Glucagon-Like Peptide-1 Receptor Agonists in Atherosclerosis: History
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Contributor:
Dalgisio Lecis
,
Francesca Romana Prandi
,
Lucy Barone
,
Martina Belli
,
Domenico Sergi
,
Susanna Longo
,
Saverio Muscoli
,
Francesco Romeo
,
Massimo Federici
,
Stamatios Lerakis
,
Francesco Barillà

Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies.

  • GLP-1RAs
  • diabetes mellitus
  • cardiovascular disease

1. GLP-1 Receptors and Their Agonists

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid peptide derived from preproglucagon and expressed predominantly in the gut, pancreas, and brain [1][2]. In the gut, the two bioactive forms of GLP-1, GLP-17e37 and GLP-17e36 amide, are secreted by epithelial enteroendocrine L cells in response to an oral glucose load. Furthermore, the intestinal release of GLP-1 is stimulated by the gut microbiota, which use undigested food nutrients, fiber, and bile acids to produce metabolites and induce further secretion of GLP-1 from enteroendocrine L cells [2]. The half-life of native GLP-1 is only ~2–3 min. It is degraded locally by the enzyme dipeptidyl peptidase-4 (DPP4) and minimally by the neutral endopeptidase, and it is eliminated by the kidney. Therefore, only 10–15% of endogenous GLP-1 reaches the systemic circulation [1][3].
GLP-1 receptors (GLP-1Rs) are coupled to G proteins, which stimulate the production of cyclic adenosine monophosphate, and they are ubiquitously located. In the pancreas, GLP-1 mediates the insulin secretory response to glucose ingestion with the direct activation of GLP-1Rs on beta cells and through paracrine mechanisms involving vagal afferents. GLP-1 also inhibits glucagon secretion and endogenous glucose production by acting directly on pancreatic alpha cells or by stimulating somatostatin production from delta cells. The final effect is to decrease the postmeal hyperglycemia. Moreover, GLP-1Rs are expressed in the hindbrain, hypothalamus, hippocampus, and mesolimbic system. At this site GLP-1 suppresses the appetite and inhibits gastric emptying, promoting weight loss and reducing postprandial hyperglycemia. The inhibitory effect on appetite also depends on the paracrine action of GLP-1 via intestinal vagal afferents that transmit the signal to the hypothalamus [2][4][5]. GLP-1Rs are also localized on white and brown adipose tissue where they increase energy expenditure. They have lower expression in the heart, lung, intestine, muscle, kidney, liver, and peripheral nervous system [1][2][3][6].
All available GLP-1 RAs are synthetic peptides derived from human GLP-1 or exendin-4, a 39-amino-acid peptide obtained from the saliva of the lizard Heloderma awareum. GLP-1RAs are more resistant to degradation than native GLP-1 [7]. Based on their pharmacokinetic profile, they are divided into short-acting agonists (exenatide and lixisenatide) and long-acting agonists (liraglutide; long-acting exenatide; albiglutide; dulaglutide; and long-acting, subcutaneous or oral semaglutide) [4][8]. Short-acting GLP-1RAs have a short half-life and are administered before a meal once or twice a day, showing higher postprandial plasma concentrations than in the fasting. Therefore, they reduce postprandial hyperglycemia and influence gastrointestinal motility. Vice versa, long-acting GLP-1RAs are administered once a week, and they reduce fasting blood glucose predominantly through direct pancreatic action, have greater body weight reduction potential, and show fewer effects on gastrointestinal motility [1]. GLP-1RAs also show nonglycemic effects, including decreases in weight; cytoprotective and proliferative effects on alpha, beta, and delta cells; and improvements in systolic blood pressure and cardiovascular risk markers, such as triglycerides and total cholesterol [2][4]. Their effect is glucose dependent, so the risk of hypoglycemia is very low [8]. The most observed adverse effect is intestinal nausea, which could be reduced by using low doses at the beginning of therapy [4].

2. GLP-1RAs and Reduction in Cardiovascular Risk

CVDs are the leading cause of morbidity and mortality in patients with diabetes; therefore, the prevention of cardiovascular (CV) complications is essential in the treatment of T2DM [9]. In recent years, there has been an expansion of the armamentarium for T2DM treatment with drugs that are not limited exclusively to glycemic control but also have positive effects on reducing CV risk. Among these, sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and GLP-1RAs proved to have several vascular actions going beyond simple antihyperglycemic effects. GLP-1RAs are a new class of drugs that showed robust reductions in atherosclerotic events and all-cause mortality in all studies, with the exception of lixisenatide [10]. The LEADER (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes) is the first trial to demonstrate positive outcomes in CVDs in patients with T2DM [11]. Liraglutide resulted in a statistically significant reduction not only in the incidence of MACEs but also in CV and all-cause mortality. However, no differences were observed in rates of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure between the liraglutide and placebo arms. Husain et al. performed an analysis to assess the effects of oral and injectable semaglutide versus placebo on MACEs in subjects with T2DM in a combined population from SUSTAIN 6 and PIONEER 6 [12]. The abovementioned analysis showed a significant protection against MACEs, equal to 24%, in the semaglutide group compared with the control group [12]. These results [13] are particularly significant considering the small sample size and the brief duration of observation [14]. Most CV outcome trials with GLP-1RAs recruited patients with T2DM characterized by established CVD or with a high risk of CV events. Indeed, these studies were originally designed primarily as safety studies, and the accumulation of a large number of CV events in high-risk patients was a strategy to limit the sample size and duration of these trials [14]. In the EXSCEL (Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes) trial [15], exenatide failed to demonstrate superiority in preventing CV events, despite having a 9% reduction in the incidence of the primary endpoint (first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke). The lack of cardiovascular efficacy in the EXSCEL trial may be related to multiple factors. The median follow-up time in the EXSCEL trial was shorter than that in the LEADER trial (3.2 years vs. 3.8 years), as was the duration of exposure to the trial regimen (2.4 years vs. 3.5 years); in addition, the baseline glycated hemoglobin level in the EXSCEL trial was lower than that in the LEADER trial (8.0% vs. 8.7%), and the rate of discontinuation of the trial regimen was higher. AMPLITUDE-O (Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes), on the other hand, is a trial in which weekly subcutaneous injections of efpeglenatide (4 or 6 mg) for a median of 1.8 years led to a 27% lower risk of incident MACEs and a 32% lower risk of a composite renal outcome event than placebo among persons with T2DM and either a history of CVD or current kidney disease [16]. A meta-analysis summarized the results of these randomized trials, showing a significant reduction in MACEs, CV death, stroke, myocardial infarction, death from all causes, heart failure, and kidney disease, emphasizing the important glycometabolic effects and extraglycemic actions that would determine a significant clinical benefit in patients with T2DM [17].
The GLP-1RAs were shown to have pleiotropic CV effects [18] including reduction in blood pressure (BP) [19]. Specifically, the use of GLP-1RAs results in a reduction in BP (reduction in systolic BP by 1 mmHg with lixisenatide and by 5.4 mmHg with semaglutide) through a natriuretic and vasodilatory effect, likely mediated by the atrial natriuretic peptide, released as a result of binding to specific receptors expressed in the atria [20]. This beneficial effect on blood pressure reduction exerted by GLP-1RAs is consistent with the reduction in CV risk associated with their use. Endothelial cells play a key role in BP control. GLP-1RAs stimulate acetylcholine-induced vasodilation and promote nitric oxide release, thus reducing vascular tone with benefits to both systolic and diastolic BP [21].

3. Metabolic Effects of GLP-1RA Administration

The administration of GLP-1RAs, like liraglutide, exenatide, semaglutide, and lixisenatide, has multiple metabolic effects, such as glucose-dependent insulin secretion, slower gastric emptying, increased natriuresis and diuresis, increased pancreatic β-cell mass, regulation of lipid metabolism, and decreased fat deposition, and has attracted considerable interest in recent years for its role in improving glycemic control and aiding weight loss in T2DM patients [22].
Drugs like liraglutide not only enhance pancreatic β-cell mass, leading to better oral glucose tolerance and reduced peak serum glucose timings, but also contribute to weight management by lowering body weight, HbA1c, and liver fat content [23]. Exenatide, semaglutide, and lixisenatide have shown efficacy in controlling postprandial glucose levels, an important aspect of diabetes management [21][24][25][26].
Remarkably, these agents also address dyslipidemia, a common comorbidity in T2DM. A significant meta-analysis highlighted GLP-1RAs’ ability to lower total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels compared to other antidiabetic agents or placebo. In particular, liraglutide and taspoglutide stand out for their cholesterol-lowering effects, notably impacting total cholesterol and triglycerides, showcasing a broader therapeutic impact beyond glucose modulation [27].
This lipid-modifying potential is not confined to diabetic patients alone; individuals with obesity also experience reductions in the numbers of small- and medium-sized LDL particles and the total cholesterol with GLP-1RA treatment [28]. As such, the utility of GLP-1RAs might expand to the improvement of cardiovascular risk profiles, given that dyslipidemia is a key player in cardiovascular disease.

4. Atherosclerotic Plaque Pathways Targeted by GLP-1RAs

The use of liraglutide and semaglutide, as shown in the LEADER and SUSTAIN-6 trials, reduces the occurrence of MACEs in high-risk CVD patients with diabetes. This effect is the consequence of GLP-1RAs’ anti-atherosclerotic action.
Some preclinical studies investigated how different pathways involved in atherosclerosis initiation and development are affected by the administration of GLP-1RAs. The genesis of foam cells is critical for the development of the atherosclerotic plaques. Acetyl-coenzyme A acetyltransferase 1 (ACAT1) expression is upregulated during the differentiation of monocytes to macrophages, and it is abundantly expressed in macrophage foam cells of atherosclerotic lesions [29]. It has been shown that, during ischemic stress, macrophages increase their uptake of ox-LDL cholesterol, leading to increased ACAT1 activity and the formation of toxic levels of cholesterol esters [30]. The esterification of cholesterol results in its storage in cellular lipid droplets, making it unavailable for ATP-binding cassette A1–mediated efflux from the cell and leading to the formation of macrophage foam cells. The treatment of mouse peritoneal macrophages with an ACAT inhibitor significantly reduced 7-ketocholesterol-induced apoptosis [31]. Kharbanda et al. were the first to report the effects of systemic ACAT inhibition in humans. Hypercholesterolemic human subjects treated for 8 weeks with avasimibe, an ACAT inhibitor, showed a small reduction in plasma cholesterol levels but had significantly lower levels of circulating tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine [32]. Tashiro et al. showed that liraglutide could prevent the development of atherosclerotic lesions by suppressing macrophage foam cell formation mainly associated with ACAT1 downregulation [33].
Nagashima et al. showed that the infusion of native incretins (GLP-1 and GIP) in ApoE−/− mice also resulted in a reduction in foam cell formation through the downregulation of the CD36 and ACAT1 pathways [34]. GLP-1 and GIP receptors were both detected in Apoe−/− mouse macrophages. CD36 plays a significant role in the pathogenesis of atherosclerosis by serving as a highly specific receptor for oxidized phospholipids prevalent in ox-LDL. The interaction of ox-LDL with CD36 triggers a signaling cascade that is necessary for ox-LDL uptake and foam cell formation and that alters cytoskeletal dynamics and inhibits migration, thus contributing to the trapping of foam cells within the atherosclerotic plaque [35].
Rapikovski et al. showed the effects of semaglutide on aortic plaque formation in ApoE−/− and LDLr−/− mice through the evaluation of gene expression from collected aorta samples. The expression of 275 genes involved in the atherosclerotic process has been investigated [36]. This interesting and comprehensive analysis documented that the administration of a daily dose of semaglutide of 60 μg/kg for 12 to 14 weeks in ApoE−/− mice or for 17 weeks in LDLr−/− mice impacted multiple pathways and stages characterizing the pathogenesis of atherosclerosis. Semaglutide reduced the leukocyte recruitment by the downregulation of IL-6, IL-1RN, and chemokine (C-C motif) ligand 2 (CCL2) gene expression. Moreover, the leukocyte rolling, adhesion, and extravasation process was affected by E-selectin (SELE) and vascular cell adhesion molecule 1 (VCAM-1) downregulation. Interestingly, semaglutide probably plays a role in plaque vulnerability, since the gene expression of proteins involved in extracellular matrix turnover (MMP-3 and MMP-13) and plaque hemorrhage (CD163) was reduced in the semaglutide-treated group [36].
The anti-inflammatory effects of semaglutide were investigated by analyzing the plasma levels of the inflammatory cytokines TNF-α and IFN-γ in lean C57BL/6J mice challenged with a single dose of LPS. Pretreatment with semaglutide reduced the TNF-α and IFN-γ response after LPS exposure [36]. An important pro-inflammatory cytokine that also plays a role in immune cell recruitment is osteopontin (OPN) [37]. Giachelli et al. demonstrated that elevated circulating OPN levels were associated with an increased CVD risk in T2DM [38]. Semaglutide decreased plasma OPN levels following an LPS challenge; moreover, OPN expression was decreased in aortic tissue with semaglutide treatment [36].
Lastly, liraglutide has been shown to be able to affect the M1/M2 ratio, promoting an M2 phenotype in apoE−/− mice with an atheroprotective effect [39]. Bruen et al. demonstrated that liraglutide reduced pro-inflammatory immune cell populations and mediators from plaque-burdened murine aortas in vivo and augmented pro-resolving bone-marrow-derived macrophages in the attenuation of atherosclerotic disease [40]. A recent study compared the distribution of macrophages and their surface GLP-1Rs in patients with confirmed or unconfirmed CVD through coronary angiography and without bias from the difference in T2DM distribution or GHbA1c level between the two groups [41]. The data show that the expression of GLP-1Rs on total and M2 macrophages differed between the CVD group and the healthy control group (p < 0.05). The expression of GLP-1Rs was higher in the healthy group. The two groups did not exhibit any notable distinctions in the surface expression of GLP-1Rs on M1 macrophages or the proportions of total, M1, and M2 macrophages. This implies that alterations in GLP-1R expression levels are a more responsive indicator than the proportional macrophage composition when considering the chronic inflammatory progression of atherosclerosis. 

This entry is adapted from the peer-reviewed paper 10.3390/biom13121695

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