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Original Investigation
December 13, 2016

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated PatientsThe GLAGOV Randomized Clinical Trial

Author Affiliations
  • 1South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia
  • 2Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio
  • 3Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
  • 4The Methodist DeBakey Heart and Vascular Center, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas
  • 5Academic Medical Center, Department of Vascular Medicine, University of Amsterdam, Amsterdam, the Netherlands
  • 6Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
  • 7DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
  • 8Department of Internal Medicine, University of Ulm Medical Center, Ulm, Germany
  • 9Amgen Inc, Thousand Oaks, California
  • 10Department of Cardiology, University of Szeged, Hungary
  • 11Department of Interventional Cardiology, Cardiology Institute, Jagiellonian University, College of Medicine and the John Paul II Hospital, Krakow, Poland
  • 12Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands
  • 13Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar, the Netherlands
JAMA. 2016;316(22):2373-2384. doi:10.1001/jama.2016.16951
Key Points

Question  Does treatment with a PCSK9 inhibitor modify coronary atherosclerosis disease progression?

Findings  In this clinical trial in which 968 patients with coronary disease were treated with the PCSK9 inhibitor evolocumab or placebo monthly for 76 weeks and underwent serial intravascular ultrasound determination of coronary atheroma volume, lower low-density lipoprotein cholesterol levels were observed in the evolocumab group (36.6 vs 93.0 mg/dL), which also was associated with a reduction in percent atheroma volume for evolocumab (−0.95%) but not placebo (+0.05%) and a greater percentage of patients demonstrating plaque regression (64.3% vs 47.3%).

Meaning  Addition of the PCSK9 inhibitor evolocumab to statin therapy produced greater low-density lipoprotein cholesterol lowering and atheroma regression.

Abstract

Importance  Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated.

Objective  To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.

Design, Setting, and Participants  The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography.

Interventions  Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins.

Main Outcomes and Measures  The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.

Results  Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, −1.0% [95% CI, −1.8% to −0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, −4.9 mm3 [95% CI, −7.3 to −2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV).

Conclusions and Relevance  Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT01813422

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