Research Progress on the Cardiovascular Protective Effect of Glucagon-Like Peptide-1 Receptor Agonists

Song, Rui; Qian, Hang; Wang, Yunlian; Li, Qingmei; Li, Dongfeng; Chen, Jishun; Yang, Jingning; Zhong, Jixin; Yang, Handong; Min, Xinwen; Xu, Hao; Yang, Yong; Chen, Jun

doi:https://doi.org/10.1155/2022/4554996

Journal of Diabetes Research

On this page

Abstract Introduction Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 4554996 | https://doi.org/10.1155/2022/4554996

Research Progress on the Cardiovascular Protective Effect of Glucagon-Like Peptide-1 Receptor Agonists

Rui Song,¹Hang Qian,¹Yunlian Wang,¹Qingmei Li,¹Dongfeng Li,¹Jishun Chen,¹Jingning Yang,²Jixin Zhong,³Handong Yang,¹Xinwen Min,¹Hao Xu,¹and Yong Yang¹ et al.

Academic Editor: Takayuki Masaki

Received13 Jan 2022

Revised17 Mar 2022

Accepted21 Mar 2022

Published08 Apr 2022

Abstract

The risk of cardiovascular diseases is closely related to diabetes. Macrovascular disease is the main cause of death and disability in patients with type 2 diabetes. In recent years, the glucagon-like peptide-1 receptor agonist (GLP-1RA), a new type of hypoglycemic drug, has been shown to regulate blood sugar levels, improve myocardial ischemia, regulate lipid metabolism, improve endothelial function, and exert a protective role in the cardiovascular system. This study reviewed the protective effects of GLP-1RA on the cardiovascular system.

1. Introduction

The prevalence of type 2 diabetes (T2DM) continues to increase every year. The International Diabetes Federation data predicts that the number of patients worldwide will reach 629 million by 2045 [1]. Diabetes-associated complications are mainly divided into microvascular disease and macrovascular disease. Macrovascular disease mainly manifests as atherosclerotic disease, which is the main cause of death and disability in patients with T2DM. The occurrence and development of atherosclerosis (AS) are caused by multiple factors, including smoking, hypertension, hyperlipidemia, hyperuric acid, hyperglycemia, and other factors [2, 3]. Glucagon-like peptide-1 receptor agonist (GLP-1RA) is a new type of drug for treating diabetes. Studies have shown that GLP-1RA can exert hypoglycemic and cardiovascular protective effects. This study reviewed the protective effects of GLP-1RA on the cardiovascular system and provided a theoretical basis for the prevention and treatment of cardiovascular diseases.

1.1. Incretin System

Incretin involves the direct stimulation of intestinal epithelial cells by nutrients, leading to the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), which promotes an insulin secretion. GLP-1 is a glucose concentration-dependent enteropeptidtide hormone encoded by the glucagon gene secreted by L cells of the jejunum, ileum, and colon, which cleaves into two different existing forms of GLP-1 after cleavage by proprotein converting 1(PC1). The first form is the amidated form of GLP-1 consisting of 30 amino acids, namely, GLP-1 (7-36) amide; the second form is the 31-peptide form extending into the glycine, namely, GLP-1 (7-37). Most of the effective GLP-1 is dissolved in the form of GLP-1 (7-36) amide: GLP-1:78-107 and 78-108 [4].

GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a hypoglycemic effect. In addition, GLP-1 also participates in blood sugar regulation by reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite [5]. GLP-1R is a G protein–coupled receptor widely distributed in the pancreas, lung, heart, kidney, vascular smooth muscle, fat cells, gastrointestinal tract, central nervous system, and other tissues [6]. GLP-1 recognizes and binds to GLP-1R, activating GLP-1R, upregulating the cyclic adenosine monophosphate (AMP) level and intracellular Ca²⁺ concentration in the body and subsequently releasing glucose-dependent insulin, thereby protecting the function of islets and regulating blood sugar levels. The natural GLP-1 in the human body is easily degraded by dipeptidyl peptidase-IV (DPP-IV) and can lose its activity quickly. Glucagon-like peptide-1 receptor agonist (GLP-1RA) works by simulating natural GLP-1 to activate GLP-1A. It is not easily degraded by DPP-IV with prolonged half-life and increased concentration of active GLP-1 in the body. The products of GLP-1RA include liraglutide, exenatide, albiglutide, losenatide, dulaglutide, and semaglutide.

GLP-1R is widely expressed in the cardiovascular system, muscle, fat, liver, and other tissues. It is involved in intracellular metabolism and signal transduction. These metabolites have biological activities. They can reduce intravascular oxidative stress, protect the cardiovascular system, increase the vitality of myocardial cells, improve heart function, promote vasodilation, protect pancreatic β-cells, and inhibit hepatocyte gluconeogenesis and oxidative stress, thereby directly or indirectly playing a protective role in the cardiovascular system [7].

1.2. Direct Protective Effect of GLP-1RA on the Cardiovascular System

1.2.1. Impact on AS

AS is the pathological basis of diseases such as coronary heart disease (CHD), peripheral arterial disease (PAD), and cardiovascular desease (CVD). The inflammatory response induced by the adhesion of monocytes and vascular wall damage plays an important role in the early stages of AS. Studies have found that, besides lowering blood sugar levels, GLP-1RA also has an antiatherosclerotic effect. GLP-1RA reduces the infiltration of inflammatory cells, inhibits the release of inflammatory factors, and improves oxidative stress, thereby reducing the damage to the cell endothelium, improving endothelial cell function, and inhibiting the occurrence of AS [8]. In the atherosclerotic lesions, the use of GLP-1RA inhibited further vascular intimal macrophage infiltration, calcium deposition, extra cellular matrix (ECM) remodeling, and vascular smooth muscle cell (VSMC) proliferation, acting to limit further thickening and plaque rupture [9].

During oxidative stress, platelet overactivity has an important influence on the risk of atherosclerotic thrombotic events. The effect of GLP-1RA on mitochondria not only changes fatty acid oxidation and energy consumption but also has antiapoptotic and antioxidant effects [10]. Exenatide inhibits the expression of inflammatory markers such as high-sensitivity C-reactive protein and monocyte chemoattractant protein-1 in patients with AS, thereby reducing the damage caused by oxidative stress and inflammatory response to vascular endothelial cells [11]. In addition, exenatide increases the release of cyclic adenylate and further inhibits platelet aggregation induced by thrombin, adenosine diphosphate, or collagen [12]. In the AS model induced in Apoe^-/- mice, the administration of GLP-1RA effectively inhibited the progression of early-onset, low-load atherosclerotic disease [13]. Jojima et al. [14] observed that the liraglutide induced a cell cycle arrest by activating the AMP-activated protein kinase (AMPK) signal and inhibited the proliferation of vascular smooth muscle cells induced by angiotensin II, thereby delaying AS progression, which had nothing to do with the hypoglycemic effect. Moreover, it also reduced the expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule-1 in human vascular endothelial cells and inhibited the development of AS. The mechanism might be related to the inhibition of pancreatic β-cell apoptosis, increase in insulin synthesis, and reduction in glycogen decomposition.

1.2.2. Impact on Heart Failure

The role of GLP-1RA in heart failure is still controversial. Clinical studies have shown that the administration of GLP-RA for 5 weeks could improve the left ventricular ejection fraction and 6-min walking distance and increase the maximum oxygen uptake (VO₂ max) in patients with heart failure [15]. GLP-1RA improves the insulin receptor in cardiomyocytes, increases glucose uptake and utilization, promotes the recovery of coronary blood flow, and reduces the level of atrial natriuretic peptide and peripheral vascular resistance, thereby exerting a cardiovascular protective effect in patients with heart failure [16].

Matsubara et al. [17] established an animal myocardial ischemia–reperfusion model and showed that the infusion of GLP-1 and human transferrin could significantly prolong the half-life of the drug and improve the wall motion score index and the left ventricular ejection fraction, confirming that GLP-1 intervention could significantly reduce the infarct size, improve the wall motion index and left ventricular ejection fraction after reperfusion, and ameliorate myocardial reperfusion injury. GLP-1RA can slightly increase the resting heart rate of patients with heart failure and reduce the heart rate variability, thereby improving the outcome of cardiovascular diseases [18]. The administration of albiglutide for 12 weeks can improve the oxygen consumption of cardiomyocytes in patients with heart failure [19]. Chen et al. [20] observed that the left ventricular ejection fraction was slightly improved and the markers of inflammation and endothelial function improved with the short-term use of liraglutide in patients with non-ST-segment elevation myocardial infarction (NSTEMI). The use of exenatide improved the diastolic function of patients with T2DM and reduced the degree of AS [21]. A meta-analysis including 29,034 patients with diabetes treated with GLP-1RA showed that GLP-1RA reduced cardiovascular mortality and heart failure hospitalization rate [22]. A retrospective study by Velez et al. [23] showed that GLP-1RA reduced the incidence of heart failure by 49% (95% confidence interval 0.34–0.77, ). In addition, the exenatide caused no significant difference in the risk of heart failure hospitalization compared with placebo [24]. However, the use of liraglutide significantly reduced cardiovascular mortality, nonfatality myocardial infarction, and nonfatal stroke compared with placebo, but the risk of hospitalization for heart failure was reduced by 13% [25]. As an adjuvant treatment for patients with heart failure, GLP-1RA still requires further basic experiments and clinical studies for validation.

1.2.3. Impact on Myocardial Infarction

The protective effect of GLP-1 receptor agonists on ischemic myocardium works through the AMPK/phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt) pathway [26]. GLP-1RA activates cAMP through PI3K, thereby inhibiting the expression of apoptotic factors and ultimately inhibiting cardiomyocyte apoptosis and improving cardiac function [27].

Sassoon et al. [28] established an animal model of myocardial infarction (MI) and showed that the activation of GLP-1 effectively reduced the expression of the β1-adrenergic receptor in myocardial tissues, increased diastolic function and cardiac output, and reduced myocardial oxygen consumption. After MI occurs, GLP-1 induces human heart fibroblasts to produce new elastic fibers, restricts the expansion of the heart, and plays a beneficial role in the recovery of heart function [29]. In patients with NSTEMI, direct percutaneous coronary intervention can be performed, and exenatide adjuvant therapy during reperfusion can increase myocardial ischemia–reperfusion, thereby showing cardioprotection. Meanwhile, Lilaru peptides also have similar effects [30]. In a double-blind trial, the follow-up of patients with T2DM having a high risk of CVD showed that the incidence of death from cardiovascular diseases and stroke in patients taking liraglutide was significantly lower than that in the placebo group [25]. Lonborg et al. [31] found that the postoperative cardiac magnetic resonance examination in patients with myocardial infarction, percutaneous coronary intervention, and continuous infusion of exenatide for 6 h showed that the MI area was reduced compared with earlier. The evaluation after 90 days showed that the intervention effectively reduced the degree of myocardial necrosis and improved postoperative heart function. A meta-analysis showed that GLP-1RA reduced the relative risk of MI by 9%, stroke by 14% and cardiovascular death by 12% [32]. A recent study found that the incidence of major cardiovascular events in patients treated with semaglutide was significantly lower than that in patients treated with placebo [33].

It has been confirmed that liraglutide, semaglutide, and dulaglutide all have cardiovascular protective effects. In 2020, the American Diabetes Association released the “Cardiovascular Disease and Cardiovascular Risk Management,” which pointed out that GLP-1RA with cardiovascular benefits was recommended for patients with coronary heart disease or multiple risk factors for coronary heart disease [34].

1.3. Indirect Protective Effect of GLP-1RA on the Cardiovascular System

Cardiovascular diseases are associated with vascular inflammation, endothelial dysfunction, and oxidative stress [35]. GLP-1 receptor agonists inhibit the proliferation of vascular smooth muscle cells and vascular endothelial cells, reduce oxidative stress, promote the increase in the production of nitric oxide (NO), and increase microvascular blood flow, which have beneficial cardiovascular outcomes [36].

1.3.1. Blood Pressure

The mechanism of GLP-1 receptor agonists in lowering blood pressure is not yet fully understood, but the possible mechanisms include changes in the nervous system or changes in the vasopressin regulatory system [9]. According to UKPDS research, liraglutide and exenatide can lower blood pressure by 1-5 mm Hg. The antihypertensive effect is probably exerted via directly activating GLP-1R in the arterial and renal systems, improving vascular endothelial function, and inhibiting the renin–angiotensin–aldosterone system (RAAS), thereby playing a role in vasodilation and natriuresis. Other mechanisms may be the activation of NO by guanosine monophosphate, exerting a vasodilator effect and lowering blood pressure [37].

Tonneijck et al. [38] pointed out that the continuous use of GLP-1 receptor agonists for 8 weeks significantly increased renal sodium excretion, which might be one of the important factors for lowering blood pressure. Animal studies have found that GLP-1 receptors are widely expressed in the atria and GLP-1 receptor agonists can reduce blood pressure by increasing the secretion of atrial natriuretic factors [39]. Many studies found that GLP-1 RA drugs lowered blood pressure. The meta-analysis conducted by Wang et al. [40] showed that GLP-1 receptor agonists lowered blood pressure. Compared with placebo, exenatide and liraglutide reduced systolic and diastolic blood pressures by 1–5 mm Hg () in patients with T2DM. A randomized clinical trial showed that liraglutide reduced systolic blood pressure by 2–7 mm Hg in patients with T2DM [41]. A similar antihypertensive effect was also observed in the clinical trials of exenatide [42, 43]. In the study by Maringwa et al. [44], the administration of GLP-1 receptor agonists in patients with diabetes and obesity could reduce systolic blood pressure by 2.8 mm Hg on average without any significant effect on diastolic blood pressure. A study by Ferdinand et al. [45] showed that compared with placebo, dulaglutide could significantly reduce 24-h systolic blood pressure. The changes in diurnal systolic blood pressure indicated that dulaglutide also reduced day and night systolic blood pressure. However, no differences of day or night diastolic blood pressure were found between the two groups.

1.3.2. Blood Lipids

Hyperlipidemia is the main risk factor for arteriosclerotic cardiovascular disease [46]. Besides increasing insulin secretion, GLP-1 receptor agonists can improve the level of lipid metabolism in patients. They also inhibit liver peroxidase β oxidation, reduce the intestinal absorption of lipids in food, reduce triglyceride level after meals, and induce the decrease in LDL-C levels by enhancing liver fatty acid oxidation [47, 48].

In a randomized controlled clinical study, patients with T2DM, who used GLP-1 receptor agonists to reduce the blood sugar level, showed significantly reduced levels of triglyceride (TC), Apo B-48, and Apo C-III [26]. Wismann et al. [49] confirmed that the decreased secretion of chylomicrons in intestinal epithelial cells might be caused by GLP1R, which is mainly distributed in intestinal neurons and lymphocytes and indirectly mediated by nerve signals. Liraglutide and exenatide reduced postprandial blood lipid levels 2 weeks after the initial treatment, which had nothing to do with gastric emptying [50]. An 18-month prospective study found that waist circumference, body mass index, fasting blood glucose, glycosylated hemoglobin, total cholesterol and low-density lipoprotein cholesterol, triglycerides, and carotid artery intima-media thickness all improved after 18 months of liraglutide treatment in overweight and obese patients [51]. A previous study showed that after administering exenatide into a mouse model of hyperlipidemia, the levels of free fatty acids, triglycerides, and leptin significantly reduced [52]. Nauck et al. [53] observed that the protective effect of GLP-1 receptor agonists on the cardiovascular system did not depend on weight loss, reduction of glycosylated hemoglobin level, and severe hypoglycemia.

These data indicated that GLP-1 receptor agonists improved dyslipidemia and protected the cardiovascular system by regulating the body’s metabolic disorders by reducing postprandial blood lipids and blood sugar, improving myocardial and vascular inflammation, controlling blood pressure, and reducing weight [9].

1.3.3. Blood Sugar

Diabetes is closely related to the occurrence of cardiovascular diseases. The risk of cardiovascular and cerebrovascular diseases increases by two to four times in patients with diabetes than in nondiabetic patients. A prospective study in the United Kingdom showed that the early control of blood sugar in patients with diabetes significantly reduced the incidence of cardiovascular events and mortality [54]. GLP-1 binds to the GLP-1 receptor on pancreatic β-cells and directly stimulates the secretion of insulin from pancreatic β-cells in a glucose-dependent manner. It also promotes the proliferation of pancreatic β-cells, inhibits apoptosis, increases the number of β-cells, and promotes insulin synthesis, thus playing a hypoglycemic effect [5]. GLP-1 receptor agonists can increase glucose-dependent insulin secretion, reduce the level of glucagon, and reduce fasting and 2-h postprandial blood sugar levels.

Besides lowering blood sugar levels, GLP-1RA can improve insulin sensitivity by improving endocrine and metabolic disorders such as hyperlipidemia and obesity, increasing glucose uptake by peripheral tissues, and exerting a hypoglycemic effect. Recent studies have found that GLP-1RA can reduce the endogenous glucose level, but its specific mechanism needs to be further investigated. Seghieri et al. [55] found that the changes in insulin and glucagon levels did not affect the influence of GLP-1 on inhibiting endogenous glucose production. Baggio et al. [56] showed that GLP-1RA acted on pancreatic islet α cells and inhibited the release of glucagon, thereby reducing liver glucose production. GLP-1 receptor agonists specifically bind to GLP-1 receptors in nerve afferent nerves to inhibit gastrin and gastric acid secretion after eating, delay gastric emptying, and reduce postprandial blood sugar levels [57, 58].

In addition, GLP-1 receptor agonists also participate in blood glucose regulation by enhancing glucose utilization in peripheral tissues, increasing satiety, and reducing appetite. They have the characteristics of blood glucose–dependent effects, leading to a low chance of hypoglycemia [59]. Current studies have found that fasting blood glucose, postprandial blood glucose, and glycosylated hemoglobin levels all improved after GLP-1RA treatment in patients with diabetes [60]. Short-acting GLP-1RA preparations mainly affect postprandial blood glucose levels, while long-acting GLP-1RA can reduce fasting and postprandial blood glucose levels.

The hypoglycemic mechanism of GLP-1RA is more complicated, mainly through specific binding with GLP-1 receptors in the central, liver, muscle, adipose, and other tissues to work together to play a hypoglycemic effect.

1.3.4. Vascular Endothelium

Driven by vascular endothelial inflammation, ECM remodels, vascular smooth muscle cell activation, proliferation and migration, macrophage infiltration, and foam cell formation contribute to AS [61].

Animal studies have shown that liraglutide promotes the expression of vascular endothelial nitric oxide synthase, reduces intercellular adhesion molecule-1, and improves mouse vascular endothelium. Exendin-4 attenuates the expression of plasminogen activator inhibitor type 1(PAI-1) and VCAM in human vascular endothelial cells in vitro, increases ROS levels, promotes NO production, and reverses homocysteine acid–induced endothelial dysfunction [62]. Lnborg et al. [31] constructed a myocardial ischemia–reperfusion model and observed that exenatide activated adenosine triphosphate–sensitive potassium channels to protect endothelial dysfunction induced by ischemia–reperfusion. Aya Shiraki et al. [63] showed that liraglutide had an antioxidant and antiinflammatory effect on vascular endothelial cells. It inhibited tumor necrosis factor-α– (TNF-α–) induced oxidative stress damage of endothelial cells by increasing the expression of catalase, superoxide dismutase-2(SOD-2), and glutathione peroxidase (GPX) protein levels. Chang et al. [64] showed that the liraglutide reduced the damage caused by oxidized low-density lipoproteins to vascular endothelium by inhibiting the activation of p53.

GLP-1 RA can activate GLP-1R and AMPK, induce vasodilation, and reduce vascular endothelial dysfunction caused by hyperglycemia or hyperlipidemia probably through improving metabolism and directly acting via vascular mechanisms [65].

1.3.5. Weight Loss

Weight control can significantly reduce the occurrence of cardiovascular events, and GLP-1 RA has the effect of reducing body mass. GLP-1 acts on the hypothalamic paraventricular nucleus, arcuate nucleus, and lateral hypothalamus to suppress appetite, reduce food consumption, inhibit gastric emptying, and increase satiety, thereby increasing gastric dilatation and reducing gastric acid secretion [66, 67]. Cirincione et al. [68] showed that GLP-1 receptor agonists easily passed through the blood–brain barrier and directly acted on the center of satiety and food intake through the vagus nerve-dependent and independent pathways, thereby suppressing appetite. Current studies have found that GLP-1R receptor agonists reduce weight in a variety of ways, delay gastric emptying, reduce appetite and hunger, and increase satiety, thereby reducing body weight [69, 70].

In pharmacological trials, GLP-1RA has been shown to delay gastric emptying in the first hour after a meal. Coveleski et al. [71] found that the use of GLP-1RA increased the connection between the hypothalamus and thalamus and the nucleus tractus solitarii, thereby reducing hunger and food intake and promoting weight loss. Studies in obese mouse models have shown that GLP-1RAs can bind to GLP-1 receptors in specific brain regions related to appetite regulation, leading to the stimulation of proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons, inhibition of neuropeptide Y, increased satiety, reduced hunger, and subsequent reduction in energy intake, thus playing a role in weight loss [72]. Animal studies have shown that GLP-1RA specifically binds to the GLP-1 receptor in the central system to stimulate the thermogenesis of brown adipose tissue and the browning of white adipose tissue, reduce food intake, and increase energy consumption [73]. VAN CAN et al. [70] observed that the GLP-1RA treatment in obese patients significantly reduced energy intake and appetite, especially for high-fat foods. The continuous use of liraglutide can reduce body weight by 2–3 kg, which is considered to be related to slowing down gastric emptying, promoting satiety, and reducing food intake.

1.4. Cardiovascular Risk with GLP-1RA

Due to the short half-life of natural GLP1, existing research is aimed at developing GLP-1RA with longer half-life. GLP-1RAs can be classified into short-acting (exenatide and lixisenatide) and long-acting (liraglutide, albiglutide, dulaglutide, and semaglutide) according to the duration of their action on the receptor. Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and compulsory cardiovascular outcome trials (CVOTs) have become an important evaluating new antidiabetes drug development [74]. Several studies published to date demonstrated statistical evidence of CV benefit of GLP1RA.The LEADER CVOT with liraglutide was the first study to show cardioprotection effect of GLP-1 [25]. Fewer patients occurred a primary outcome in the liraglutide group than in the placebo group (13.0% vs. 14.9%, hazard ratio, 0.87; 95% confidence interval, 0.78-0.97; for noninferiority; for superiority). The EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trial published in 2017 is the largest () CVOT with GLP-1RAs to date. Exenatide ER revealed a statistical noninferiority versus placebo in the primary outcome of major adverse cardiovascular events (HR 0.91; 95% CI, 0.83-1; for noninferiority) and no statistical superiority () [24]. The SUSTAIN 6 study, published in 2016, was a trail to evaluate the cardiovascular and other long-term outcomes with semaglutide (subcutaneous injection once-weekly of 0.5 mg or 1.0 mg) () [33]. A post hoc analysis of the sustain 6 trial demonstrated superiority of once-weekly semaglutide 0.5 mg or 1 mg versus placebo for the primary composite MACE (CV death, nonfatal MI, or nonfatal stroke) endpoint (). CVOT of oral semaglutide 14 mg, the first GLP-1RA to be developed in an oral form, was evaluated in the PIONEER 6 clinical trials. The primary outcome of a major adverse cardiovascular event was noninferior with oral semaglutide to that of placebo. But there were more gastrointestinal adverse events of oral semaglutide, which may lead to poor compliance of patients [75]. Nevertheless, it is worth discussing which kind of preparation will give more clinical benefit in the treatment of type 2 diabetes, oral semaglutide or subcutaneous semaglutide? We tend to attribute the observed cardiovascular benefit of GLP-1RA to glucose-lowering effect. Other aspects include improving insulin resistance, lowering of LDL-c and triglycerides, and reductions body weight.

2. Conclusions

As a novel hypoglycemic drug, the GLP-1RA can reduce blood sugar but not cause hypoglycemic events. It further improves myocardial ischemia, inhibits plaque progression, regulates lipid metabolism, reduces myocardial oxygen consumption, improves vascular endothelial function, and reduces weight by reducing oxidative stress, inflammation, apoptosis, and myocardial fibrosis, thereby exerting direct or indirect protective effects on the cardiovascular system. Whether the cardiovascular beneficial effects of GLP-1RA drugs are independent of the hypoglycemic mechanism is still unclear. Further research is required to provide more theoretical basis for the prevention and treatment of cardiovascular diseases.

Data Availability

There is no raw data associated with this review.

Conflicts of Interest

The authors declare that there is no conflict of interest.

Authors’ Contributions

Rui Song, Hang Qian, and Yunlian Wang contributed equally to this work.

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (81400288 and 81573244), the Foundation of Health Commission of Hubei (WJ2021M061 and WJ2019F071), the Natural Science Foundation of the Bureau of Science and Technology of Shiyan City (grant nos. 21Y71 and 19Y89), the Faculty Development Grants from Hubei University of Medicine (2018QDJZR04), and Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (grant no. WDCM2020010).

References

International Diabetes Federation, IDF Diabetes Atlas, 9th Edition [DB/OL] Brussels, International Diabetes Federation, Belgium, 2019.
G. Gallo, G. Pierelli, M. Forte, R. Coluccia, M. Volpe, and S. Rubattu, “Role of oxidative stress in the process of vascular remodeling following coronary revascularization,” International journal of cardiology, vol. 268, pp. 27–33, 2018.
View at: Publisher Site | Google Scholar
P. Karki and K. G. Birukov, “Lipid mediators in the regulation of endothelial barriers,” Tissue Barriers, vol. 6, no. 1, article e1385573, 2018.
View at: Publisher Site | Google Scholar
D. J. Drucker, “Mechanisms of action and therapeutic application of glucagon-like peptide-1,” Cell Metabolism, vol. 27, no. 4, pp. 740–756, 2018.
View at: Publisher Site | Google Scholar
D. A. Sandoval and D. A. D'alessio, “Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease,” Physiological Reviews, vol. 95, no. 2, pp. 513–548, 2015.
View at: Publisher Site | Google Scholar
C. Pyke, R. S. Heller, R. K. Kirk et al., “GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody,” Endocrinology, vol. 155, no. 4, pp. 1280–1290, 2014.
View at: Publisher Site | Google Scholar
G. Cantini, E. Mannucci, and M. Luconi, “Perspectives in GLP-1 research: new targets, new receptors,” Trends in Endocrinology and Metabolism: TEM, vol. 27, no. 6, pp. 427–438, 2016.
View at: Publisher Site | Google Scholar
E. Gallego-Colon, W. Wojakowski, and T. Francuz, “Incretin drugs as modulators of atherosclerosis,” Atherosclerosis, vol. 278, pp. 29–38, 2018.
View at: Publisher Site | Google Scholar
D. J. Drucker, “The cardiovascular biology of glucagon-like peptide-1,” Cell Metabolism, vol. 24, no. 1, pp. 15–30, 2016.
View at: Publisher Site | Google Scholar
E. Tomas and J. F. Habener, “Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis,” Trends in Endocrinology and Metabolism: TEM, vol. 21, no. 2, pp. 59–67, 2010.
View at: Publisher Site | Google Scholar
Q. Li, Y. Lin, S. Wang, L. Zhang, and L. Guo, “GLP-1 inhibits high-glucose-induced oxidative injury of vascular endothelial cells,” Scientific Reports, vol. 7, no. 1, p. 8008, 2017.
View at: Publisher Site | Google Scholar
A. Gaiz, S. Mosawy, N. Colson, and I. Singh, “Thrombotic and cardiovascular risks in type two diabetes; role of platelet hyperactivity,” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 94, pp. 679–686, 2017.
View at: Publisher Site | Google Scholar
T. Gaspari, I. Welungoda, R. E. Widdop, R. W. Simpson, and A. E. Dear, “The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model,” Diabetes & Vascular Disease Research, vol. 10, no. 4, pp. 353–360, 2013.
View at: Publisher Site | Google Scholar
T. Jojima, K. Uchida, K. Akimoto et al., “Liraglutide, a GLP-1 receptor agonist, inhibits vascular smooth muscle cell proliferation by enhancing AMP-activated protein kinase and cell cycle regulation, and delays atherosclerosis in _ApoE_ deficient mice,” Atherosclerosis, vol. 261, pp. 44–51, 2017.
View at: Publisher Site | Google Scholar
G. G. Sokos, L. A. Nikolaidis, S. Mankad, D. Elahi, and R. P. Shannon, “Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure,” Journal of cardiac failure, vol. 12, no. 9, pp. 694–699, 2006.
View at: Publisher Site | Google Scholar
J. R. Ussher and D. J. Drucker, “Cardiovascular actions of incretin-based therapies,” Circulation research, vol. 114, no. 11, pp. 1788–1803, 2014.
View at: Publisher Site | Google Scholar
M. Matsubara, S. Kanemoto, B. G. Leshnower et al., “Single dose GLP-1-Tf ameliorates myocardial ischemia/reperfusion injury,” The Journal of Surgical Research, vol. 165, no. 1, pp. 38–45, 2011.
View at: Publisher Site | Google Scholar
A. J. Scheen, “GLP-1 receptor agonists and heart failure in diabetes,” Diabetes & Metabolism, vol. 43, pp. 2S13–2S19, 2017.
View at: Publisher Site | Google Scholar
J. Lepore, E. Olson, L. Demopoulos et al., “Effects of the novel long-acting GLP-1 agonist, albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction,” JACC Heart Failure, vol. 4, no. 7, pp. 559–566, 2016.
View at: Publisher Site | Google Scholar
W. R. Chen, X. Q. Shen, Y. Zhang et al., “Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction,” Endocrine, vol. 52, no. 3, pp. 516–526, 2016.
View at: Publisher Site | Google Scholar
R. L. Scalzo, K. L. Moreau, C. Ozemek et al., “Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes,” Journal of Diabetes and its Complications, vol. 31, no. 2, pp. 449–455, 2017.
View at: Publisher Site | Google Scholar
W. QIAN, F. LIU, and Q. YANG, “Effect of glucagon-like peptide-1 receptor agonists in subjects with type 2 diabetes mellitus: A meta-analysis,” Journal of Clinical Pharmacy and Therapeutics, vol. 46, no. 6, pp. 1650–1658, 2021.
View at: Publisher Site | Google Scholar
M. Velez, E. L. Peterson, K. Wells et al., “Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes,” Journal of Cardiac Failure, vol. 21, no. 1, pp. 2–8, 2015.
View at: Publisher Site | Google Scholar
R. R. Holman, M. A. Bethel, R. J. Mentz et al., “Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes,” The New England Journal of Medicine, vol. 377, no. 13, pp. 1228–1239, 2017.
View at: Publisher Site | Google Scholar
S. Marso, G. H. Daniels, K. Brown-Frandsen et al., “Liraglutide and cardiovascular outcomes in type 2 diabetes,” The New England Journal of Medicine, vol. 375, no. 4, pp. 311–322, 2016.
View at: Publisher Site | Google Scholar
B. Vergès and B. Charbonnel, “After the LEADER trial and SUSTAIN-6, how do we explain the cardiovascular benefits of some GLP-1 receptor agonists?” Diabetes & Metabolism, vol. 43, pp. 2S3–2S12, 2017.
View at: Publisher Site | Google Scholar
E. Hamaguchi, K. Tanaka, R. Tsutsumi et al., “Exendin-4, glucagon-like peptide-1 receptor agonist, enhances isoflurane-induced preconditioning against myocardial infarction via caveolin-3 expression,” European Review for Medical and Pharmacological Sciences, vol. 19, no. 7, pp. 1285–1290, 2015.
View at: Google Scholar
D. J. Sassoon, J. D. Tune, K. J. Mather et al., “Glucagon-like peptide 1 receptor activation augments cardiac output and improves cardiac efficiency in obese swine after myocardial infarction,” Diabetes, vol. 66, no. 8, pp. 2230–2240, 2017.
View at: Publisher Site | Google Scholar
N. Qa'aty, Y. Wang, A. Wang et al., “The antidiabetic hormone glucagon-like peptide-1 induces formation of new elastic fibers in human cardiac fibroblasts after cross-activation of IGF-IR,” Endocrinology, vol. 156, no. 1, pp. 90–102, 2015.
View at: Publisher Site | Google Scholar
W. R. Chen, Y. D. Chen, F. Tian et al., “Effects of liraglutide on reperfusion injury in patients with ST-segment-elevation myocardial infarction,” Circulation Cardiovascular imaging, vol. 9, no. 12, 2016.
View at: Publisher Site | Google Scholar
J. Lønborg, N. Vejlstrup, H. Kelbæk et al., “Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction,” European Heart Journal, vol. 33, no. 12, pp. 1491–1499, 2012.
View at: Publisher Site | Google Scholar
T. A. Zelniker, S. D. Wiviott, I. Raz et al., “Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus,” Circulation, vol. 139, no. 17, pp. 2022–2031, 2019.
View at: Publisher Site | Google Scholar
S. P. Marso, A. G. Holst, and T. Vilsbøll, “Semaglutide and cardiovascular outcomes in patients with type 2 diabetes,” The New England Journal of Medicine, vol. 376, no. 9, pp. 891-892, 2017.
View at: Publisher Site | Google Scholar
American Diabetes Association, “Cardiovascular Disease and Risk Management:Standards of Medical Care in Diabetes-2020,” Diabetes Care, vol. 43, Supplement 1, pp. S111–S134, 2020.
View at: Publisher Site | Google Scholar
M. S. Shah and M. Brownlee, “Molecular and cellular mechanisms of cardiovascular disorders in diabetes,” Circulation Research, vol. 118, no. 11, pp. 1808–1829, 2016.
View at: Publisher Site | Google Scholar
M. Almutairi, R. al Batran, and J. R. Ussher, “Glucagon-like peptide-1 receptor action in the vasculature,” Peptides, vol. 111, pp. 26–32, 2019.
View at: Publisher Site | Google Scholar
A. C. Sposito, O. Berwanger, L. S. F. de Carvalho, and J. F. K. Saraiva, “Correction to: GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data,” Cardiovascular Diabetology, vol. 18, no. 1, p. 23, 2019.
View at: Publisher Site | Google Scholar
L. Tonneijck, M. H. A. Muskiet, M. M. Smits et al., “Postprandial renal haemodynamic effect of lixisenatide vs once-daily insulin-glulisine in patients with type 2 diabetes on insulin-glargine: an 8-week, randomised, open-label trial,” Diabetes, Obesity & Metabolism, vol. 19, no. 12, pp. 1669–1680, 2017.
View at: Publisher Site | Google Scholar
M. Kim, M. J. Platt, T. Shibasaki et al., “GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure,” Nature Medicine, vol. 19, no. 5, pp. 567–575, 2013.
View at: Publisher Site | Google Scholar
B. Wang, J. Zhong, H. Lin et al., “Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials,” Diabetes, Obesity & Metabolism, vol. 15, no. 8, pp. 737–749, 2013.
View at: Publisher Site | Google Scholar
P. M. O'neil, A. L. Birkenfeld, B. McGowan, and O. Mosenzon, “Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial,” The Lancet, vol. 392, no. 10148, pp. 637–649, 2018.
View at: Publisher Site | Google Scholar
T. Okerson, P. Yan, A. Stonehouse, and R. Brodows, “Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes,” American Journal of Hypertension, vol. 23, no. 3, pp. 334–339, 2010.
View at: Publisher Site | Google Scholar
Z. Z. Htike, F. Zaccardi, D. Papamargaritis, D. R. Webb, K. Khunti, and M. J. Davies, “Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis,” Diabetes, Obesity & Metabolism, vol. 19, no. 4, pp. 524–536, 2017.
View at: Publisher Site | Google Scholar
J. Maringwa, M. L. Sardu, Y. Hang et al., “Characterizing effects of antidiabetic drugs on heart rate, systolic and diastolic blood pressure,” Clinical Pharmacology and Therapeutics, vol. 109, no. 6, pp. 1583–1592, 2021.
View at: Publisher Site | Google Scholar
K. C. Ferdinand, W. B. White, D. A. Calhoun et al., “Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus,” Hypertension, vol. 64, no. 4, pp. 731–737, 2014.
View at: Publisher Site | Google Scholar
V. Higgins and K. Adeli, “Postprandial dyslipidemia: pathophysiology and cardiovascular disease risk assessment,” Ejifcc, vol. 28, no. 3, pp. 168–184, 2017.
View at: Google Scholar
A. Varbo, J. J. Freiberg, and B. G. NordeSTGAARD, “Remnant cholesterol and myocardial infarction in Normal weight, overweight, and obese individuals from the copenhagen general population study,” Clinical Chemistry, vol. 64, no. 1, pp. 219–230, 2018.
View at: Publisher Site | Google Scholar
J. Decara, S. Arrabal, D. Beiroa et al., “Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators,” BioFactors, vol. 42, no. 6, pp. 600–611, 2016.
View at: Publisher Site | Google Scholar
P. Wismann, P. Barkholt, T. Secher et al., “The endogenous preproglucagon system is not essential for gut growth homeostasis in mice,” Molecular Metabolism, vol. 6, no. 7, pp. 681–692, 2017.
View at: Publisher Site | Google Scholar
M. Voukali, I. Kastrinelli, S. Stragalinou et al., “Study of postprandial lipaemia in type 2 diabetes mellitus: exenatide versus liraglutide,” Journal of Diabetes Research, vol. 2014, Article ID 304032, 7 pages, 2014.
View at: Publisher Site | Google Scholar
M. Rizzo, A. A. Rizvi, A. M. Patti et al., “Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study,” Cardiovascular Diabetology, vol. 15, no. 1, p. 162, 2016.
View at: Publisher Site | Google Scholar
Q. Wei, L. Li, J. A. Chen, S. H. Wang, and Z. L. Sun, “Exendin-4 improves thermogenic capacity by regulating fat metabolism on brown adipose tissue in mice with diet-induced obesity,” Annals of Clinical and Laboratory Science, vol. 45, no. 2, pp. 158–165, 2015.
View at: Google Scholar
M. A. Nauck, J. J. Meier, M. A. Cavender, M. Abd el Aziz, and D. J. Drucker, “Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors,” Circulation, vol. 136, no. 9, pp. 849–870, 2017.
View at: Publisher Site | Google Scholar
R. R. Holman, S. K. Paul, M. A. Bethel, D. R. Matthews, and H. A. W. Neil, “10-year follow-up of intensive glucose control in type 2 diabetes,” The New England Journal of Medicine, vol. 359, no. 15, pp. 1577–1589, 2008.
View at: Publisher Site | Google Scholar
M. Seghieri, E. Rebelos, A. Gastaldelli et al., “Direct effect of GLP-1 infusion on endogenous glucose production in humans,” Diabetologia, vol. 56, no. 1, pp. 156–161, 2013.
View at: Publisher Site | Google Scholar
L. L. Baggio and D. J. Drucker, “Biology of incretins: GLP-1 and GIP,” Gastroenterology, vol. 132, no. 6, pp. 2131–2157, 2007.
View at: Publisher Site | Google Scholar
J. Tong and D. D'alessio, “Give the receptor a brake: slowing gastric emptying by GLP-1,” Diabetes, vol. 63, no. 2, pp. 407–409, 2014.
View at: Publisher Site | Google Scholar
P. A. Levin, H. Nguyen, E. Wittbrodt, and S. C. Kim, “Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 10, pp. 123–139, 2017.
View at: Publisher Site | Google Scholar
K. H. Sheahan, E. A. Wahlberg, and M. P. Gilbert, “An overview of GLP-1 agonists and recent cardiovascular outcomes trials,” Postgraduate Medical Journal, vol. 96, no. 1133, pp. 156–161, 2020.
View at: Publisher Site | Google Scholar
K. M. Dungan, S. T. Povedano, T. Forst et al., “Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial,” The Lancet, vol. 384, no. 9951, pp. 1349–1357, 2014.
View at: Publisher Site | Google Scholar
Y. M. Hong, “Atherosclerotic cardiovascular disease beginning in childhood,” Korean Circulation Journal, vol. 40, no. 1, pp. 1–9, 2010.
View at: Publisher Site | Google Scholar
R. Wei, S. Ma, C. Wang et al., “Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner,” American Journal of Physiology Endocrinology and Metabolism, vol. 310, no. 11, pp. E947–E957, 2016.
View at: Publisher Site | Google Scholar
A. Shiraki, J. I. Oyama, H. Komoda et al., “The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells,” Atherosclerosis, vol. 221, no. 2, pp. 375–382, 2012.
View at: Publisher Site | Google Scholar
W. Chang, F. Zhu, H. Zheng et al., “Glucagon-like peptide-1 receptor agonist dulaglutide prevents ox-LDL-induced adhesion of monocytes to human endothelial cells: an implication in the treatment of atherosclerosis,” Molecular Immunology, vol. 116, pp. 73–79, 2019.
View at: Publisher Site | Google Scholar
J. Koska, M. Sands, C. Burciu et al., “Exenatide protects against glucose- and lipid-induced endothelial dysfunction: evidence for direct vasodilation effect of GLP-1 receptor agonists in humans,” Diabetes, vol. 64, no. 7, pp. 2624–2635, 2015.
View at: Publisher Site | Google Scholar
L. Prasad-Reddy and D. Isaacs, “A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond,” Drugs in Context, vol. 4, pp. 1–19, 2015.
View at: Publisher Site | Google Scholar
J. Ard, A. Fitch, S. Fruh, and L. Herman, “Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists,” Advances in Therapy, vol. 38, no. 6, pp. 2821–2839, 2021.
View at: Publisher Site | Google Scholar
B. Cirincione, J. Edwards, and D. E. Mager, “Population pharmacokinetics of an extended-release formulation of exenatide following single- and multiple-dose administration,” The AAPS Journal, vol. 19, no. 2, pp. 487–496, 2017.
View at: Publisher Site | Google Scholar
J. Van Can, B. Sloth, C. B. Jensen, A. Flint, E. E. Blaak, and W. H. Saris, “Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults,” International Journal Of Obesity, vol. 38, no. 6, pp. 784–793, 2014.
View at: Google Scholar
J. Blundell, G. Finlayson, M. Axelsen et al., “Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity,” Diabetes, Obesity & Metabolism, vol. 19, no. 9, pp. 1242–1251, 2017.
View at: Publisher Site | Google Scholar
K. Coveleskie, L. A. Kilpatrick, A. Gupta et al., “The effect of the GLP-1 analogue exenatide on functional connectivity within an NTS-based network in women with and without obesity,” Obesity Science & Practice, vol. 3, no. 4, pp. 434–445, 2017.
View at: Publisher Site | Google Scholar
A. Secher, J. Jelsing, A. F. Baquero et al., “The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss,” The Journal of Clinical Investigation, vol. 124, no. 10, pp. 4473–4488, 2014.
View at: Publisher Site | Google Scholar
D. Beiroa, M. Imbernon, R. Gallego et al., “GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK,” Diabetes, vol. 63, no. 10, pp. 3346–3358, 2014.
View at: Publisher Site | Google Scholar
S. Urquhart and S. Willis, “Long-acting GLP-1 receptor agonists: findings and implications of cardiovascular outcomes trials,” JAAPA, vol. 33, pp. 19–30, 2020.
View at: Google Scholar
M. Husain, A. L. Birkenfeld, M. Donsmark et al., “Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes,” The New England Journal of Medicine, vol. 381, no. 9, pp. 841–851, 2019.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Rui Song et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

494

Downloads

639

Citations