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Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic vs. hepatic actions of semaglutide.

ABSTRACT: Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used to treat diabetes and obesity and reduce rates of major cardiovascular events such as stroke and myocardial infarction. Nevertheless, the identity of GLP-1R-expressing cell types mediating the cardiovascular benefits of GLP-1RA remains incompletely characterized. Herein, we investigated the importance of murine Glp1r expression within endothelial and hematopoietic cells. Mice with targeted inactivation of the Glp1r in Tie2+ cells exhibited reduced levels of Glp1r mRNA transcripts in aorta, liver, spleen, blood and gut. Glp1r expression in bone marrow cells was very low, and not further reduced in Glp1rTie2-/- mice. The GLP-1RA semaglutide reduced the development of atherosclerosis induced by viral PCSK9 expression in both Glp1rTie2+/+ and Glp1rTie2-/- mice. Hepatic Glp1r mRNA transcripts were reduced in Glp1rTie2-/- mice and liver Glp1r expression was localized to γδ T cells. Moreover, semaglutide reduced hepatic Tnf, Abcg1, Tgfb1, Cd3g, Ccl2, and Il2 expression, triglyceride content and collagen accumulation in high fat high cholesterol (HFHC) diet-fed Glp1rTie2+/+ but not Glp1rTie2-/- mice. Collectively, these findings demonstrate that Tie2+ endothelial or hematopoietic cell GLP-1Rs are dispensable for the anti-atherogenic actions of GLP-1RA, whereas Tie2-targeted GLP-1R+ cells are required for a subset of the anti-inflammatory actions of semaglutide in the liver.

SUBMITTER: McLean B

PROVIDER: S-EPMC8663785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsTo investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function.MethodsIn this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n = 7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞ ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43.ResultsSemaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed.ConclusionsSemaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.

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Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic vs. hepatic actions of semaglutide.

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