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

Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):962-975. doi: 10.1161/ATVBAHA.120.315446. Epub 2020 Dec 24.

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 VLDL2 plasma 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.

Keywords: apolipoprotein; cardiovascular diseases; chylomicrons; evolocumab; kinetics.

Publication types

  • Clinical Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Apolipoprotein B-100 / blood*
  • Apolipoprotein B-48 / blood*
  • Biomarkers / blood
  • Cholesterol / blood
  • Cholesterol, LDL / blood
  • Cholesterol, VLDL / blood
  • Chylomicron Remnants / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dietary Fats / administration & dosage*
  • Dietary Fats / blood
  • Dyslipidemias / blood
  • Dyslipidemias / diagnosis
  • Dyslipidemias / drug therapy
  • Female
  • Humans
  • Kinetics
  • Lipoproteins / blood
  • Lipoproteins, VLDL / blood
  • Male
  • Middle Aged
  • PCSK9 Inhibitors
  • Postprandial Period
  • Proprotein Convertase 9 / metabolism
  • Serine Proteinase Inhibitors / adverse effects
  • Serine Proteinase Inhibitors / therapeutic use*
  • Time Factors
  • Treatment Outcome
  • Triglycerides / blood
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents
  • Apolipoprotein B-100
  • Apolipoprotein B-48
  • Biomarkers
  • Cholesterol, LDL
  • Cholesterol, VLDL
  • Chylomicron Remnants
  • Dietary Fats
  • Lipoproteins
  • Lipoproteins, VLDL
  • PCSK9 Inhibitors
  • Serine Proteinase Inhibitors
  • Triglycerides
  • lipoprotein cholesterol
  • very low density lipoprotein triglyceride
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • evolocumab

Associated data

  • ClinicalTrials.gov/NCT02948777