Treatment with PCSK9 inhibitors reduces atherogenic VLDL remnants in a real-world study

Hollstein, Tim; Vogt, Anja; Grenkowitz, Thomas; Stojaković, Tatjana; März, Winfried; Laufs, Ulrich; Bölükbasi, Bediha; Steinhagen‐Thiessen, Elisabeth; Scharnagl, Hubert; Kassner, Ursula

doi:10.1016/j.vph.2019.03.002

Cited by 25 publications

(16 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are consistent with the findings of a post-hoc analysis of a randomized controlled phase 2 trial with 29 participants [ 39 ]. Of relevance, we also confirmed a previous study of our group with 350 participants wherein alirocumab treatment was suggested to be associated with an increase in VLDL size, which was estimated by an increased VLDL triglycerides/VLDL ApoB ratio, and a reduction in VLDL-associated apolipoproteins, suggesting higher clearance of small atherogenic VLDL remnant particles [ 31 ]. The present nuclear magnetic resonance spectroscopy data support this hypothesis regarding the increase in VLDL size.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 89%

“…Apolipoproteins (Apo), ApoB in VLDL and LDL, and Lp(a) were determined by immunoturbidimetry using reagents from DiaSys (Holzheim, Germany) and standards from Siemens (Marburg, Germany; ApoAI, ApoB, ApoE), Kamiya Biomedical (Seattle, WA, USA; ApoAII, ApoCII, ApoCIII), and Diasys (Lp(a)). The coefficients of variation were <5% [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Elevated plasma PCSK9 levels are positively associated with plasma TG levels in humans upon a short-term high-fructose intake (45). Treatments with PCSK9 inhibitors increase clearance of VLDL remnants in patients (46). Alirocumab, a fully human PCSK9 monoclonal antibody, reduces LDL particles by 56.3% in human patients.…”

Section: Pcsk9 and Triglyceride-rich Lipoproteinsmentioning

confidence: 99%

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

Xia

Peng

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein receptor (LDLR) and plays a central role in regulating plasma levels of LDL cholesterol levels, lipoprotein(a) and triglyceride-rich lipoproteins, increasing the risk of cardiovascular disease. Additionally, PCSK9 promotes degradation of major histocompatibility protein class I and reduces intratumoral infiltration of cytotoxic T cells. Inhibition of PCSK9 increases expression of LDLR, thereby reducing plasma levels of lipoproteins and the risk of cardiovascular disease. PCSK9 inhibition also increases cell surface levels of major histocompatibility protein class I in cancer cells and suppresses tumor growth. Therefore, PCSK9 plays a vital role in the pathogenesis of cardiovascular disease and cancer, the top two causes of morbidity and mortality worldwide. Monoclonal anti-PCSK9 antibody-based therapy is currently the only available treatment that can effectively reduce plasma LDL-C levels and suppress tumor growth. However, high expenses limit their widespread use. PCSK9 promotes lysosomal degradation of its substrates, but the detailed molecular mechanism by which PCSK9 promotes degradation of its substrates is not completely understood, impeding the development of more cost-effective alternative strategies to inhibit PCSK9. Here, we review our current understanding of PCSK9 and focus on the regulation of its expression and functions.

show abstract

“…Importantly, however, the metabolic changes induced by treatment with antibodies against PCSK9 and statin therapy are not identical. While both approaches lower LDL-C, triglycerides, apolipoprotein B, and increase HDL cholesterol, statins additionally reduce C-reactive protein (CRP) (Sabatine, 2019), which PSCK9 antibodies do not -although a mouse model suggested anti-inflammatory effects to be involved in the anti-atherosclerotic effects of PCSK9 antibodies (Schuster et al, 2019), and PCSK9 antibodies decrease lipoprotein(a) by mechanisms that are not fully understood, whereas statins do not change or may even slightly increase lipoprotein(a) level (Hollstein et al, 2019;Sabatine, 2019). However, the clinical relevance of these different metabolic changes is uncertain and difficult to assess.…”

Section: Consequences Of Therapeutic Inhibition Of Pcsk9mentioning

confidence: 99%

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

2020

Self Cite

View full text Add to dashboard Cite

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.

show abstract

Treatment with PCSK9 inhibitors reduces atherogenic VLDL remnants in a real-world study

Cited by 25 publications

References 29 publications

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

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

Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications

PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

Contact Info

Product

Resources

About