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.