Benefits of GLP-1 Mimetics on Epicardial Adiposity

Abstract

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

1. INTRODUCTION

Epicardial adipose tissue (EAT) is a fatty tissue surrounding the myocardium lying between the myocardium and epicardium with no distinct anatomical barrier with the myocardium (Fig. 1) [1, 2]. It differs from adipose tissues surrounding the heart and pericardial adipose tissue and is in close contact with the coronary arteries [3]. In physiologic states, it has many vital roles and provides cardiac benefits such as protection of the heart and metabolic substrates for cardiomyocytes [3, 4]. However, in pathologic conditions with increased volume and thickness, it is converted into a threat to cardiac functions and induces some pathophysiologic states such as dysrhythmia and atherosclerosis [5-7]. So recent evidence has emphasized the importance of its control to prevent cardiac failure, especially in the diabetic milieu [8, 9]. Glucagon-like peptide-1 (GLP-1) mimetics are a class of medications approved for the treatment of diabetes and obesity which regulate post-prandial glucose via several well-defined pathways [10]. They have modulatory effects on many physiologic systems and tissues and provide physiologic benefits through these impacts [10]. More recent evidence suggests that these drugs interact with EAT and may provide modifying effects [11, 12]. If true, they will be able to offer extra-glycemic benefits reducing the risk of cardiovascular complications in the diabetic milieu, which is intrinsically a talented milieu for cardiovascular disorder development. Our current study provides evidence of critical benefits.

Fig (1).

Heart wall structure and the location of epicardial adipose tissue.

2. CLASSIFICATIONS OF DIABETES MELLITUS

Diabetes mellitus (DM) is commonly classified into three main classes type1, type2, and gestational diabetes (Table 1) [13]. Also, there are other forms of DM with minor frequencies, such as LADA Latent Autoimmune Diabetes in Adults (LADA), Maturity Onset Diabetes of the Young (MODY), and diabetes that is secondary to different conditions such as pancreatitis or drugs (e.g., corticosteroids) [14, 15].

Table 1.

Three main classes of diabetes mellitus.

Type of DM	Pathophysiology	Prevalence (Among Diabetics)	References
Type 1 DM (T1DM) or Insulin-dependent diabetes mellitus (IDDM)	Lower circulatory insulin due to beta cells failure	5-10%	[13]
Type 2 DM (T2DM) or non-insulin-dependent diabetes mellitus (NIDDM)	Insulin resistance in peripheral tissues	90-95%	[13]
Gestational Diabetes	Hormonal variations during pregnancy	-	[13, 16]

2.1. GLP-1 Mimetics

Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a newly introduced class of drugs recently approved by the FDA for treating patients with diabetes and obesity [17]. These drugs provide hypoglycemic influences by mimicking the incretin hormones' effects; a family of metabolic peptides included of GLP-1 and GIP (gastric inhibitory peptide), that decrease postprandial blood glucose by stimulating insulin release and inhibiting glucagon secretion [18-21]. They also provide additional physiologic effects helping to post-prandial blood glucose reduction by delaying gastric emptying, improving lipid metabolism, nutrient absorption reduction, appetite suppression, and supporting pancreatic β--cells’ functions (Fig. 2) [20, 22-33]. GLP-1 specific receptors are predominantly located in the pancreatic β--cells [21, 34]. They are G-protein coupled receptors that increase cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP) production and induce intra-cellular processes leading to insulin secretion and glucagon suppression [21, 34].

Fig. (2).

Schematic pic explaining how GLP-1 mimetics modify blood glucose. GLP-1 is secreted mainly from L cells of intestine and exerts its hypoglycemic effects by other tissues.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are another class of incretin-based antidiabetics which provide hypoglycemic effects through increasing circulating levels of GLP-1 through DPP-4 inhibition; an enzyme that metabolizes and inactivates it [35, 36]. Therefore, the DPP-4i have similar antidiabetic effects to GLP-1ra, although they differ with regards to adverse effects and impact on body weight [35] (Table 2).

Table 2.

Two main classes of GLP-1 mimetics.

Classes	Approved Forms	Mechanisms of Action	References
GLP-1ra	Exenatide (Exendin-4), Albiglutide, Liraglutide, Lixisenatide Semaglutide, Dulaglutide	Mimic glucose-lowering effects of the incretins via glucagon suppression, insulin release, appetite inhibition, and slowing the gastric emptying	[18, 19]
DPP-4i	Sitagliptin, Saxagliptin, Vildagliptin, Linagliptin	Increase the active circulatory levels of GLP-1	[35, 36]

2.2. Epicardial Adipose Tissue

Epicardial adipose tissue (EAT) is a layer of fat that envelops the myocardium and lies between the myocardium and the epicardium (Fig. 3) [3]. It has no distinct anatomical barrier with the myocardium and is in close contact with the coronary arteries [1, 2]. EAT differs from adipose tissues surrounding the heart, named pericardial adipose tissues [3]. Also, they have different embryological origins; while pericardial adipose tissues evolved mainly from thoracic mesenchymal cells, EAT originated from splanchno-pleuric mesenchymal cells [3, 37]. Moreover, they have different vascularization Fields [38]. Coronary arteries support the EAT, but pericardial adipose tissues are supplied by branches of the internal mammary artery [38]. However, these two adipose tissues are not disconnected by a distinct fascia. They may have close functional and releasing interactions as they synthesize and secretion of different modifying adipokines into the heart muscle and arteries [3, 38].

Fig. (3).

EA induces cardiovascular problems via induction of injurious pathways such as inflammation and fibrosis, and atherosclerosis Abbreviations: (ACT= α1-antichymotrypsin, TGF-β= Transforming growth factor- β, IL-6= interleukin 6, TNF-α= Tumor necrosis factor-alpha).

In addition to energy storage, EAT has important biologic endocrine and paracrine activities by expressing and releasing the different adipocyte-derived cytokines (adipokines) involved in metabolic processes and inflammatory responses [3, 4]. Also, it provides protective effects for cardiac muscles, i.e., thermoregulation and releasing primary metabolic substrate of cardiac muscles as fatty acids [1]. EAT supports coronary arteries and prevents or reduces the injuries induced by myocardial contraction or external mechanical forces [9]. Due to higher lipogenesis and lipolysis rate than other adipose tissues, EAT is a reliable lipid storage providing required free fatty acids for the metabolic needs of the myocardium [39, 40]. EAT can synthesize and release anti-inflammatory cytokines of adiponectin and adrenomedullin, which can ameliorate inflammatory processes and fat deposition around the heart muscles [41]. Moreover, EAT modulates vascular contractility and regulates vascular smooth muscle cell proliferation via its antioxidant and anti-apoptotic effects [42-44]. Furthermore, it has been suggested that EAT prevents hypothermia-induced fatal arrhythmia by expressing Uncoupling protein-1 (UCP-1) [9, 45]. EAT is a white type of fatty tissue, although it has evolved from brown adipocytes and has some features of brown fat [1].

2.3. Epicardial Adiposity and Heart Failure

More recent observations have shown that EA is associated with a higher risk of heart failure and cardiovascular disorders via several pathways [5-7]. Higher amounts of EAT enveloping the heart threaten the normal pumping function of cardiac muscles. More recent evidence suggests that EA is an independent risk factor for cardiac function [1, 9]. They have shown that higher levels of EA are associated with adverse prognosis and higher mortality risk in patients with heart failure [5, 46]. EAT reduces the space surrounding the heart and imposes external mechanical forces on the myocardium at severe levels [8, 9]. Fibrotic EAT is a limiter fascia enveloping the heart [5, 6]. So it can restrict the space required for normal heart pumping function and decline ejection fraction and total cardiac output [5, 8, 9]. Also, EA impairs normal cardiac rhythmicity and induces different forms of dysrhythmia [8, 9]. This fatty layer slows the conduction velocity, impairs local electrophysiological properties via the effects of adipocyte-derived cytokines, and induces electrical remodeling in the cardiomyocytes [47]. Thickness or volume of EAT could be a marked predictor of presence, severity, and recurrence of atrial fibrillation [48].

Like other adipose tissues, EAT synthesizes different adipocyte-derived cytokines such as CC motif chemokine ligand (CCL2), Inetrleukine-6 (IL-6), Tumor necrosis factor (TNF), chemerin, intelectin-1, JUN N-terminal kinase (JNK), Nuclear factor-κb (NF-κb, and Toll- like receptors (TLRs) [6]. Since there is not a distinct separating tissue between the myocardium and EAT and due to their anatomical vicinity, EAT releases these inflammatory mediators via paracrine or vasocrine mechanisms directly into the myocardium, where they induce inflammatory responses and make an inflammatory milieu around the heart, disturbing its normal function through well-defined pathways [9]. These inflammatory mediators can also negatively modulate cardiomyocyte electrophysiology and cardiac cell remodeling [47]. EAT modulates different profibrotic mediators such as ACT 9, MMPs 10, TGF-β 11, and c-TGF 12 and induces and progresses fibrotic processes in cardiac tissues [6, 49, 50]. Also, it has higher concentrations of M1-macrophages that secrete inflammatory cytokine into the coronary arteries and make systemic inflammation [6, 51, 52].

Furthermore, EAT is involved in cardiovascular disorders via modulating local metabolic pathways of glucose and lipids [6, 53, 54]. Interestingly, the Glut-4 9 in EA in patients with heart failure is lower than in the normal population, so it induces local insulin resistance in coronary arteries [53]. Also, it can cause more Advanced glycation end-product (AGE)- Receptors for AGE (RAGE) interaction and increase oxidative stress levels in coronary arteries, which in turn induces atherogenic processes and cardiovascular disorders such as atherosclerosis [6, 55]. Neuronal mechanisms may be another link between EA and heart failure [6, 56]. It has been shown that increased EAT thickness is correlated to enhanced sympathetic activity and catecholamine expression/release and, so, a higher risk of heart failure [56]. The adverse effects of EA are likely dependent on its regional distribution [6]. For example, pericoronary EAT increases the risk of coronary artery disease [57], but left atrial EAT induces atrial fibrillation [58].

3. GLP-1 MIMETICS AND EPICARDIAL ADIPOSITY

Recent studies suggest that GLP-1 mimetics may interact with EAT [11, 12]. They have shown that incretins modulate EAT thickness and reduce EA in patients with diabetes [12]. Also, the recent discovery of GLP-1 receptors in EAT confirms this relationship [2]. Iacobellis and colleagues 2017 discovered that human EAT expresses GLP-1 receptors [2]. They have shown in another study that GLP-1 mimetic of liraglutide induces a rapid reduction in EAT volume in patients with T2DM [59]. It was later confirmed by Dozio and colleagues, who demonstrated that GLP-1R1 and GLP-1R2 are expressed in EAT and may be new targets for GLP-1 mimetics [11]. This was later confirmed by another study that assayed the epicardial fat of patients with heart failure and observed the GLP-1 receptor expression in this tissue [60]. These findings suggest a promising mechanism for the cardiovascular benefits of GLP-1 mimetics via EAT modulation [61].

Another clinical study similarly demonstrated that GLP-1 mimetics of semaglutide or dulaglutide reduce EAT [12]. It reported that 12 weeks of incretin therapy induced a rapid, substantial, and dose-dependent decrease in EAT thickness in patients with T2DM [12]. Moreover, Zhao and colleagues recently demonstrated similar effects for liraglutide, which reduced EAT thickness in T2DM with abdominal obesity [62]. We have more evidence to confirm it. Dutour and colleagues in 2016 were shown that three months of exenatide therapy reduces epicardial fat in patients with obesity and T2DM [63]. Also, Lima and colleagues 2016 provided evidence indicating sitagliptin induces a rapid, significant reduction in EAT in patients with T2DM, probably [64]. However, there are some controversies. A double-blind, randomized trial in patients with T2DM demonstrated that liraglutide has no significant effects on EAT thickness [65]. Also, in another clinical study, liraglutide could not reduce EAT in patients with T2DM, although it decreased the body weight [66]. Table 3 presents the primary related clinical evidence. Based on this evidence, all forms of GLP-1 mimetics have reduced the EA in patients with T2DM. But, liraglutide was unable to do it in two studies on T2DM patients [65, 66], although it did it in other studies [62, 67]. Interestingly, in both studies, with a significant decrease in EA, liraglutide was injected at a dose of 1.2 mg/day [62, 67]. While in both studies, with no significant reduction in EAT, it was injected at a dose of 1.8 mg/day [65, 66], and so it seems that the effects of this drug on EAT are dose-dependent and are more effective at lower doses. The molecular differences of GLP-1 mimetics used in these clinical trials are presented in Table 4.

Table 3.

Primary clinical evidence showing the effects of incretin-based drugs on epicardial adipose tissue (EAT).

Drugs	Patients	Duration	Effects on EAT Volume/Thickness	References
Semaglutide & Dulaglutide	80 patients with T2DM	12 weeks	A rapid, substantial, and dose-dependent reduction	[12]
Liraglutide	21 patients with T2DM and abdominal obesity	3 months	Significant decrease	[62]
Liraglutide	47 patients with T2DM	26 weeks	No significant effect	[65]
Exenatide	44 patients with obesity and T2DM	3 months	Significant reduction	[63]
Liraglutide	95 patients with obesity and T2DM	6 months	Substantial and rapid reduction	[59]
Liraglutide & Exenatide	25 patients with T2DM	3 months	Significant reduction	[67]
Liraglutide	50 patients with T2DM	26 weeks	No significant effect	[66]
Sitagliptin	26 patients with T2DM	24 weeks	Significant and rapid reduction	[64]

Table 4.

Molecular properties of GLP-1 mimetics with approved effects on EAT.

Name	Molecular Weight (D)	Half-life	Dosage
Exenatide	4,186.6	2.4 h	Twice daily (or once weekly in sustained release preparation)
Liraglutide	3,751	13 h	Once daily
Dulaglutide	62,561	90 h	Once weekly
Semaglutide	4,113	160 h	Once weekly
Sitagliptin	407.31	8-14 h	Once daily

3.1. Possible Involved Mechanisms

The modulatory effects of GLP-1 mimetics on epicardial adipose tissues have been recently discovered, so we have not had enough direct evidence exploring the involved pathways. However, extant evidence suggests some mechanisms (Fig. 4). For example, Dutour and colleagues demonstrated that exenatide therapy reduces EAT thorough a weight-loss-dependent manner in patients with obesity and T2DM [63]. They explained that observed EAT reduction is directly associated with body weight reduction [63]. Also, they have shown that GLP-1 mimetics can modulate body fat distribution and reduce ectopic fat storage [63]. Similarly, Zhao and colleagues demonstrated that liraglutide reduces EAT thickness in T2DM dependent on body weight [62].

Fig. (4).

GLP-1 mimetics reduce EA via suppressing adipogenesis, inhibiting white to brown adipocyte differentiation, and promoting fat burning/β-oxidation.

As explained before, both GLP-1 receptors are expressed in adipose tissues, and recent studies have isolated them from human epicardial adipocytes [2, 11]. Due to the pleiotropic roles of these receptors in metabolic pathways [68], it is hypothesized that GLP-1 mimetics exert extensive modulatory effects on EAT [62]. Zhao and colleagues found that liraglutide normalizes metabolic factors such as glucose (FBS, 2hPP, HbA1c) and lipids (triglyceride and cholesterol), as well as body weight and waist circumference, and BMI in patients with T2DM [62]. Moreover, Dozio and colleagues found that GLP-1 mimetics decrease EAT volume through metabolism (beta-oxidation), reduce adipogenesis, increase fat burning and decrease the white--to-brown adipocyte differentiation [11]. So, any improvement in metabolic factors may be another link between GLP-1 mimetics and EAT [62].

GLP-1 mimetics have potent modulatory roles on adipocyte differentiation and regulate this physiologic process [69]. In clinical evidence provided by Lima and colleagues in 2016, sitagliptin induced a rapid, significant reduction in EAT in patients with T2DM by decreasing adipocyte differentiation [64]. Another study reported that epicardial adipocytes’ GLP-1 receptors are closely associated with metabolic genes in adipocyte differentiation and fatty acid beta-oxidation [11]. Also, Morano and colleagues reported that both exenatide and liraglutide re-distributed body fats and reduced EA in patients with T2DM [67]. So, it is highly suggested that they have potent modulatory roles in EAT volume via control of adipocyte maturation [11]. Thus, it may be other possible links that need further examination.

CONCLUSION

EA is now recognized as a potent risk factor for cardiac function since it can induce cardiovascular disorders through several pathways as induction and promotion of pathophysiologic processes of inflammation, fibrosis, atherosclerosis, and electrophysiologic problems. Newly introduced antidiabetics of GLP-1 mimetics rapidly decrease the thickness and volume of EAT. This was confirmed by increasing clinical evidence, although there are also some controversies. We do not entirely understand possible involved mechanisms, but some are suggested. It may depend on fat burning and body weight reduction, which reduce the local spots of fats around the heart. This was highly recommended by studies confirming the GLP-1 receptor's expression in the EAT and clinical studies showing body fat reduction by GLP-1 therapy. Also, they strongly impact metabolic pathways and may reduce EA volume by modifying these pathways. GLP-1 mimetics can also modulate adipocyte differentiation so it may be another possible link. Taken together, GLP-1 mimetics are effective agents to reduce the EAT volume and so could provide further cardiovascular benefits in patients with diabetes.

LIST OF ABBREVIATIONS

EAT

Epicardial adipose tissue

GLP-1

Glucagon-like peptide-1

DM

Diabetes mellitus

DDP-4i

Dipeptidyl peptidase-4 inhibitors

UCP-1

Uncoupling protein-1

CCL2

Chemokine ligand

IL-6

Inetrleukine-6

TNF

Tumor necrosis factor

JNK

JUNN-terminal kinase

NF-κb

Nuclear factor-κb