Type 2 diabetes mellitus is associated with chronic low-grade inflammation contributing to endothelial dysfunction, metabolic imbalance, and cardiovascular complications. Although semaglutide (SEM) and tirzepatide (TIR) provide important metabolic and cardioprotective benefits, their early anti-inflammatory effects and potential sex-dependent differences remain incompletely understood. This study comparatively evaluated the effects of SEM and TIR on systemic inflammatory biomarkers in a murine model of streptozotocin-induced diabetes mellitus. Thirty BALB/c mice were allocated into six experimental groups according to sex and treatment: control, SEM, and TIR groups (n = 5/group). Diabetes was induced by intraperitoneal streptozotocin administration, followed by treatment with SEM or TIR. Circulating interleukin-1β (IL-1β) and pentraxin-3 (PTX-3) levels were measured at baseline, one week after streptozotocin administration, and after six weeks of treatment. Control groups exhibited progressive increases in IL-1β and PTX-3 levels, indicating sustained inflammatory activation. In contrast, SEM- and TIR-treated animals showed attenuated inflammatory responses characterized by transient or stabilized biomarker profiles. Differential inflammatory responses were observed between treatments and sexes. Male SEM and Male TIR groups demonstrated stable IL-1β levels, whereas female treated groups showed persistent elevations, particularly Female TIR animals. PTX-3 responses also displayed differential sex-dependent patterns, with Female SEM animals exhibiting the most stable inflammatory profile. These findings suggest differential early immunomodulatory effects of the two modern antidiabetic drugs, characterized by distinct biomarker responses according to sex and inflammatory marker profile. IL-1β and PTX-3 may represent complementary biomarkers for the assessment of early inflammatory activation associated with diabetes mellitus and its cardiometabolic complications.

Both diabetes mellitus (DM) and stroke are major global health challenges with high morbidity and mortality. DM is a major risk factor for stroke, contributing to both increased incidence and worse clinical outcomes. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), as well as dual agonists like tirzepatide, have demonstrated significant cardiovascular benefits, raising interest in their potential cerebrovascular effects. This narrative review examines the pathophysiological links between DM and stroke and summarizes recent clinical evidence on the efficacy of GLP-1 RAs and dual GLP-1/GIP receptor agonists (GLP-1/GIP RAs) in stroke prevention and management. Current evidence from large cardiovascular outcome trials supports the role of GLP-1 RAs in reducing major adverse cardiovascular events, including stroke, primarily in the context of primary and secondary prevention. Findings suggest that semaglutide and liraglutide may reduce non-fatal stroke incidence, decrease hospitalizations, and improve neurological outcomes in patients with prior stroke. Comparative analyses of major trials suggest that, although stroke reduction may be a class effect of GLP-1 RAs, meaningful differences exist between individual agents, likely due to variations in pharmacokinetics, receptor affinity, and study populations. Additionally, much of the evidence in acute stroke derives from early-phase or ongoing trials, warranting cautious interpretation. Novel therapies, including orforglipron and retatrutide, as well as combinations like Maridebart cafraglutide and CagriSema, may expand future therapeutic options for individuals at high cerebrovascular risk. GLP-1-based therapies show promising neurovascular effects, but large-scale, long-term studies are needed to define their role in post-stroke management and cerebrovascular risk reduction. Overall, GLP-1 RAs should currently be regarded primarily as agents for long-term vascular risk reduction rather than established therapies for acute stroke. While potential neuroprotective effects are emerging, these require confirmation in adequately powered randomized trials. Future studies should aim to identify the patient subgroups most likely to benefit and to determine whether specific agents confer advantages in acute cerebrovascular contexts. A better understanding of the mechanisms underlying potential neuroprotection will be essential to determine whether these therapies can be effectively integrated into stroke management strategies.