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A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia
Open accessAbstract
BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS: We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS: Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).
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“The current trial and the FOURIER trial showed similar improvements in composite cardiovascular outcomes with PCSK9 inhibition among patients who had a baseline LDL cholesterol level of 70 mg or more per deciliter and whose average baseline LDL cholesterol level was approximately 90 mg per deciliter. 10”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [10]
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“Treatment of hyperlipidemic patients with monoclonal antibodies that target and inactivate PCSK9 results in increased hepatic LDLR expression and significantly reduced plasma LDL-C40,41.”
From RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels (2023) · cites this paper as [41]
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“Treatment with PCSK9 inhibitors reduces LDL-C by approximately − 60% [75–79].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [79]
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“These findings have led to the development of monoclonal antibodies to PCSK9 that produce substantial reductions in LDL cholesterol when administered alone or with a statin. 8-12”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [10]
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“ASO silencing of Rnf130 resulted in a 50% decrease in LDL-C, a change comparable to inhibiting PCSK940,41, further supporting that RNF130 is a significant regulator of LDLR and LDL-C levels.”
From RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels (2023) · cites this paper as [41]
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Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)
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Self-citationMcKenney, J. M., Koren, M. J., Kereiakes, D. J., Hanotin, C., Ferrand, A.-C., & Stein, E. A. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.03.007 · Cited by 514
Self-citationRaal, F. J., Scott, R. C., Somaratne, R. M., Bridges, I. M., Li, G., Wasserman, S. M., & Stein, E. A. (2012) · Circulation · doi:10.1161/circulationaha.112.144055 · Cited by 506
Self-citationAtorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia
Roth, E. M., McKenney, J. M., Hanotin, C., Asset, G., & Stein, E. A. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1201832 · Cited by 462
Self-citationLambert (2012) · doi:10.1194/jlr.r026658 · Cited by 448
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Self-citationGiugliano, R. P., Desai, N. R., Kohli, P., Rogers, W. J., Somaratne, R. M., Huang, F., Liu, T., Mohanavelu, S., Hoffman, E. B., McDonald, S. T., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61770-x · Cited by 428
Self-citationMyers, G. L., Cooper, G. R., Winn, C., & Smith, S. J. (1989) · Clinics in Laboratory Medicine · doi:10.1016/s0272-2712(18)30645-0 · Cited by 404
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Self-citationEffects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels
Dias, C. S., Shaywitz, A. J., Wasserman, S. M., Smith, B. P., Gao, B., Stolman, D., Crispino, C., Smirnakis, K. V., Emery, M. G., Colbert, A., et al. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.986 · Cited by 233
Self-citationKoren, M. J., Giugliano, R. P., Raal, F. J., SULLIVAN, D. R., Bolognese, M. A., Langslet, G., Civeira, F., Somaratne, R. M., Nelson, P., Liu, T., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.007012 · Cited by 218
Self-citationPotential of Proprotein Convertase Subtilisin/Kexin Type 9 Based Therapeutics
Stein, E. A., & Swergold, G. D. (2013) · Current Atherosclerosis Reports · doi:10.1007/s11883-013-0310-3 · Cited by 84
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Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138
Self-citationAlirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634
Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events
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Self-citationMechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
Sabatine, M. S., Giugliano, R. P., Wiviott, S. D., Raal, F. J., Blom, D. J., Robinson, J., Ballantyne, C. M., Somaratne, R., Legg, J., Wasserman, S. M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500858 · Cited by 1,509
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Metadata
- Authors
- Blom, D. J., Hala, T., Bolognese, M., Lillestol, M. J., Toth, P. D., Burgess, L., Ceska, R., Roth, E., Koren, M. J., Ballantyne, C. M., Monsalvo, M. L., Tsirtsonis, K., Kim, J. B., Scott, R., Wasserman, S. M., & Stein, E. A.
- Affiliations
- University of Cape Town (ZA)
- National Institutes of Health (US)
- Midwest Institute for Clinical Research (US)
- Stellenbosch University (ZA)
- Sterling Research Group (US)
- Jacksonville Center for Clinical Research (US)
- Houston Methodist (US)
- Amgen (United States) (US)
- Amgen (United Kingdom) (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-05-08
- Volume
- 370
- Issue
- 19
- Pages
- 1809-1819
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2155259933
- Semantic Scholar
- 8d480541d9ba40d0cf45fea465f3b42bfc2b2f19
- Cited by
- 720
- References
- 16
- Citations by year
- 2026: 25 · 2025: 35 · 2024: 44 · 2023: 44 · 2022: 26 · 2021: 33 · 2020: 46 · 2019: 49 · 2018: 62 · 2017: 92 · 2016: 110 · 2015: 103 · 2014: 48
- FWCI
- 116.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Open University of Cape Town (University of Cape Town) (submittedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- evolocumab, PCSK9 inhibition, hyperlipidemia, LDL cholesterol lowering, monoclonal antibodies, atorvastatin, ezetimibe, apolipoprotein B, lipoprotein(a), triglycerides, non-HDL cholesterol, treatment safety
- MeSH terms
- Atorvastatin, Ezetimibe, Proprotein Convertase 9, Adult, Aged, Antibodies, Monoclonal, Azetidines, Combined Modality Therapy, Double-Blind Method, Female, Heptanoic Acids, Humans, Hyperlipidemias, Cholesterol, LDL, Male, Middle Aged, Pyrroles, Serine Endopeptidases, Least-Squares Analysis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertases, Antibodies, Monoclonal, Humanized
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