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).