Effects of PCSK9 Inhibitors on Other than Low-Density Lipoprotein Cholesterol Lipid Variables

Abstract

Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, but other lipid variables such as triglycerides (TRGs), high-density lipoprotein cholesterol (HDL-C) and lipoprotein a [Lp(a)] also affect cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-C concentration but also modestly improve the concentrations of TRGs and HDL-C and more robustly decrease Lp(a) levels. The review presents the associated mechanisms of the beneficial effects of PCSK9 inhibitors on the other than LDL-C lipid variables, including the effects on lipid/apolipoprotein secretion and clearance and the heteroexchange between lipoproteins, as well as the possible effects on other variables involved in lipid metabolism such as sortilin. Proprotein convertase subtilisin/kexin type 9 inhibitors improve the overall lipid profile, and these beneficial effects may play a role in the reduction of cardiovascular risk.

Association between proprotein convertase subtilisin/kexin 9 (PCSK9) and lipoprotein subclasses in children with type 1 diabetes mellitus: Effects of glycemic control

“…On the other hand, limited data regarding the link between PCSK9 and HDL subclasses has been reported and no previous study investigated this association in diabetes. Apparently, higher PCSK9 is associated with smaller HDL subclasses in patients with CVD [24] and PCSK9 inhibitor therapy predominantly increases large HDL particles [25]. In the current study, higher PCSK9 levels were positively associated with smaller HDL 3c subclasses in patients with suboptimal and poor glycemic control (Table 3).…”

New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges

“…Results from the FOURIER trials indicate that PCSK9 inhibition is associated with a mild-moderate reduction in triglyceride levels [59]. The biological mechanism underlying this effect may include several pathways beyond the increased LDL-R activity that are associated with the increased catabolism of TGRLs [94]. It is known that PCSK9 modulates lipoprotein assembly and secretion by the intestine and the liver and affects TGRL and fatty acid uptake in peripheral tissues via expression of the very-low-density lipoprotein receptor (VLDL-R), the ApoE2 receptor, and the CD36 receptor [16,76].…”

Lipid Target in Very High-Risk Cardiovascular Patients: Lesson from PCSK9 Monoclonal Antibodies

“…Results from the FOURIER trials indicate that PCSK9 inhibition is associated with a mild–moderate reduction in triglyceride levels [ 59 ]. The biological mechanism underlying this effect may include several pathways beyond the increased LDL-R activity that are associated with the increased catabolism of TGRLs [ 94 ]. It is known that PCSK9 modulates lipoprotein assembly and secretion by the intestine and the liver and affects TGRL and fatty acid uptake in peripheral tissues via expression of the very-low-density lipoprotein receptor (VLDL-R), the ApoE2 receptor, and the CD36 receptor [ 16 , 76 ].…”

“…Summarizing, the lower plasma triglyceride concentrations and the decreased postprandial lipemia may be the results of the following mechanisms [ 94 ]: (a) reduced intestine ApoB48 production, leading to decreased chylomicron secretion; (b) increased ApoB degradation, resulting in reduced ApoB-rich lipoproteins; (c) increased chylomicrons, chylomicron remnants, and VLDL remnants clearance via increased LDL-related protein 1 activity and CD36 scavenger receptor upregulation; (d) VLDL receptors and ApoE receptors.…”