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Results of the GLAGOV trial

December 1, 2017|Cleveland Clinic Journal of Medicine
Steven E. Nissen, MD;Stephen J. Nicholls, MBBS, PhD
Author and Disclosure Information

Steven E. Nissen, MD
Chairman, Department of Cardiovascular Medicine, Heart & Vascular Institute; Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland Clinic

Stephen J. Nicholls, MBBS, PhD
Professor of Cardiology, Theme Leader, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia; Consultant, Cardiovascular Trials, Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Cleveland, OH

Correspondence: Steven E. Nissen, MD, Department of Cardiovascular Medicine, Heart & Vascular Institute, J2-3, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; nissens@ccf.org

This article is based on Drs. Nissen’s and Nicholls’s presentation at the Sones/Favaloro Scientific Program, “Transforming the Delivery of Cardiovascular Care: Research and Innovation in the Heart & Vascular Institute,” held in Cleveland, OH, November 18, 2016. It was also presented at the American Association for Thoracic Surgery. The article was drafted by Cleveland Clinic Journal of Medicine and was then reviewed, revised, and approved by Drs. Nissen and Nicholls.

Dr. Nissen reported research/grant support for the Cleveland Clinic Center for Clinical Research to perform clinical trials from AbbVie, AstraZeneca, Amgen, Cerenis Therapeutics, Eli Lilly, Esperion, Pfizer, The Medicines Company, Takeda, and Orexigen Therapeutics. Dr. Nissen is involved with these multicentered clinical trials, but receives no personal remumeration for his participation. Dr. Nissen consults for many pharmaceutical companies but requires them to donate any honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr. Nicholls reported research grant support and consulting fees from Amgen, Sanofi, and Regeneron.

ABSTRACT

Statins therapy reduces atheroma in proportion to the reduction of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are a new class of injectable human monoclonal antibodies shown to lower LDL-C when added to statin therapy. In a randomized, double-blind, placebo-controlled study, 968 patients with symptomatic coronary artery disease were treated with statins alone or combined with the PCSK9 inhibitor, evolocumab, and assessed for change in percent, total volume, and regression of coronary atheroma. Treatment with statins plus evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in percent of atheroma volume of about 1% (P < .001), and induced regression in a greater percentage of patients. The clinical benefits of LDL-C as low as 20 mg/dL shown in this trial warrant further investigation.

KEY POINTS

  • Statin therapy achieves regression of atherosclerosis in proportion to reductions in LDL-C.
  • PCSK9 inhibitors are a new class of injectable human monoclonal antibodies shown to lower LDL-C when added to statin therapy.
  • Treatment with statins plus the PCSK9 inhibitor, evolocumab, achieved mean LDL-C levels of 36.6 mg/dL, atheroma regression, and demonstrated clinical benefit for LDL-C as low as 20 mg/dL.

Intravascular ultrasonography (IVUS) has been used for the past 20 years to measure atheromatous plaque in patients with coronary artery disease. The total volume of atherosclerosis in a coronary artery segment can be calculated using IVUS. A rotating transducer produces an image of a single, cross-sectional slice of the artery from which the atheroma area is calculated. A motorized device is used to withdraw the catheter, obtaining a series of cross-sectional slices at 1-mm intervals. The atheroma area for each slice is summated to obtain the total volume of atherosclerosis in the artery.

IVUS has demonstrated that statins slow the progression or even induce regression of coronary atherosclerosis in proportion to the degree of reduction in low-density lipoprotein cholesterol (LDL-C).1–4 No LDL-C-lowering therapy other than statins has shown regression of atherosclerosis in a trial using IVUS. The lowest LDL-C achieved in prior trials using statins was about 60 mg/dL.1,3 While this is very low, lower levels have not previously been explored.

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, a new class of drugs, are injectable, fully human monoclonal antibodies that inactivate the PCSK9 protein. PCSK9 inhibitors have been shown to lower LDL-C incrementally when added to statins, achieving very low LDL-C levels.5,6 However, no data exist describing the effect of low LDL-C levels reached using PCSK9 inhibitors on the progression of atherosclerosis.

THE GLAGOV TRIAL

GLAGOV trial design.
Based on information from reference 7.
Figure 1. GLAGOV trial design.
The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial assessed the effect of PCSK9 inhibitor therapy on coronary atheroma.7 The primary end point was the change in percent atheroma volume (PAV) after treatment, and secondary end points were the change in total atheroma volume and percent of patients with atheroma regression. This randomized, double-blind, placebo-controlled study included 968 patients with symptomatic coronary artery disease and other high-risk features from 197 centers around the world. Patients had a coronary angiogram with a vessel that contained an intermediate stenosis and received statin therapy for at least 4 weeks and had LDL-C levels greater than 80 mg/dL or 60 to 80 mg/dL with additional high-risk features. Following IVUS, patients were randomized for 18 months of treatment with either a statin alone or a statin plus a monthly injection of the PCSK9 inhibitor evolocumab. At the end of treatment, IVUS was performed in the same artery that we imaged at the beginning of the study (Figure 1).

Table 1 shows the patients’ baseline demographic features and statin use. The average age of patients was 60 and almost all were on statin therapy, with most taking high levels of high-intensity statins. Baseline LDL-C was very good at 92 mg/dL to 93 mg/dL, a level that would be considered good control by contemporary standards.

RESULTS

LDL-C levels

Figure 2. Change in LDL-C for statin monotherapy and statin evolocumab treatment arms. LDL-C = low-density lipoprotein cholesterol
After 18 months of treatment, patients receiving statin monotherapy had a mean LDL-C of 93 mg/dL, which was essentially unchanged from the start of the study. Patients receiving statin therapy with the addition of the PCSK9 inhibitor evolocumab had a mean LDL-C of 36.6 mg/dL and a trough level of 29 mg/dL 2 weeks after dosing (Figure 2). To our knowledge, these are the lowest LDL-C levels that have ever been achieved in a major trial at the time.

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