Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression
RESEARCH DESIGN AND METHODS: We performed an in vivo kinetic study with stable isotopes (L-[1-13C] leucine) in 10 T2DM patients before and after 6-month treatment with liraglutide (1.2 mg/day). We also evaluated, in mice, the effect of liraglutide on the expression of genes involved in apoB100 containing lipoprotein clearance.
RESULTS: In T2DM patients, liraglutide treatment significantly reduced plasma apoB100 (0.93±0.13 vs. 1.09±0.11 g/L, p=0.011) and fasting triglycerides (1.76±0.37 vs. 2.48±0.69 mmol/L, p=0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL1-apoB100 (4.11±1.91 vs. 2.96±1.61 day-1,p=0.005), VLDL2-apoB100 (5.17±2.53 vs. 2.84±1.65 day-1,p=0.008), IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day-1,p=0.017) and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day-1,p=0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced Proprotein convertase subtilisin/kexin type 9 (PCSK9), Retinol Binding Protein 4 (RBP4) and Tumor Necrosis Factor alpha (TNF alpha) gene expression in adipose tissue, and decreased PCSK9 mRNA and increased LDL-receptor protein expression, in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver.
CONCLUSIONS: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100 containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2DM.