Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism
| Autor: | Rob Scott, Gerald F. Watts, Scott M. Wasserman, Ransi Somaratne, Ricardo Dent, Dick C. Chan, P. Hugh R. Barrett, Sally Burrows |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Adolescent medicine.drug_class Atorvastatin 030204 cardiovascular system & hematology Antibodies Monoclonal Humanized Monoclonal antibody Young Adult 03 medical and health sciences 0302 clinical medicine Double-Blind Method Physiology (medical) Internal medicine medicine Humans Aged business.industry PCSK9 Subtilisin Antibodies Monoclonal Middle Aged Proprotein convertase Evolocumab 030104 developmental biology Endocrinology Kexin lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors Cardiology and Cardiovascular Medicine business medicine.drug Lipoprotein |
| Zdroj: | Circulation. 135:338-351 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. Methods: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)–apolipoprotein B-100 (apoB), intermediate-density lipoprotein–apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. Results: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB ( P P .032, respectively), intermediate-density lipoprotein–apoB ( P =0.021 and P =.002, respectively), and LDL-apoB ( P P =0.043) and LDL-apoB ( P P Conclusions: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02189837. |
| Databáze: | OpenAIRE |
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