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)

Am Heart J. 2016 Jun;176:83-92. doi: 10.1016/j.ahj.2016.01.019. Epub 2016 Feb 17.

Abstract

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.

Aims: 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).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents / administration & dosage
  • Cholesterol, LDL / blood*
  • Coronary Angiography / methods
  • Coronary Artery Disease* / diagnosis
  • Coronary Artery Disease* / drug therapy
  • Coronary Vessels / diagnostic imaging
  • Disease Progression
  • Double-Blind Method
  • Drug Monitoring / methods
  • Female
  • Humans
  • Male
  • Middle Aged
  • PCSK9 Inhibitors
  • Plaque, Atherosclerotic* / diagnostic imaging
  • Plaque, Atherosclerotic* / drug therapy
  • Proprotein Convertase 9* / immunology
  • Ultrasonography, Interventional / methods*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • PCSK9 Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • evolocumab

Associated data

  • ClinicalTrials.gov/NCT01813422