No interindividual variation in robust LDL-c reduction with PCSK9 inhibition in CVD
Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab An Analysis of FOURIER Trial Data
Introduction and methods
It has been shown that inhibition of proprotein convertase subtilisinkexin type 9 (PCSK9) with evolocumab reduces LDL-c levels and the risk of CV events in patients with stable atherosclerotic CVD on background statin therapy [1]. However, the interindividual variability in LDL-c reduction in response to PCSK9 inhibitors is unclear and its magnitude has not been defined in a large-scale trial. This subanalysis (n=21.768) of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial therefore examined the interindividual variability in LDL-c level reduction in response to PCSK9 inhibition with evolocumab.
The FOURIER trial randomized 27.564 patients with prior myocardial infarction, non-hemorrhagic stroke, or symptomatic peripheral artery disease, and LDL-c levels ≥70 mL/dL (1.8 mmol/L) or HDL-c levels ≥100 mg/dL (2.59 mmol/L) while taking background lipid-lowering therapies to either evolocumab or placebo.
Interindividual variation was assessed as percentage reduction in LDL-c from baseline with evolocumab vs. placebo at week 4 and over the course of the first year.
Main results
LDL-c reduction with evolocumab
- In patients treated with evolocumab, the median percentage of reduction in LDL-c levels from baseline to week 4 was 66% (IQR: 54-76), median baseline value was 90 [IQR: 79-105] mg/dL and post-change value was 31 [21-44] mg/dL at week 4.
- Within the first year, 94.7% of patients treated with evolocumab showed a reduction of ≥50% in LDL-c levels, 97.9% demonstrated a reduction of ≥30%, and 99.5% had at least some reduction in LDL-c.
LDL-c reduction with placebo
- In patients treated with placebo, the median percentage of reduction in LDL-c levels from baseline to week 4 was 4% (IQR: -13 to +6), median baseline value was 90 [IQR: 70-106] mg/dL and post-change value was 87 [74-103] mg/dL at week 4.
- In the placebo group, 4.9% demonstrated an increase of ≥25% in LDL-c levels and 9.1% showed a decrease of ≥25% within the first year .
Placebo-adjusted LDL-c reduction with evolocumab
- After adjustment for changes in the placebo group, the median percentage of reduction in LDL-c with evolocumab was 61% (IQR: 58-63) at week 4.
- After adjustment for changes in the placebo group, 90.5% of the patients treated with evolocumab showed reduced LDL-c levels by ≥50%, and in 99.8% by ≥30%, within the first year.
Conclusion
In this subanalysis of the FOURIER trial evolocumab reduced LDL-c levels by ≥50% in more than 90% of CVD patients and by ≥30% in more than 99% of CVD patients. These results provide reassurance that LDL-c level can be robustly reduced with evolocumab without concern for variation in response to treatment in CVD patients on background lipid-lowering treatment.
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