Potential bone marrow-driven reduction of circulating inflammatory monocytes by semaglutide in Type 2 diabetes.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular disease (CVD) in type 2 diabetes (T2D) and have anti-inflammatory effects in experimental studies, but their mechanism of action in humans remains unclear. This study characterized the cardiovascular-haematopoietic axis in individuals with T2D receiving semaglutide, as a potential mediator of GLP-1RA cardioprotective properties. METHODS: In 16 individuals with T2D [63.2 ± 6.1 years, 37.5% female, weight 82.3 ± 15.3 kg, body mass index (BMI) 28.33 ± 3.5 kg/m2, LDL cholesterol 2.2 ± 0.9 mmol/L, glycated haemoglobin (HbA1c) 78.1 ± 13.1 mmol/mol, high-sensitivity C-reactive protein (hsCRP) 1.9 (1.2, 5.8) mg/L], blood and sternal bone marrow aspirates (subset, n = 14) were collected at baseline and after 6 months of semaglutide ≤2.0 mg weekly. Circulating monocytes and haematopoietic precursors were quantified by flow cytometry, plasma cytokines using an nELISA™ assay (Nomic Bio) and inflammatory macrophages in coronary arteries, bone marrow, and spleen by gallium-68-labelled DOTA-(Tyr3)-octreotate (68Ga-DOTATATE) positron emission tomography-computed tomography scans. RESULTS: After 6 months of semaglutide, significant reductions in HbA1c (-21.1 mmol/mol, P < .0001), weight (-6.7 kg, P < .001), BMI (-2.5 kg/m2, P < .001), and hsCRP (-1.0 mg/L, P = .005) were observed. Circulating CD16+ monocytes were markedly lower (-18.8%, P = .034), with increased bone marrow retention correlating with weight loss, alongside reductions in interleukin-1 receptor antagonist, leptin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), C-C motif chemokine ligand 2, C-C motif chemokine ligand 11, and C-X-C motif chemokine ligand 13. Gallium-68-labelled DOTA-(Tyr3)-octreotate PET-CT showed lower bone marrow uptake (-17.5%, P = .037), but not in spleen or coronary arteries. CONCLUSIONS: Semaglutide in T2D potentially reduces circulating inflammatory monocytes, increases bone marrow retention, and lowers markers of endothelial inflammation, with no reduction in coronary artery inflammatory macrophages. Semaglutide is associated with lower bone marrow 68Ga-DOTATATE uptake, which may relate to anti-inflammatory effects relevant to CVD risk.