TY - JOUR
T1 - Composition and distribution of lipoproteins after evolocumab in familial dysbetalipoproteinemia. A randomized controlled trial
AU - Heidemann, Britt E.
AU - Marais, A. David
AU - Mulder, Monique T.
AU - Visseren, Frank L.J.
AU - Roeters van Lennep, Jeanine E.
AU - Stroes, Erik S.G.
AU - Riksen, Niels P.
AU - van Vark – van der Zee, Leonie C.
AU - Blackhurst, Dee M.
AU - Koopal, Charlotte
N1 - Funding Information:
The authors gratefully acknowledge the contribution of the patients and the help of participating sites and laboratories:, University Medical Center Utrecht: C.A.M. Joosten and I.P. Klaassen, Erasmus Medical Center Rotterdam: K.A. Steward, Amsterdam University Medical Center: P.J.M. Zweers, drs. A.J. Cupido, drs. A.C. Fenneman, Radboud University Medical Center Nijmegen: A. Rasing-Hoogveld, dr. E. Abbink, Independent study physician: dr. J. Westerink, Central laboratory: M. Wesseling, dr. M ten Berg, dr. I Hofer, Central pharmacy: dr. A. Lalmohamed, Laboratory of Chemical Pathology, University of Cape Town: Joanne Pillay and Sarah Lampert carried out the retinyl palmitate analyses.
Publisher Copyright:
© 2023
PY - 2023/9
Y1 - 2023/9
N2 - Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. Objective: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. Methods: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. Results: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41–59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. Conclusion: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.
AB - Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. Objective: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. Methods: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. Results: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41–59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. Conclusion: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.
KW - Apolipoprotein B
KW - Clinical trial
KW - Familial dysbetalipoproteinemia
KW - Fasting
KW - Lipoproteins
KW - PCSK9 monoclonal antibodies
KW - Postprandial
KW - Type III hyperlipoproteinemia
UR - http://www.scopus.com/inward/record.url?scp=85166300854&partnerID=8YFLogxK
U2 - 10.1016/j.jacl.2023.07.004
DO - 10.1016/j.jacl.2023.07.004
M3 - Article
C2 - 37517914
AN - SCOPUS:85166300854
SN - 1933-2874
VL - 17
SP - 666
EP - 676
JO - Journal of Clinical Lipidology
JF - Journal of Clinical Lipidology
IS - 5
ER -