[Skip to Content]
[Skip to Content Landing]
Brief Report
January 2019

Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab: An Analysis of FOURIER Trial Data

Author Affiliations
  • 1Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
  • 3Amgen, Thousand Oaks, California
  • 4National Heart and Lung Institute, Imperial College London, London, United Kingdom
  • 5Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway
  • 6Deputy Editor, JAMA Cardiology
JAMA Cardiol. 2019;4(1):59-63. doi:10.1001/jamacardio.2018.4178
Key Points

Question  What is the magnitude of interindividual variation in low-density lipoprotein cholesterol level reduction with the proprotein convertase subtilisin kexin 9 inhibitor evolocumab?

Findings  In an analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial data, placebo-adjusted analyses show that evolocumab reduced low-density lipoprotein cholesterol levels by 50% or more in 90.5% of patients and by 30% or more in 99.8% of patients.

Meaning  The addition of evolocumab to statin therapy provides a consistent and reliable low-density lipoprotein cholesterol level reduction in most patients.


Importance  Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications.

Objective  To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab.

Design, Setting, and Participants  We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018.

Main Outcomes and Measures  Interindividual variation in percent reduction in LDL-C with evolocumab.

Results  There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10 325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups.

Conclusions and Relevance  There appears to be a highly consistent robust reduction in LDL-C levels with evolocumab use.

Trial Registration  ClinicalTrials.gov identifier: NCT01764633