Semaglutide reduces vascular inflammation investigated by PET in a rabbit model of advanced atherosclerosis

BACKGROUND AND AIMS: The objective of this study was to investigate the effects of semaglutide, a long acting glucagon-like peptide-1 receptor agonist, on atherosclerotic inflammation and calcification using a multimodality positron emission tomography and computed tomography (PET/CT) approach. METHODS: Atherosclerotic New Zealand White rabbits were randomized to an intervention- (n = 12) or placebo group (n = 11) receiving either semaglutide or saline-placebo. PET/CT imaging was done before and after 16-weeks of intervention. Three different radiotracers were used: [(64)Cu]Cu-DOTATATE for imaging of activated macrophages, [(18)F]FDG imaging cellular metabolism and [(18)F]NaF PET visualizing micro-calcifications. Tracer uptake was quantified by maximum standardized uptake value (SUV(max)) and target-to-background-ratio (TBR(max)). Animals were euthanized for autoradiographic imaging and histological analyses. RESULTS: A reduction in activated macrophage tracer-uptake was observed in the semaglutide group (SUV(max): p = 0.001 and TBR(max): p = 0.029). When imaging cellular metabolism, an attenuation of SUV(max) and TBR(max) was observed in the semaglutide group (p = 0.034 and p = 0.044). We found no difference in uptake of the micro-calcification tracer between the two groups (SUV(max): p = 0.62 and TBR(max): p = 0.36). Values of macrophage density in the vessel wall were significantly correlated with SUV(max) values of the activated macrophage (r = 0.54, p = 0.0086) and cellular metabolism tracers (r = 0.51, p = 0.013). CONCLUSIONS: Semaglutide decreased vascular uptake of tracers imaging activated macrophages and cellular metabolism but not micro-calcifications compared to a saline placebo. This supports the hypothesis that semaglutide reduces atherosclerotic inflammation by means of decreased activated macrophage activity

Effect of liraglutide on expression of inflammatory genes in type 2 diabetes

Anti-inflammatory effects of glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment in T2D may contribute to the cardiovascular benefits observed with GLP-1 RAs in outcome studies. We investigated if the GLP-1 RA liraglutide exerts anti-inflammatory effects through modulation of inflammatory gene expression in peripheral blood mononuclear cells (PBMCs). From 54 participants of a double-blinded trial where individuals with type 2 diabetes (T2D) were randomized to liraglutide (1.8 mg/day) or placebo for 26 weeks, a sub-study was performed in which PBMCs were extracted from fresh blood at study start and at end-of-treatment. The expression of selected inflammatory genes in PBMCs were measured by quantitative real-time polymerase chain reaction (PCR). Moreover, the expression of the GLP-1 receptor (GLP1R) was examined in a subset (n = 40) of the PBMC samples. The human monocytic cell line THP-1 was used for in vitro GLP-1 exposure experiments. The expression of tumor necrosis factor-α (TNFA) (p = 0.004) and interleukin-1β (IL1B) was downregulated (p = 0.046) in the liraglutide-treated group (n = 31), and unchanged in the placebo group (n = 21, p ≥ 0.11), with no significant differences between the two groups (p ≥ 0.67). The expression of interferon-γ (IFNG) and cluster of differentiation 163 (CD163) were upregulated in both groups (p ≤ 0.006) with no differences between groups (p ≥ 0.47). C–C Motif Chemokine Ligand 5 (CCL5) was upregulated in the liraglutide-treated group (p = 0.002) and unchanged in the placebo group (p = 0.14), with no significant difference between groups (p = 0.36). Intercellular adhesion molecule 1 (ICAM1) was unchanged in both groups (p ≥ 0.43). GLP1R expression in the PBMCs was undetectable. In vitro experiments showed no effect of GLP-1 treatment on inflammatory gene expression in THP-1 cells. GLP1R expression in THP-1 cells was not detectable. In summary, we observed a discrete modulatory effect of liraglutide on the expression of inflammatory genes in PBMCs. The lack of evidence for GLP1R expression in PBMCs and THP-1 cells suggests that possible effects of liraglutide on the PBMCs’ gene expression are most likely indirect. Further investigations are needed to establish the anti-inflammatory potential of GLP-1 RAs