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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 41; no. 2; pp. 962 - 975
• Main Authors: Taskinen, Marja-Riitta, Björnson, Elias, Kahri, Juhani, Söderlund, Sanni, Matikainen, Niina, Porthan, Kimmo, Ainola, Mari, Hakkarainen, Antti, Lundbom, Nina, Fermanelli, Valentina, Fuchs, Johannes, Thorsell, Annika, Kronenberg, Florian, Andersson, Linda, Adiels, Martin, Packard, Chris J., Borén, Jan
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2021
• Subjects: 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; Endocrinology and Diabetes; Endokrinologi och diabetes; 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; apolipoprotein; cardiovascular diseases; kinetics; chylomicrons; evolocumab
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.120.315446

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 VLDL (very low-density lipoprotein) and VLDL ; and apoB100 in VLDL , VLDL , IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL . In contrast, the fractional catabolic rates of VLDL -apoB100 and VLDL -triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL 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 VLDL - and IDL-apoB100 concentrations. Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL ) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL , IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.