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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.

Safety

Many people have expressed concerns about adverse effects of very low cholesterol levels. While this study was too small to evaluate morbidity and mortality, the rates of death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, and coronary vascularization trended in a favorable direction (Table 2). Essentially, no safety findings of any significance were reported in patients treated to these extremely low LDL-C levels.

Limitations

Like all trials, this one has limitations. The population is very select: these are patients with clinically indicated angiogram, not a primary prevention population. Some study participants dropped out, which is always a limitation. And of course, this is a surrogate measure; it is a measure of disease activity, not a measure of morbidity and mortality. Morbidity and mortality data for this new class of drugs should be available in about a year, though this study suggests that those data will be favorable.

CONCLUSION

High LDL-C is universally accepted as a factor in the formation of arterial plaque and atherosclerosis. Statin therapy reduces LDL-C levels to slow or induce regression of coronary atherosclerosis in proportion to the magnitude of LDL-C reduction as measured by IVUS. However, the question of how far to reduce lipid levels has evolved over the last 4 decades. In the 1970s, a normal total cholesterol was < 300 mg/dL. More recent data that suggest optimal LDL-C levels for patients with coronary artery disease may be much lower than commonly achieved.

In this study, in patients with symptomatic coronary artery disease, treatment with statins and the addition of the PCSK9 inhibitor evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in PAV of about 1% (P < .001), induced regression in a greater percentage of patients, and showed incremental benefit for treatment of LDL-C down to as low as 20 mg/dL. The GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL; however, the sample size of the trial was modest, providing limited power for safety assessments.

Since this presentation, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial achieved a median LDL-C of 30 mg/dL and reduced risk of cardiovascular events in patients with atherosclerotic cardiovascular disease treated with evolocumab added to statin therapy.8 Additional large outcomes trials of PCSK9 inhibitors and their role in reducing LDL-C and regression of coronary atheroma and atherosclerosis are eagerly awaited.

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