stress in hypertensive heart disease. Liraglutide has been shown to exhibit antioxidant and anti-inflammatory properties that reduce eNOS uncoupling and increase NO bioavailability, NO bioavailability is thereby maintained, endothelium-mediated vasorelaxation is preserved, and vascular remodeling and fibrosis are prevented. Liraglutide also ameliorated ATII-induced rolling and infiltration of leukocytes by downregulation of central proinflammatory mediators (NF-κb, TNF-α, and IL-1β) with concomitant reduced expression of adhesion molecules (VCAM-1, ICAM-1, and P-selectin) [79] (refer to Fig. 1).

In a separate study utilizing angiotensin II-induced hypertensive mouse models to examine the effects of liraglutide on diastolic dysfunction in HFpEF, improvement in diastolic dysfunction was linked to alterations in amino acid levels within the cardiac tissue. These changes were associated with enhanced markers of protein translation, indicative of increased protein turnover and amino acid uptake, which provide protection against fibrotic remodeling and diastolic dysfunction [80].

Findings from this study were supported by another study in which the cascade of hypertension- induced vascular injury was mitigated by the use of liraglutide and a dipeptidyl peptidase-4 inhibitor to prevent the endogenous degradation of GLP-1, linagliptin; this was shown to protect against Ang II-induced injury in the heart and aorta, potentially associated with inhibition of NOX4 expression and preservation of mitochondrial integrity, reduced the protein levels of NADPH oxidase 4 (NOX4) and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts culminating in reduced aortic wall thickness [81].

Another study examined the effects of Liraglutide in obesity mice models, and it has demonstrated anti-inflammatory properties, treatment with Liraglutide has reduced markers of inflammation TNF-α, nuclear translocation of nuclear factor kappa B (NFκB), prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro. maintained endothelial function by correction of obesity-induced decreases in endothelial nitric oxide synthase (eNOS), reduced markers of hypertrophy and fibrosis. liraglutide protects isolated mouse neonatal cardiomyocytes and human coronary smooth muscle cells from palmitate-induced lipotoxicity. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function by an AMP-activated protein kinase-dependent mechanism [82].

In another study performed to examine the potential cardioprotective effects in elderly hearts, a model of aging rats was used in which the effects were tested in aged rats. liraglutide treatment significantly mitigated the prolongation of QRS duration and elevated both systolic and diastolic blood pressure, accompanied by a restoration of plasma oxidant and antioxidant statuses. The prolonged action potential durations and depolarized membrane potentials in isolated cardiomyocytes from aged rats were normalized through the recovery of K⁺ channel currents with liraglutide treatment. Additionally, alterations in Ca²⁺ regulation, including leaky ryanodine receptors (RyR2), were ameliorated via the recovery of Na⁺/Ca2⁺ exchanger currents. Direct liraglutide treatment of isolated aged rat cardiomyocytes restored the depolarized mitochondrial membrane potential, reduced reactive oxygen and nitrogen species (ROS and RNS), and normalized cytosolic Na⁺ levels, despite the Na⁺ channel currents remaining unaffected by aging. Notably, liraglutide treatment significantly inhibited activated sodium-glucose co- transporter-2 (SGLT2) restored depressed insulin receptor substrate 1 (IRS1), and increased protein kinase G (PKG) levels. The recovery of the phospho-endothelial nitric oxide synthase (pNOS3) to NOS3 protein ratio in liraglutide-treated cardiomyocytes suggests that liraglutide- associated inhibition of oxidative stress-induced injury occurs via the IRS1-eNOS-PKG pathway in the aging heart [83].

To date, preclinical HFpEF models have primarily utilized single perturbations to replicate the human HFpEF phenotype. However, these models have faced challenges in reproducing the wide range of symptoms observed in human HFpEF, since usually one organ system is targeted and the pathology is replicated in a relatively acute setting in comparison to the natural course of HFpEF in humans.

A recent study investigated the effects of GLP-1R agonists in a multi-hit mouse model in which the combination of a high-fat diet and angiotensin II-induced a cardiometabolic HFpEF phenotype that resembles the human HFpEF phenotype to a large extent characterized by obesity, impaired glucose handling, and metabolic dysregulation accompanied by inflammation. This multifactorial approach resulted in the manifestation of typical clinical HFpEF features, including ventricular hypertrophy, increased collagen deposition and fibrosis, elevated blood pressure, and diastolic dysfunction; as well as left atrial enlargement, pulmonary congestion, and raised natriuretic peptides all features of clinical HFpEF. Liraglutide treatment in this model has alleviated cardiometabolic dysregulation and enhanced cardiac function, resulting in reduced cardiac hypertrophy and fibrosis, as well as diminished atrial weight, natriuretic peptide levels, and lung congestion [84].

Study	Animal model	Drugs used	Results	Mechanism
Helmstädter et al. [60]	Hypertensive mouse model murine, nondiabetic model of angiotensin II-induced arterial hypertension Wild-type (C57BL/6 J), global (Glp1r−/−), as well as endothelial (Glp1rflox/ floxxCdh5cre) and myeloid cell–specific knockout mice (Glp1rflox/ floxxLysMcre) of the GLP-1R	Liraglutide	Improvement in blood pressure and cardiac hypertrophy Reduction in cardiac and whole blood oxidative stress Improvement ATII-induced endothelial dysfunction and vascular fibrosis Amelioration of ATII-induced inflammation of the vasculature	Suppression of inflammation and NADPH oxidase activity Reduction of vascular oxidative stress and recoupling of eNOS Prevention of ly6g−ly6c+- and ly6g+ ly6c+ cell infiltration to the vessel wall
Rutledge et al. [80]	Hypertensive mouse model mouse model of angiotensin II-mediated diastolic dysfunction	Liraglutide	Protection against AngII-mediated diastolic dysfunction	Promoting amino acid uptake and protein turnover in the heart
Banks et al. [81]	Hypertensive model Sprague–Dawley rat model of Ang II infusion	Liraglutide and dipeptidyl peptides-4 inhibitor linagliptin	Protection against Ang II-induced injury in the heart and aorta A significant reduction in cardiac fibrosis.Reduction in aortic wall thickness and fibrotic areaReduction in mean blood pressure	Downregulation of the expression of NOX4 and intercellular adhesion molecule 1 Enhanced endothelial NOS expression Reduction in the protein levels of NOX4 and TGFβ1 and Reduced expression of monocyte chemoattractant protein 1, Attenuation in the proliferation of myofibroblasts Decrease in the
Noyan-Ashraf et al. [82]	Obesity model Obesity mice model C57Bl6 mice were placed on a 45% high-fat diet or a regular chow diet	Liraglutide	Reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, Reversed obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis Reduction in cardiac endoplasmic reticulum stress response Improved cardiac function	AMP-activated protein kinase– dependent mechanism Prevention of palmitate- induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells Preventing the adhesion of human monocytes to tumor necrosis factor-α– activated human endothelial cells in vitro
Durak and Turan [83]	Aged rats	Liraglutide	Reduction in the prolongation of QRS duration Increase in both systolic and diastolic blood pressure Recovery in plasma oxidant and antioxidant statuses At the cellular level, normalizing the action potential (AP) parameters, ionic currents, and Ca2+ regulation in freshly isolated	Recoveries in K+ channel currents and Na+/Ca2+ exchanger currents Inhibition of activated sodium-glucose co-transporter-2 (SGLT2) Recoveries in the depressed insulin receptor substrate 1 (IRS1) and increased protein kinase G (PKG) Recovery in the ratio of phosphor endothelial nitric oxide (pNOS3) level to NOS3
Withaar et al. [84]	Multi-hit mouse model aged female C57BL/6 J mice were administered a high-fat diet and angiotensin II. The combined treatment of high-fat diet and angiotensin II (HFD + ANGII) induced a cardiometabolic phenotype consistent with heart failure with preserved ejection fraction (HFpEF)	Liraglutide and Dapagliflozin	Treatment with liraglutide ameliorated cardiometabolic dysregulation Enhancing cardiac function by reducing cardiac hypertrophy and myocardial fibrosis Attenuated atrial weight, natriuretic peptide levels, and lung congestion Dapagliflozin treatment improved glucose metabolism but had only mild effects on the HFpEF	Liraglutide alleviated left ventricular load, enhanced diastolic function, and exhibited anti- atherosclerotic properties via an anti- inflammatory mechanism The effectiveness of SGLT2 inhibitors can be attributed, at least in part, to their natriuretic effects

Data from clinical studies

In an observational study involving 20 diabetic subjects receiving background metformin therapy, exenatide treatment over 16 weeks resulted in improved flow-mediated vasodilation of the brachial artery following 5 min of forearm ischemia, as assessed by ultrasound echocardiography, compared to patients treated with glimepiride [85].

In another study, exenatide's impact on postprandial endothelial function (EF) in type 2 diabetes and its mechanisms of vasodilation were investigated. Two crossover studies were conducted: participants with type 2 diabetes received exenatide vs. controls, and their EF, glucose, and lipid responses to meals were measured. Ex vivo studies were also conducted on human subcutaneous adipose tissue arterioles and endothelial cells. Results showed that subcutaneous exenatide increased postprandial EF independently of glucose and triglyceride reductions. Intravenous exenatide improved fasting EF, an effect nullified by exendin-9 (GLP-1R antagonist). Exenatide activated eNOS and NO production in endothelial cells, induced dose-dependent vasorelaxation, and mitigated high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo, effects which were reduced by AMPK (AMP-activated protein kinase) inhibition [86].

A recent metanalysis [87] has assessed the impact of oral antidiabetic drugs (OADs) and GLP-1 receptor agonists on left ventricular diastolic function in patients with type 2 diabetes, the findings indicated that, compared to placebo and OADs, only liraglutide significantly improved left ventricular diastolic function. This was supported by a recent metanalysis in which, twenty- two randomized controlled trials involving 61,412 patients who were either T2DM patients with or without cardiovascular disease or patients with cardiovascular disease alone, were included in the meta-analysis, and results have shown the diastolic function according to echocardiography was significantly improved by GLP-1R agonists [88].

In a 2022 metanalysis [89] of previous randomized controlled trials, 20 papers from 19 randomized placebo-controlled trials were included, comprising a total sample size of 2062.

patients on the potential effects of GLP1R agonists on the cardiovascular system. In patients with type 2 DM, GLP-1R agonists have demonstrated a reduction in circumferential strain and improvement in markers of diastolic function, a key component of diabetic cardiomyopathy and the risk of developing heart failure; this effect was plausibly exerted through the diuretic and natriuretic effect of GLP-1R agonists reducing preload. In heart failure patients, there was a lack of changes in cardiac imaging parameters correlates with the lack of impact on outcomes among patients with pre-existing heart failure in major GLP-1 receptor agonist trials. Findings were supported by a recently updated metanalysis of 15 trials involving 898 patients were included in this analysis, GLP-1R agonists were found to have a positive impact on left ventricle diastolic function, hypertrophy, and exercise capacity [90].

Data from the Semaglutide Treatment Effect in People with Obesity (STEP) trials, which examined the weight loss effects of semaglutide, demonstrated a 30–40% reduction in C-reactive protein levels, indicating a significant anti-inflammatory effect. Recently, the STEP-HFpEF trial enrolled 529 non-diabetic patients with HFpEF and obesity, who were randomly assigned to receive either once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. This trial observed statistically significant improvements in quality of life scores, weight loss, 6-min walk distance, C-reactive protein levels, and N-terminal pro–B-type natriuretic peptide levels. These findings were supported by another study in which liraglutide improved diastolic function in diabetic patients [91, 92].

Additionally, the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trial demonstrated that semaglutide consistently reduced major cardiovascular event endpoints by approximately 20% compared to placebo over an approximately 3-year follow-up period in patients with overweight or obesity and cardiovascular disease (Table 1), but without diabetes [93].

Table 1 Therapeutic effects of GLP-1 receptor agonists on HFpEF

The currently ongoing SUMMIT trial (A Study of Tirzepatide in Participants With Heart Failure With Preserved Ejection Fraction and Obesity; NCT04847557) seeks to evaluate the effect of tirzepatide (is a dual agonist for the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors) over 52 weeks in 700 patients with heart failure with preserved ejection fraction (HFpEF) and obesity.

A limitation of these studies is the absence of stratification of heart failure patients based on ejection fraction, therefore additional clinical research specifically investigating the effects of GLP-1 receptor agonists in patients with heart failure with preserved ejection fraction (HFpEF) is warranted [94].

Conclusion

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent a promising therapeutic avenue for heart failure with preserved ejection fraction (HFpEF). By targeting endothelial dysfunction—a central component of HFpEF pathophysiology—GLP-1RAs offer cardioprotective benefits that extend beyond their established metabolic effects. These include improving vascular function, reducing systemic inflammation, enhancing coronary microvascular function, and mitigating comorbid conditions like metabolic dysfunction-associated steatotic liver disease (MASLD) and chronic kidney disease (CKD). Emerging clinical evidence, such as the STEP-HFpEF and FLOW trials, underscores the efficacy of GLP-1RAs in alleviating symptoms, improving quality of life, and slowing disease progression in HFpEF patients.

Limitations

Despite their promise, several limitations exist. Current evidence is derived primarily from preclinical studies and a limited number of clinical trials, which may not fully represent the diverse HFpEF population. Many trials lack stratification based on ejection fraction, hindering the ability to determine the differential effects of GLP-1RAs in various heart failure subtypes. Furthermore, the precise mechanisms by which GLP-1RAs confer their cardioprotective effects remain incompletely understood, necessitating further investigation. Lastly, questions about long-term safety, efficacy, and optimal patient selection criteria remain unanswered.

Areas of future research

Future studies should focus on addressing these gaps. Large-scale, randomized controlled trials with robust stratification of HFpEF phenotypes are needed to confirm the efficacy and safety of GLP-1RAs in this population. Mechanistic studies should aim to elucidate how GLP-1RAs influence endothelial function, inflammation, and myocardial remodeling in HFpEF. Exploring potential synergistic effects of GLP-1RAs with other established therapies, such as SGLT2 inhibitors, could unlock combination approaches for improved outcomes. Finally, economic evaluations are necessary to assess cost-effectiveness and accessibility in clinical practice.

As our understanding of HFpEF evolves, GLP-1RAs have the potential to become a cornerstone of therapy, addressing the multifactorial nature of this condition and improving outcomes in a challenging patient population.