How GLP-1 Receptor Agonists May Improve Blood Flow to the Heart and Related Health Outcomes

Dysfunctional microvascular endothelial activity is intricately interwoven with both systemic and localized inflammatory processes [22]. Inflammatory mediators modulate the secretion of NO and cytokines, thereby impairing the autoregulatory capacity of coronary blood flow [23]. Moreover, endothelial dysfunction within the coronary microcirculation perpetuates a cycle of inflammation and immune activation, characterized by the release of pro-inflammatory cytokines such as interleukin and tumor necrosis factor-alpha (TNF-α) [24]. Beyond its localized effects, systemic immune-inflammatory responses associated with macrovascular atherosclerosis exacerbate this dysfunction by elevating circulating levels of TNF-α and C-reactive protein, which in turn engage endothelial surface receptors within the microvasculature [25,26]. This inflammatory cascade culminates in a significant downregulation of endothelial NO synthase (eNOS) expression and NO bioavailability, ultimately disrupting vasomotor tone and impairing the adaptive capacity of the coronary microcirculation [27]. Key molecular mediators of large-vessel atherosclerosis, including Toll-like receptors (TLRs), NLRP3 inflammasome, and nuclear factor kappa B (NF-κB), are also potent inducers of oxidative stress within the microvascular endothelium [28]. This heightened oxidative burden disrupts endothelial homeostasis, impairing its regulatory capacity and predisposing the microcirculation to dysfunction.

Beyond localized vascular effects, systemic inflammatory disorders, such as chronic autoimmune diseases, provoke dysregulated immune activation, particularly involving T lymphocytes and monocytes [29,30]. This pathological immune response extends to the coronary microvasculature, where it perturbs endothelial function and contributes to maladaptive vascular remodeling. Evidence further suggests that systemic inflammation is linked to exacerbated ischemic electrocardiographic abnormalities, particularly in individuals with elevated circulating C-reactive protein (CRP) levels, underscoring the inflammatory regulation of coronary microcirculatory dynamics [31].

Metabolic dysregulation, particularly in the context of obesity, compounds these effects by fostering a pro-inflammatory milieu characterized by increased levels of leptin, adiponectin, interleukin-6 (IL-6), and TNF-α [32,33]. These adipokines and cytokines act synergistically to disrupt endothelial signaling, impair vasomotor function, and ultimately compromise the adaptive perfusion capacity of the coronary microvasculature [32,33].

Oxidative stress, driven by the excessive production and accumulation of reactive oxygen species (ROS), alongside the ensuing inflammatory cascade, represents a fundamental pathogenetic axis in the development of coronary microvascular dysfunction (CMD) [34]. Under hyperglycemic conditions, mitochondrial electron transport chain activity intensifies, leading to a substantial increase in superoxide anion generation [35]. This surge in oxidative stress is further amplified via the protein kinase C (PKC)/NADPH oxidase signaling axis, exacerbating intracellular ROS accumulation [35].

Beyond direct oxidative injury, mitochondrial-derived superoxide anions play a critical role in accelerating the formation of advanced glycation end products (AGEs) within endothelial cells [36]. This AGEs-mediated endothelial dysfunction further exacerbates CMD through activation of the endoplasmic reticulum (ER) stress pathway, specifically engaging the PERK/CaN/NFATc4 signaling cascade [36]. The resultant cellular stress response disrupts microvascular homeostasis, promoting maladaptive vascular remodeling and impairing coronary perfusion regulation [36].

Hyperglycemia and insulin resistance are central pathological drivers of microvascular dysfunction in diabetes, reinforcing a reciprocal cycle of metabolic and vascular impairment [2,37]. Elevated blood glucose levels disrupt endothelial homeostasis by impairing NO-dependent vasodilation and amplifying intracellular oxidative stress within microvascular endothelial cells, ultimately dysregulating NO metabolism and promoting endothelial dysfunction [2].

Conversely, microvascular dysfunction itself exacerbates diabetes progression by impairing insulin and glucose transport, further compounding metabolic dysregulation [38]. Insulin resistance contributes to this dysfunction by attenuating NO production and eNOS activity, while sustained hyperinsulinemia leads to excessive fatty acid accumulation [35,39]. This, in turn, activates PKC, triggering a pro-inflammatory cascade that further compromises microvascular integrity [35,39]. Notably, metabolic insulin resistance is closely intertwined with vascular and microvascular insulin resistance, highlighting their interconnected pathophysiology [40]. The evidence suggests that myocardial perfusion is significantly diminished in individuals with T2D, particularly in the postprandial state, emphasizing the systemic impact of microvascular dysfunction on cardiac metabolic regulation [41].

The structural integrity and functional competence of endothelial cells are fundamental to the dynamic regulation of vascular tone and blood flow modulation [50]. Endothelial dysfunction represents an early hallmark of coronary vascular disease, often precipitated by a reduction in eNOS expression, impaired phosphorylation of eNOS at the serine 1177 residue, and diminished availability of essential eNOS substrates or cofactors [51]. Collectively, these disturbances culminate in decreased NO bioavailability, impairing vasodilatory capacity and predisposing to vascular pathology [52]. GLP-1R agonists, such as exenatide, have demonstrated the ability to enhance NO production and promote eNOS phosphorylation, thereby significantly improving coronary endothelial function. This vasoprotective effect is thought to be mediated through the activation of the AMPK/PI3K-Akt/eNOS signaling cascade via a GLP-1R/cAMP-dependent mechanism [53]. Figure 1 provides a schematic illustration summarizing the key mechanisms by which GLP-1 and GLP-1 receptor agonists improve myocardial microvascular perfusion.

Liraglutide, a GLP-1R agonist, has also been shown to enhance NO activity, promoting microvascular dilation and improving perfusion [54,55]. Of note, the activation of eNOS by GLP-1 receptor agonists appears to be predominantly endothelium-specific, as evidenced by studies showing that their vasodilatory effects are abolished in models with endothelial-specific GLP-1R deletion [55]. While low-level GLP-1R expression has been identified in other tissues, current evidence suggests that the observed vascular benefits are largely receptor-mediated and confined to the endothelium, with minimal off-target effects reported at therapeutic doses [56]. Mechanistic investigations suggest that liraglutide preserves endothelial function by preventing the decline of NO and endothelium-derived hyperpolarization factors within the microvasculature [54]. This effect is mediated through the upregulation of eNOS and VEGF expression, coupled with a reduction in the vasoconstrictor ET-1, thereby augmenting microvascular dilation and myocardial microvascular perfusion. Notably, these vasoprotective properties of liraglutide are abolished when GLP-1R is genetically deleted, either globally or selectively in endothelial cells, underscoring the receptor's essential role in mediating its vascular benefits [55]. Similarly, GLP-1 has been shown to elevate intracellular cAMP and NO levels in human umbilical vein endothelial cells (HUVECs), reinforcing its role in preserving endothelial integrity and function [57].

In Dahl salt-sensitive rats, prolonged GLP-1 administration has been shown to enhance endothelial function and attenuate hypertension progression, likely through the augmentation of acetylcholine (ACh)-induced vasodilation [58]. This vasodilatory effect of GLP-1 has also been observed in healthy individuals, suggesting its broader physiological relevance [59]. Given the vasoprotective properties of GLP-1, GLP-1R agonists may exert similar benefits. Preclinical studies further support this notion, as liraglutide treatment of obese Zucker rats successfully restored ACh-induced microvascular dilation [54]. In individuals with newly diagnosed T2D, a six-month course of liraglutide has been associated with improved endothelial function, as evidenced by enhanced flow-mediated dilation, as well as a reduction in arterial stiffness [60]. The resultant decrease in afterload may contribute to improved myocardial perfusion, highlighting the cardiometabolic benefits of GLP-1R activation. Beyond its direct endothelial effects, emerging evidence suggests that GLP-1R activation in atrial myocytes promotes blood pressure reduction through an EPAC2-dependent mechanism, facilitating atrial natriuretic peptide (ANP) release [61]. This GLP-1 signaling-mediated increase in circulating ANP and brain natriuretic peptide (BNP) levels has been corroborated in human studies [62]. However, the GLP-1–ANP axis appears to be species-specific, with robust evidence currently limited to murine models [63].

In individuals with diabetic cardiomyopathy (DCM), aberrant glucose metabolism and insulin resistance may directly precipitate myocardial microvascular injury, distinguishing them from those with normal metabolic function [41,64]. Among the key pathological drivers, oxidative stress inflicts endothelial damage, disrupts NO-mediated vasodilation, and promotes the upregulation of vasoconstrictive factors, thereby impairing vascular homeostasis [65]. Beyond oxidative damage, localized vascular inflammation plays a pivotal role in endothelial dysfunction and compromised vasodilation [65]. Hyperglycemia and dyslipidemia further exacerbate these vascular abnormalities by perturbing the intricate crosstalk between immune cells and endothelial metabolic processes [66]. Notably, insulin analogs have demonstrated the capacity to partially restore the myocardial perfusion abnormalities observed in the postprandial state by improving glycemic control [67]. However, the therapeutic potential of GLP-1 and its receptor agonists extends beyond their role in modulating systemic glucose metabolism and insulin sensitivity. These agents confer direct endothelial protection and preserve myocardial perfusion by attenuating oxidative stress and mitigating vascular inflammation, underscoring their potential as multifaceted interventions in diabetic cardiovascular disease.

These cardioprotective effects of GLP-1 signaling appear to extend beyond its well-characterized metabolic regulatory functions [68,69]. Advanced imaging studies employing ¹³C-magnetic resonance spectroscopy (MRS) in animal models have revealed that GLP-1 activation markedly enhances myocardial glucose uptake and oxidative phosphorylation, thereby optimizing cellular energy metabolism [70]. In the streptozotocin (STZ)-induced diabetic rat model, treatment with vildagliptin or exenatide significantly increased cardiac microvascular density and reinforced endothelial barrier integrity, as evidenced by a reduction in lanthanum nitrate diffusion across endothelial cells [71]. Notably, this endothelial protection was independent of glucose-lowering effects, suggesting an alternative mechanistic pathway. A potential explanation lies in the inhibition of the Rho/ROCK signaling axis, a key mediator of oxidative stress-induced endothelial damage [71]. Further corroborating these findings, liraglutide has demonstrated profound vascular benefits in hypertensive mice [55]. Its administration led to substantial reductions in blood pressure, alleviated cardiac hypertrophy, mitigated vascular fibrosis, and improved endothelial function. Mechanistically, these effects were mediated through suppression of oxidative stress and vascular inflammation via GLP-1R activation. Specifically, liraglutide reduced NADPH oxidase activity, lowered asymmetric dimethylarginine (ADMA) levels, and decreased F4/80 expression in cardiac tissue, collectively reinforcing its protective role in maintaining coronary microvascular barrier integrity [55].

To elucidate the molecular mechanisms underlying its vascular protective effects, in vitro studies using coronary microvascular endothelial cells (CMECs) cultured under hyperglycemic conditions have demonstrated that GLP-1 mitigates high glucose-induced oxidative stress and apoptosis [55]. This protective effect is mediated through inhibition of the Rho/ROCK signaling cascade, a critical regulator of endothelial dysfunction and cytoskeletal remodeling [55]. Consistent with these findings, chronic liraglutide therapy in obese Zucker rats has been shown to enhance vasodilatory capacity across both the coronary macro- and microcirculation. This improvement is partially attributed to a 40% reduction in pro-inflammatory mediators, including NF-κB, CD68, IL-1β, and TGF-β1, within the myocardium [54]. Additionally, liraglutide influences macrophage polarization, a key determinant of inflammation resolution and tissue repair, further reinforcing its anti-inflammatory and cardioprotective properties [72]. Clinical studies in patients with T2D provide further support for these vascular benefits. The combination of GLP-1 with insulin has been associated with a significant reduction in systemic markers of vascular inflammation, including soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and IL-6 [73]. By attenuating these inflammatory pathways, GLP-1 enhances endothelial function and restores vascular perfusion, underscoring its potential as a therapeutic strategy for improving microvascular integrity in metabolic disorders [73].

A recent study by Stone et al. [74] investigated the cardioprotective effects of semaglutide in a large animal model of coronary artery disease (CAD), independent of diabetes or obesity. Using a porcine model with induced myocardial ischemia, the study demonstrated that semaglutide administration significantly improved myocardial perfusion and left ventricular systolic performance [74]. These effects were accompanied by reduced perivascular and interstitial fibrosis, lower apoptotic activity, and enhanced activation of the AMPK–eNOS pathway [74]. Notably, these benefits were observed both at rest and during cardiac stress, highlighting the potential of GLP-1R agonists to enhance coronary microcirculation and myocardial adaptation to ischemia [74]. These findings suggest that GLP-1R activation may offer direct vascular benefits in CAD, beyond its metabolic effects, reinforcing its potential as an adjunctive therapy for ischemic heart disease [74].

Angiogenesis plays a crucial role in patients for whom conventional revascularization strategies are not viable, as it facilitates microvascular expansion and enhances endothelial exchange capacity. Endothelial cells possess an intrinsic proliferative potential, enabling their active participation in neovascularization. GLP-1 has been shown to potentiate angiogenic signaling via the PI3K/Akt, PKA, and Src pathways, as demonstrated in HUVEC models [75]. Furthermore, vildagliptin-induced elevations in GLP-1 levels have been linked to the suppression of oxidative stress-mediated proteasome activation, thereby preventing the degradation of hypoxia-inducible factor-1α (HIF-1α). This stabilization of HIF-1α enhances VEGF activation, leading to increased capillary density and improved microvascular function [76]. Additional evidence highlights the angiogenic capacity of exendin-4, which has been shown to promote proliferation in human coronary artery endothelial cells (HCAECs) via PKA–PI3K/Akt–eNOS signaling [77]. Importantly, these angiogenic properties of GLP-1 signaling extend beyond in vitro models. In preclinical studies, sitagliptin administration to mice with critical limb ischemia resulted in elevated circulating GLP-1 and endothelial progenitor cell levels, ultimately enhancing neovascularization through an eNOS-dependent mechanism [78]. Table 1 provides an overview of key studies elucidating the mechanisms by which GLP-1 and its receptor agonists contribute to the improvement of coronary microvascular perfusion.

Both GLP-1 and GLP-1R agonists, whether administered as monotherapy or in combination with other agents, have demonstrated the capacity to enhance coronary microvascular dilation and augment microvascular blood volume (MBV). Under physiological conditions, GLP-1 infusion significantly increased myocardial MBV and microvascular blood flow (MBF) at both 30 and 150 min post-administration, while microvascular flow velocity (MFV) exhibited a slight reduction, indicating a redistribution of perfusion dynamics without compromising overall myocardial circulation []. ⁸³

Consistent with these findings, GLP-1 infusion alone has been shown to elicit a 40% increase in MBV within cardiac muscle, with no significant alteration in MFV, leading to a substantial enhancement in MBF []. Notably, this effect remains preserved in the myocardial microvasculature even in the context of obesity, underscoring its potential for broader cardiometabolic applications []. Additionally, exenatide has been observed to increase MBF independently of myocardial glucose uptake, suggesting a direct vasodilatory effect on the coronary microcirculation beyond its metabolic actions []. ^{84 84 85}

In conditions of restricted coronary perfusion, even a modest increase in MBV can significantly enhance tissue oxygenation and myocardial function. Evidence suggests that GLP-1 promotes coronary microvascular dilation and increased myocardial perfusion without altering peripheral vascular tone []. This selective vasodilatory effect may be attributed to GLP-1R activation on ventricular myocytes, which enhances myocardial contractility and induces secondary vasodilation within the coronary microcirculation []. ^{86 86}

A key measure of coronary endothelial function, coronary flow velocity reserve (CFVR) was significantly improved following 12 weeks of exenatide therapy, coinciding with a marked reduction in soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels, reflecting reduced endothelial inflammation []. Furthermore, while direct evidence of liraglutide's effects on the coronary microcirculation remains limited, randomized controlled trials have demonstrated its ability to enhance endothelial function [,]. These benefits were characterized by upregulated eNOS expression, increased NO bioavailability, and reduced serum endothelin-1 (ET-1) and inflammatory markers, collectively indicating liraglutide's potential to improve vascular homeostasis and modulate coronary microcirculatory dynamics [,]. ^{53 55 87 55 87}

Further reinforcing these findings, a randomized, open-label, crossover trial by Chowdhary et al. [] investigated the effects of liraglutide on myocardial perfusion, cardiac energetics, and exercise capacity in patients with T2D but without established cardiovascular disease. Forty-one participants were randomized to receive either liraglutide or pioglitazone for 16 weeks, followed by an 8-week washout period, after which they switched to the alternate treatment []. Key findings revealed that liraglutide significantly enhanced myocardial perfusion, with a notable increase in stress MBF (1.62 to 2.08 mL/g/min,= 0.01) and myocardial perfusion reserve (2.40 to 2.90,= 0.01) []. Additionally, liraglutide improved myocardial energetics as evidenced by higher phosphocreatine-to-ATP ratios at rest and during stress []. Of note, these benefits translated into greater exercise capacity, demonstrated by a significant increase in the 6 min walk distance []. Another recent study assessed the effects of GLP-1R agonists on myocardial perfusion in obese individuals with high and very high cardiovascular risk using 99mTc-MIBI SPECT imaging []. After six months of treatment, myocardial perfusion inhomogeneity parameters significantly improved, particularly in patients with T2D or impaired glucose tolerance []. Notable reductions were observed in the stress impairment severity index and stress heterogeneity index, indicating enhanced coronary microvascular function []. ^{14 14 14 14 14 88 88 88} p p

In summary, GLP-1 and GLP-1R agonists play a protective role in the myocardium by reducing oxygen demand and enhancing coronary microcirculation through endothelial function improvements. Their non-invasive nature and favorable safety profile may further support greater patient adherence compared to conventional treatments. However, findings on their effects remain inconsistent, with some studies reporting no significant impact on coronary microcirculation [,,]. A randomized, double-blind sub-study of the LIVE trial investigated the effects of liraglutide on myocardial glucose uptake (MGU), MBF, and myocardial flow reserve (MFR) in non-diabetic patients with stable chronic heart failure []. Over 24 weeks, liraglutide significantly reduced body weight and improved glycemic parameters, including HbA1c and 2 h post-OGTT glucose levels. However, no significant differences were observed between the liraglutide and placebo groups in terms of changes in MGU, MBF, or MFR, suggesting that liraglutide does not enhance myocardial perfusion or glucose metabolism in this patient population []. ^{89 90 91 89 89}

Another study by Faber et al. evaluated the short-term effects of liraglutide on coronary and peripheral microvascular function in patients with T2D without overt cardiovascular disease []. Over a 10-week treatment period, liraglutide led to a modest but non-significant increase in coronary flow reserve and had no measurable effect on peripheral endothelial function, assessed via reactive hyperemia index []. Of note, a randomized, double-blind, crossover study by Nilsson et al. investigated the acute effects of DPP-4 (increasing the level of intact GLP-1) (7–36) on coronary microvascular and peripheral endothelial function in overweight adults without diabetes []. Twelve participants received intravenous GLP-1 (7–36) or saline on separate occasions, alongside DPP-4 inhibition. Coronary flow velocity reserve and flow-mediated dilation were assessed as surrogate markers of vascular function []. The study found no significant effect of GLP-1 infusion on CFVR or FMD compared to saline, suggesting no direct short-term effect of intact GLP-1 on coronary or peripheral microvascular function in this population []. Collectively, these discrepancies may stem from small sample sizes and variations in study populations, particularly differences in baseline microvascular function (). To better define their role in coronary microvascular regulation, further well-designed, large-scale clinical trials are warranted. ^{90 90 91 91 91} Table 2