Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- And B48-Containing Lipoproteins in Subjects with Type 2 Diabetes

Marja Riitta Taskinen*, Elias Björnson, Juhani Kahri, Sanni Söderlund, Niina Matikainen, Kimmo Porthan, Mari Ainola, Antti Hakkarainen, Nina Lundbom, Valentina Fermanelli, Johannes Fuchs, Annika Thorsell, Florian Kronenberg, Linda Andersson, Martin Adiels, Chris J. Packard, Jan Borén

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)

Abstract

Objective: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1(very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Original languageEnglish
Pages (from-to)962-975
Number of pages14
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume41
Issue number2
Early online date2021
DOIs
Publication statusPublished - Feb 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • apolipoprotein
  • cardiovascular diseases
  • chylomicrons
  • evolocumab
  • kinetics

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