Abstract:
Introduction : Type 2 diabetes mellitus (T2DM) represents one of the most pressing global health challenges. The diabetic population has surged dramatically, from 108 million in 1980 to an estimated 529 million in 2021. Hyperglycemia is intricately linked with endothelial dysfunction, which contributes to the development of atherosclerosis, thereby increasing the risk of cardiovascular diseases. Atherosclerotic cardiovascular disease (ASCVD) is closely associated with vulnerable plaques, influenced by numerous cytokines. Consequently, contemporary diabetes treatments must consider pleiotropic effects that mitigate cardiovascular risk.
Objectives: This study aimed to investigate the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on biomarkers indicative of atherosclerotic plaque instability, including pentraxin 3 (PTX3), copeptin (CPC), matrix metalloproteinase-9 (MMP-9), and lipoprotein(a) [Lp(a)].
Patients and Methods: Fifty subjects aged 41–81 years (mean: 60.7) with diagnosed T2DM (median HbA1c: 8.75%), dyslipidemia, and confirmed atherosclerosis via B-mode ultrasound were included. All subjects were eligible to initiate treatment with a GLP-1 RA.
Results: Following a 180-day intervention with GLP-1 RAs, our study observed a statistically significant decrease in biochemical markers associated with atherosclerotic plaque instability, including PTX3, CPC, and MMP-9 (p < 0.001), as well as Lp(a) (p < 0.05).
Conclusions: GLP-1 receptor agonists significantly reduce concentrations of PTX3, CPC, MMP-9, and Lp(a), all implicated in plaque vulnerability. This effect may contribute to the reduction of cardiovascular risk among diabetic patients.
Keywords: GLP-1 receptor agonist; Diabetes mellitus; Pentraxin 3; MMP-9, Copeptin, Lipoprotein (a); semaglutide; dulaglutide
INTRODUCTION
The global diabetic population is on the rise, estimated to have increased from 108 million in 1980 to 529 million in 2021 [1]. Individuals with diabetes face a heightened risk of complications, especially macrovascular complications including coronary artery disease, cerebrovascular disease, and peripheral artery disease, which constitute major causes of mortality, accounting for over 50% of deaths in diabetic patients [2]. The development of atherosclerosis is responsible for the onset of cardiovascular diseases [3]. Hyperglycemia is strongly linked to endothelial dysfunction, which not only initiates the formation of atherosclerotic plaques but also contributes to their progression and instability [4]. The pathomechanism of atherosclerosis is highly complex, involving multiple stages such as initiation due to endothelial dysfunction, inflammatory cell migration, atherosclerotic plaque formation, and eventual plaque rupture. Numerous cytokines play key roles in each of these stages [5]. The clinical implications of atherosclerotic cardiovascular disease (ASCVD) is associated with vulnerable plaques. This term encompasses different phenotypes of unstable atherosclerotic plaques, such as plaque rupture, intraplaque hemorrhage, erosion and plaque fissuring [6]. Cytokines involved in the vulnerability of atherosclerotic plaques include e.g. pentraxin 3 (PTX3), lipoprotein(a) [Lp(a)], copeptin (CPC), and matrix metalloproteinase 9 (MMP9).
Pentraxin 3 is emerging as a promising immunoinflammatory marker for evaluating cardiovascular risk. Within the pentraxin family, which comprises acute-phase proteins characterized by a pentameric structure, C-reactive protein (CRP) is one of the members. Importantly, while CRP is predominantly synthesized in the liver, PTX3 is locally produced and released by various cell types, particularly monocytes/macrophages. The production of PTX3 is stimulated by pro-inflammatory cytokines such as Interleukin 1 (IL-1), tumor necrosis factor α (TNFα), and oxLDL [7]. The distinctive capability of pentraxin 3 to regulate local inflammation involving macrophages and smooth muscle cells has prompted research into its role in the pathogenesis of atherosclerosis and cardiovascular disease. The observed positive correlation between PTX3 concentration and the risk of adverse outcomes in patients with coronary artery disease (CAD) suggests that PTX3 could be a valuable biomarker for cardiovascular disease [8, 9]. Furthermore, the plasma PTX3 concentration is correlated with plaque vulnerability evaluated by optical coherence tomography in individuals with coronary artery disease [10, 11].
The precursor peptide preprovasopressin produced in the hypothalamus is responsible for the release of arginine vasopressin (AVP) and an equal amount of copeptin. Their secretion occurs, among other factors, in response to stress and affects the regulation of the endocrine response of the hypothalamo-pituitary-adrenal (HPA) axis. The precise function of copeptin remains elusive. In contrast to AVP, measuring plasma copeptin concentration is more accessible. Therefore, its primary role lies in serving as an indirect indicator of the circulating plasma levels of AVP [12]. Copeptin could be a promising new marker for diagnosing acute cardiovascular events. Numerous studies indicate that, when evaluated alongside cardiac troponin (cTn), copeptin is effective in swiftly ruling out myocardial infarction. Furthermore, in cases of stroke, myocardial infarction, or heart failure, it can be employed for risk stratification and prognosis assessment [13].
Lp(a) is an independent risk factor for ASCVD [14]. Lipoprotein(a) plays a role at various stages of atherosclerosis. Within the endothelium, it undergoes more pronounced oxidation than LDL, thus intensifying the action of adhesion molecules. Lp(a) increases the synthesis of other pro-inflammatory cytokines such as IL-1, IL-6, and TNFα. Lipoprotein(a) is also involved in the instability of atherosclerotic plaques. Its prothrombotic and antifibrinolytic effects contribute to intravascular thrombotic processes [15, 16, 17]. In recent years, a correlation has been established between elevated plasma lipoprotein(a) levels and the presence of vulnerable atherosclerotic plaques in patients experiencing acute cardiovascular events [18, 19].
Matrix metalloproteinases (MMPs) are enzymes crucial for remodeling the extracellular matrix and facilitating leukocyte recruitment to inflammatory sites, thereby serving as key regulators of the inflammatory process. Consequently, excessive or imbalanced secretion of MMP-9 is linked to tissue damage in inflammation [20]. MMP-9 contributes to the progression of arteriosclerosis. Numerous studies indicate a correlation between elevated plasma levels of matrix metalloproteinases-9 and an increased risk of plaque rupture and acute cardiovascular events [21].
Hence, inhibiting the progression of atherosclerosis and preventing its instability has huge clinical significance in enhancing the prognosis for individuals with diabetes. In the treatment of type 2 diabetes, there is an increased use of ’new hypoglycemic drugs,’ such as glucagon-like peptide 1 receptor agonists (GLP-1 RA). These medications, besides affecting blood glucose levels through pleiotropic effects, also influence various cardiac risk factors [22]. In recent years, several randomized clinical trials of GLP-1 RA have demonstrated a substantial reduction in cardiovascular risk [23, 24, 25, 26]. The mechanism behind this phenomenon remains incomprehensible. In connection with the decrease in cardiovascular events among patients diagnosed with ASCVD, there was a hypothesis that these drugs affect atherogenesis [27].
Consequently, the objective of our study was to explore the impact of GLP-1 RA on biomarkers of atherosclerotic plaque instability, including PTX3, CPC, MMP-9, and Lp(a).