Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV).
BACKGROUND
Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated.


OBJECTIVE
To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy.


METHODS
A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections.


CONCLUSIONS
The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).
Cleveland Clinic Coordinating Center for Clinical Research (C5R), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; Québec Heart & Lung Institute, Québec City, QC, Canada; Department of Medicine, University of Adelaide, Adelaide, Australia.
Rishi
R
Puri
Cleveland Clinic Coordinating Center for Clinical Research (C5R), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH.
Steven E
SE
Nissen
Amgen, Inc, Thousand Oaks, CA.
Ransi
R
Somaratne
Cleveland Clinic Coordinating Center for Clinical Research (C5R), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH.
Leslie
L
Cho
Academic Medical Center, Amsterdam, the Netherlands.
John J P
JJ
Kastelein
Baylor College of Medicine and Houston Methodist DeBakey Heart and Vascular Center, Houston, TX.
Christie M
CM
Ballantyne
University of Ulm Medical Center, Ulm, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Wolfgang
W
Koenig
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, Calgary, AB, Canada.
Todd J
TJ
Anderson
Amgen, Inc, Thousand Oaks, CA.
Jingyuan
J
Yang
Amgen, Inc, Thousand Oaks, CA.
Helina
H
Kassahun
Amgen, Inc, Thousand Oaks, CA.
Scott M
SM
Wasserman
Amgen, Inc, Thousand Oaks, CA.
Robert
R
Scott
Cleveland Clinic Coordinating Center for Clinical Research (C5R), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH.
Marilyn
M
Borgman
Cleveland Clinic Coordinating Center for Clinical Research (C5R), Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; Department of Medicine, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia. Electronic address: stephen.nicholls@sahmri.com.
Stephen J
SJ
Nicholls
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D008078:Cholesterol, LDL / Q000097:blood*; D017023:Coronary Angiography / Q000379:methods; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000188:drug therapy; D003331:Coronary Vessels / Q000000981:diagnostic imaging; D018450:Disease Progression; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000188:drug therapy; D000071449:Proprotein Convertase 9 / Q000276:immunology; D018084:Ultrasonography, Interventional / Q000379:methods*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab