Physicians' Academy for Cardiovascular Education

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

Literature - Reyes-Soffer G, Pavlyha M, Ngai C, et al. - Circulation. 2017;135:352-362.

Main results

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:

Conclusion

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).

Editorial comment

In his editorial article [5], 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.’

References

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