Abstract:
Importance:Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of evolocumab varies based on an individual's baseline PCSK9 level remains unknown. Objective:To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with evolocumab differs based on PCSK9 levels. Design, Setting, and Participants:This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12. Main Outcomes and Measures:Placebo-controlled percentage change in LDL-C level with evolocumab, 140 mg every 2 weeks and 420 mg once monthly, across quartiles of baseline PCSK9 levels. Results:Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P < .001) and had significantly lower baseline LDL-C level (123 mg/dL, 124 mg/dL, 128 mg/dL, and 137 mg/dL in the fourth through first quartiles; P < .001). After stratifying by statin use, there was no correlation between PCSK9 levels and LDL-C levels (ρ = 0.03 [95% CI, -0.04 to 0.10] for nonstatin users, P = .39, and ρ = 0.03 [95% CI, -0.01 to 0.08] for statin users, P = .12). Across all quartiles of baseline PCSK9 levels, both evolocumab 140 mg every 2 weeks and 420 mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both evolocumab 140 mg every 2 weeks and 420 mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71% (P < .001), regardless of PCSK9 levels (P for interaction = .76 and .21, respectively). Conclusions and Relevance:Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.
journal_name
JAMA Cardioljournal_title
JAMA cardiologyauthors
Desai NR,Giugliano RP,Wasserman SM,Gibbs JP,Liu T,Scott R,Sabatine MSdoi
10.1001/jamacardio.2016.5395subject
Has Abstractpub_date
2017-05-01 00:00:00pages
556-560issue
5eissn
2380-6583issn
2380-6591pii
2599101journal_volume
2pub_type
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