Lotte C A Stiekema1, Erik S G Stroes1, Simone L Verweij1, Helina Kassahun2, Lisa Chen3, Scott M Wasserman2, Marc S Sabatine4, Venkatesh Mani5, Zahi A Fayad5. 1. Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, AZ Amsterdam, The Netherlands. 2. Department of Clinical Development, Amgen Inc., One Amgen Center Drive Thousand Oaks, CA, USA. 3. Department of Biostatistics, Amgen Inc., One Amgen Center Drive Thousand Oaks, CA, USA. 4. Division of Cardiovascular Medicine, TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School, Fenwood Road, Boston, MA, USA. 5. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl, New York, NY, USA.
Abstract
AIMS: Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0-67.0] years, Lp(a) 200.0 [155.5-301.5] nmol/L [80.0 (62.5-121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8-55.5] and Lp(a) by 13.9% (95% CI 19.3-8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0-268.0) nmol/L [75.2 (56.0-107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (-8.3%) vs. placebo (-5.3%) [treatment difference -3.0% (95% CI -7.4% to 1.4%); P = 0.18]. CONCLUSION:Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation. Published on behalf of the European Society of Cardiology. All rights reserved.
RCT Entities:
AIMS: Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0-67.0] years, Lp(a) 200.0 [155.5-301.5] nmol/L [80.0 (62.5-121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8-55.5] and Lp(a) by 13.9% (95% CI 19.3-8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0-268.0) nmol/L [75.2 (56.0-107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (-8.3%) vs. placebo (-5.3%) [treatment difference -3.0% (95% CI -7.4% to 1.4%); P = 0.18]. CONCLUSION:Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Fleur M van der Valk; Siroon Bekkering; Jeffrey Kroon; Calvin Yeang; Jan Van den Bossche; Jaap D van Buul; Amir Ravandi; Aart J Nederveen; Hein J Verberne; Corey Scipione; Max Nieuwdorp; Leo A B Joosten; Mihai G Netea; Marlys L Koschinsky; Joseph L Witztum; Sotirios Tsimikas; Niels P Riksen; Erik S G Stroes Journal: Circulation Date: 2016-08-05 Impact factor: 29.690
Authors: Fleur M van der Valk; Sophie J Bernelot Moens; Simone L Verweij; Aart C Strang; Aart J Nederveen; Hein J Verberne; Michael T Nurmohamed; Dominique L Baeten; Erik S G Stroes Journal: Ann Rheum Dis Date: 2016-04-15 Impact factor: 19.103
Authors: Erin A Bohula; Robert P Giugliano; Lawrence A Leiter; Subodh Verma; Jeong-Gun Park; Peter S Sever; Armando Lira Pineda; Narimon Honarpour; Huei Wang; Sabina A Murphy; Anthony Keech; Terje R Pedersen; Marc S Sabatine Journal: Circulation Date: 2018-03-12 Impact factor: 29.690
Authors: Gerald F Watts; Dick C Chan; Ransi Somaratne; Scott M Wasserman; Rob Scott; Santica M Marcovina; P Hugh R Barrett Journal: Eur Heart J Date: 2018-07-14 Impact factor: 29.983
Authors: A Michael Lincoff; Stephen J Nicholls; Jeffrey S Riesmeyer; Philip J Barter; H Bryan Brewer; Keith A A Fox; C Michael Gibson; Christopher Granger; Venu Menon; Gilles Montalescot; Daniel Rader; Alan R Tall; Ellen McErlean; Kathy Wolski; Giacomo Ruotolo; Burkhard Vangerow; Govinda Weerakkody; Shaun G Goodman; Diego Conde; Darren K McGuire; Jose C Nicolau; Jose L Leiva-Pons; Yves Pesant; Weimin Li; David Kandath; Simon Kouz; Naeem Tahirkheli; Denise Mason; Steven E Nissen Journal: N Engl J Med Date: 2017-05-18 Impact factor: 91.245
Authors: Frederick J Raal; Evan A Stein; Robert Dufour; Traci Turner; Fernando Civeira; Lesley Burgess; Gisle Langslet; Russell Scott; Anders G Olsson; David Sullivan; G Kees Hovingh; Bertrand Cariou; Ioanna Gouni-Berthold; Ransi Somaratne; Ian Bridges; Rob Scott; Scott M Wasserman; Daniel Gaudet Journal: Lancet Date: 2014-10-01 Impact factor: 79.321
Authors: John J Albers; April Slee; Kevin D O'Brien; Jennifer G Robinson; Moti L Kashyap; Peter O Kwiterovich; Ping Xu; Santica M Marcovina Journal: J Am Coll Cardiol Date: 2013-08-21 Impact factor: 24.094
Authors: Martin J Landray; Richard Haynes; Jemma C Hopewell; Sarah Parish; Theingi Aung; Joseph Tomson; Karl Wallendszus; Martin Craig; Lixin Jiang; Rory Collins; Jane Armitage Journal: N Engl J Med Date: 2014-07-17 Impact factor: 91.245
Authors: Michael B Boffa; Tanya T Marar; Calvin Yeang; Nicholas J Viney; Shuting Xia; Joseph L Witztum; Marlys L Koschinsky; Sotirios Tsimikas Journal: J Lipid Res Date: 2019-09-24 Impact factor: 5.922
Authors: Matthew T Mefford; Santica M Marcovina; Vera Bittner; Mary Cushman; Todd M Brown; Michael E Farkouh; Sotirios Tsimikas; Keri L Monda; J Antonio G López; Paul Muntner; Robert S Rosenson Journal: J Lipid Res Date: 2019-09-11 Impact factor: 5.922
Authors: Stephen J Nicholls; Steven E Nissen; Francesco Prati; Stephan Windecker; Yu Kataoka; Rishi Puri; Thomas Hucko; Helina Kassahun; Jason Liao; Ransi Somaratne; Julie Butters; Giuseppe Di Giovanni; Stephen Jones; Peter J Psaltis Journal: Cardiovasc Diagn Ther Date: 2021-02
Authors: Philip M Robson; Audrey Kaufman; Alison Pruzan; Marc R Dweck; Maria-Giovanna Trivieri; Ronan Abgral; Nicolas A Karakatsanis; Patrick M Brunner; Emma Guttman; Zahi A Fayad; Venkatesh Mani Journal: J Nucl Cardiol Date: 2021-05-27 Impact factor: 3.872