PCSK9 inhibitor increases the removal of LDL and Lp(a) from the circulation via LDL-receptors
Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans
It has been hypothesised that the PCSK9 inhibitor alirocumab lowers blood levels of LDLC and apoB by increasing LDL-receptors (LDLRs) in the liver . However, apoB enters the circulation from the liver on VLDLs, which are converted to IDLs and to LDL, whereas both VLDL and IDL particles may leave the bloodstream by interacting with LDLRs, implying that the alirocumab effects may be mediated through other mechanisms . Moreover, unexpectedly, PCSK9 inhibition has been shown to lead to reductions of Lp(a) levels, and the role of LDLRs in the removal of Lp(a) from the circulation remains controversial [3,4]. No studies in humans that characterise the effect of PCSK9 inhibition on lipoprotein metabolism have been published.
In this study, the effects of alirocumab on the flux of apoB from its entry into the circulation as VLDL, through IDL and LDL were evaluated. Moreover, the effects of PCSK9 inhibition on the metabolism of VLDL triglyceride (TG) and levels of TG-rich lipoproteins during the postprandial (PP) period were assessed, and an exploratory study of the effects of PCSK9 inhibition on the metabolism of Lp(a) was conducted.
Eighteen healthy volunteers with normal lipid levels completed the study: 8 males (mean age 39.9±9.9 years) and 10 females (mean age 47.0±12.2 years). Five doses of alirocumab treatment resulted in:
- significant reductions of fasting plasma levels of total cholesterol (34.4%), calculated LDL-C (57.9%), and apoB (46.6%),
- reduced mean apoB levels in isolated IDL (29.9%; P≤0.0001) and LDL (56.3%; P≤0.0001),
- decreased mean levels of cholesterol and TG concentrations in IDL (41.1%; P≤0.0001 and 20.9%; P=0.0005, respectively) and LDL (55.1%; P≤0.0001 and 35.5%; P≤0.0001, respectively).
- Reductions in IDL- and LDL-apoB concentrations were caused by increases in the mean fractional clearance rates (FCRs) of these lipoproteins (46.1%, P<0.001 and 80.4%, P≤0.0001, respectively), and the mean LDL-apoB production rates (PRs) were reduced by 23.9% (P<0.0001).
- The decrease in the PR of LDL-apoB was caused by the significant increase in the FCR of IDL-apoB, coupled with a mean 27.2% decrease in the conversion of IDL-apoB to LDL-apoB (P<0.005).
- Significant correlations were found between baseline PCSK9 levels and changes in levels of both LDL-C (R2 = 0.42; P=0.003) and LDL-apoB (R2= 0.22; P=0.05).
- PCSK9 inhibition caused a reduction in the median level of plasma Lp(a) of 18.7% compared with placebo (P<0.01), associated with a trend for an increase in the median FCR for apo(a) (24.6%; P=0.09) with no change in the median apo(a) PR (‒9.0%; P=0.6). A positive correlation did occur between Lp(a) isoform size and changes in apo(a) FCR on alirocumab (R2= 0.25; P=0.04).
Alirocumab treatment of healthy volunteers reduced LDL-C and LDL-apoB concentrations by 55% and 56%, respectively, in association with a near doubling of the efficiency with which LDL particles were removed from the circulation. Moreover, there was a significant decrease in LDLapoB PR caused by increased direct removal of IDL particles from the circulation. Lp(a) concentrations were reduced significantly, with a strong trend toward an increased FCR, suggestive of a role for the LDLR in the clearance of Lp(a).
In his editorial article , Packard first points out how important it is to study lipid metabolism in humans, rather than animal models, before drawing conclusions on the effects of lipid-lowering therapies, due to the notable differences in pathways and mechanisms between species.
He then considers the two studies that examined how PCSK9 inhibitors lead to LDLC reductions: ‘The agreement between the 2 current investigations in their headline findings is striking. Watts et al used a 2×2 factorial design to investigate apoB metabolism in (for a kinetic study) a large group of men’. …. ‘In these normolipidemic subjects, the PCSK9 inhibitor increased the fractional catabolic rate of VLDL, IDL, and LDL-apoB, consistent with stimulation of receptor-mediated removal of these particles from the circulation. Reyes-Soffer and colleagues reported similar substantial increases in IDL and LDL-apoB removal rates in a group of healthy subjects (about half were women) on alirocumab.’ Another similarity in the findings of the two studies was the decrease in LDL production during PCSK9 inhibition, while the most important difference was the effect of PCSK9 inhibition on VLDL-apoB clearance, which may be due to the small sample size and the difference in sex distribution and body mass index in the Reyes-Soffer et al study.
The author concludes: ‘These metabolic studies, although conducted in healthy subjects, provide important insight into the general mechanism of action of antibody-based PCSK9 inhibitors. They help establish the conceptual framework that enhanced LDL receptor activity with attendant accelerated removal of VLDL, IDL, and LDL particles is the primary cause of the profound cholesterol lowering seen with these agents.’