Impact of PCSK9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type 2 diabetic subjects

Taskinen, M.-R. et al. (2020) Impact of PCSK9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type 2 diabetic subjects. Journal of Clinical Lipidology, 14(1), pp. 77-87. (doi: 10.1016/j.jacl.2019.12.003) (PMID:31917184)

Abstract

Background: Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. Objective: This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. Methods: The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. Results: Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL1 triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in “remnant-like particles” cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P < .0001) and VLDL2 triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01). Conclusion: Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

• Item Type: Articles
• Additional Information: This project was funded by Amgen for an investigator-initiated research project. In addition, the project was funded by Swedish Heart-Lung Foundation, Sweden, Swedish Diabetes Foundation, Sweden, Swedish Research Council and Sahlgrenska University Hospital, Sigrid Juselius Foundation, Helsinki University Hospital Research funds, and Finnish Heart Foundation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Packard, Professor Chris
• Authors: Taskinen, M.-R., Bjornson, E., Andersson, L., Kahri, J., Porthan, K., Matikainen, N., Soderlund, S., Pietilainen, K., Hakkarianen, A., Lundbom, N., Nilsson, R., Stahlman, M., Adiels, M., Parini, P., Packard, C., and Boren, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Clinical Lipidology
• Publisher: Elsevier
• ISSN: 1933-2874
• ISSN (Online): 1876-4789
• Published Online: 12 December 2019
• Copyright Holders: Copyright © 2020 Published by Elsevier Inc. on behalf of National Lipid Association
• First Published: First published in Journal of Clinical Lipidology 14(1): 77-87
• Publisher Policy: Reproduced in accordance with the publisher copyright policy