Effects of Alirocumab on Triglyceride Metabolism: A Fat-Tolerance Test and Nuclear Magnetic Resonance Spectroscopy Study.

Thomas Metzner,Günther Silbernagel,Gernot Reishofer,Hermann Toplak,Hubert Scharnagl,Tatjana Stojakovic,Harald Sourij,Winfried März,Karin Mellitzer,Andrea Beck,Ulf Landmesser,Deborah R Leitner

doi:10.3390/biomedicines10010193

Abstract

Background: PCSK9 antibodies strongly reduce LDL cholesterol. The effects of PCSK9 antibodies on triglyceride metabolism are less pronounced. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators. Methods: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were two visits at the study site: the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. Fat-tolerance tests, nuclear magnetic resonance spectroscopy, and enzyme-linked immunosorbent assays were performed to analyze lipid metabolism. Results: A total of 21 participants underwent the first and second investigation. Among these, two participants only received alirocumab twice and 19 patients completed the trial per protocol. All of them had atherosclerotic vascular disease. There was no significant effect of alirocumab treatment on fasting triglycerides, post-prandial triglycerides, or lipoprotein-lipase regulating proteins. Total, large, and small LDL particle concentrations decreased, while the HDL particle concentration increased (all p < 0.001). Mean total circulating PCSK9 markedly increased in response to alirocumab treatment (p < 0.001). Whereas PCSK9 increased more than three-fold in all 19 compliant patients, it remained unchanged in those two patients with two injections only. Conclusion: Significant effects of alirocumab on triglyceride metabolism were not detectable in the ALIROCKS trial. The total circulating PCSK9 concentration might be a useful biomarker to differentiate non-adherence from non-response to PCSK9 antibodies.

Highlights

Low-density lipoprotein (LDL) cholesterol causes atherosclerotic cardiovascular disease [1]
The main finding of this pre-specified analysis of the ALIROCKS trial was that triglyceride metabolism was hardly affected by alirocumab treatment in patients with atherosclerosis and hypercholesterolemia
Proteins regulating triglyceride-rich lipoprotein metabolism, such as ApoCII, ApoCIII, GPIHBP-1, ANGPTL-3, and ANGPTL-4, remained unchanged. This supports the hypothesis that proprotein convertase subtilisin/kexin type 9 (PCSK9) does not have strong effects on lipoprotein lipase

Summary

Introduction

Low-density lipoprotein (LDL) cholesterol causes atherosclerotic cardiovascular disease [1]. The magnitude of life-long LDL cholesterol exposure is a major determinant of individual cardiovascular risk [2]. The earlier and more strongly the LDL cholesterol level is reduced, the greater the reduction in cardiovascular risk [3]. Despite substantial reductions in LDL cholesterol with statins and newer lipid-lowering agents, patients continue to experience recurrent major cardiovascular events [4]. Accumulating evidence supports the relevance of triglyceride-rich lipoproteins in the management of cardiovascular disease [5,6]. Fibrates, which reduce triglyceride-rich lipoproteins via activation of peroxisome proliferator activated receptor α, have been effective in reducing cardiovascular risk in patients with high triglycerides [8]. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators

Methods

Results

Conclusion